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Office of Naval Research

The ONR seeks proposals for developing innovative solutions that directly support the development and maintenance of a robust STEM workforce. The goal of any proposed effort should be to provide "game changing" solutions that will establish and maintain a diverse pipeline of U.S. citizens who are interested in uniformed or civilian DoN (or Navy and Marine Corps) STEM related workforce opportunities. While this announcement is relevant for any stage of the STEM pipeline, for FY15, funding efforts will be targeted primarily towards High School, Post-Secondary education, and outreach designed to enhance the DoN (or Naval) STEM workforce and its mission readiness. Emphasis will be given both to key engineering and scientific areas outlined in the Naval S&T Strategic Plan such as our National Naval Responsibilities (see ONR website), and to identified STEM related workforce gaps and new strategic goals on the uniformed and civilian side. The FULL ANNOUNCEMENT is available on the Grants.gov website.

U.S. National Science Foundation

The Directorate for STEM Education (EDU) STEM Education Postdoctoral Research Fellowships (STEM Ed PRF) Program funds postdoctoral fellowship projects designed to enhance the research knowledge, skills, and practices of STEM Education research by recent doctoral graduates in STEM, STEM Education, Education, and related disciplines. This solicitation supports individual postdoctoral fellowship awards; a companion solicitation (STEM Ed OPRF) supports organizational postdoctoral fellowship programs. The STEM Ed PRF Program as a whole seeks to broaden the pool of researchers who can advance knowledge regarding STEM learning and learning environments, broadening participation in STEM fields, and STEM workforce development. The Program is designed tosupport postdoctoral fellows engaged in experiences that will advance their career goals by developing their expertise, skills, and competencies to conduct fundamental STEM education research. Principal Investigators who are women, veterans, persons with disabilities, and from groups underrepresented in STEM, or who have attended community colleges and minority-serving institutions (e.g., Historically Black Colleges and Universities, Tribal Colleges and Universities, Hispanic Serving Institutions, Alaska Native Serving Institutions, and Hawaiian Native and Pacific Islander Serving Institutions) are especially encouraged to apply. STEM Ed IPRF awards provide direct support to Fellows to enable them to engage in ongoing research, to develop independent research, and to implement an independent professional development plan under the guidance of a sponsoring researcher. Fellows must affiliate with an appropriate host organization and are expected to devote themselves full time to the fellowship activities for the duration of the fellowship.

U.S. National Science Foundation

The Directorate for STEM Education (EDU) STEM Education Postdoctoral Research Fellowships (STEM Ed PRF) Program funds postdoctoral fellowship projects designed to enhance the research knowledge, skills, and practices of STEM Education research by recent doctoral graduates in STEM, STEM Education, Education, and related disciplines. This solicitation supports organizational postdoctoral fellowship projects; a companion solicitation (STEM Ed IPRF) supports individual postdoctoral fellowship awards. The Program is designed to broaden the pool of researchers who can advance knowledge regarding STEM learning and learning environments, broadening participation in STEM fields, and STEM workforce development. Principal Investigators who are women, veterans, persons with disabilities, and from groups underrepresented in STEM, or who have attended community colleges and minority-serving institutions (e.g. Historically Black Colleges and Universities, Tribal Colleges and Universities, Hispanic Serving Institutions, Alaska Native Serving Institutions, and Hawaiian Native and Pacific Islander Serving Institutions) are especially encouraged to apply. STEM Ed OPRF awards provide support to organizations as they develop a STEM education postdoctoral research fellowship project and support a cohort of fellows. The program should enable fellows to engage in ongoing research, to develop independent research, and to implement an independent professional development plan under the guidance of a sponsoring researcher. Fellows are expected to devote themselves full time to the fellowship activities for the duration of the fellowship.

U.S. National Science Foundation

The Science, Technology, Engineering, and Mathematics Talent Expansion Program (STEP) seeks to increase the number of students (U.S. citizens or permanent residents) receiving associate or baccalaureate degrees in established or emerging fields within science, technology, engineering, and mathematics (STEM). Type 1 proposals are solicited that provide for full implementation efforts at academic institutions. Type 2 proposals are solicited that support educational research projects on associate or baccalaureate degree attainment in STEM.

NCI - National Cancer Institute

PROJECT SUMMARY Malignant brain tumors such as glioblastomas are among the most lethal cancers. The five-year survival estimates for glioblastoma are a dismal 4 to 5%, additional treatment options are thus urgently needed. In our studies on how proliferation and differentiation are regulated during normal brain development, we identified a protein-protein interaction network comprising EphrinB, RGS3, KIF20A and SEPT7, which sequentially binds to one another (referred to as the ERKS axis). Genetic functional results demonstrated that the ERKS axis proteins are essential for maintaining a proliferative state of normal neural progenitor cells and loss-of-function of the axis leads to differentiation. Because tumors often originated from progenitor/stem cells that lost the control on proliferation vs. differentiation decisions, we reasoned that the ERKS axis may act similarly in brain tumor progenitor/stem cells to control proliferation. In proof-of-concept studies, we depleted the mitotic kinesin KIF20A in cancerous progenitor/stem cells in animal models of brain tumors. Depletion promoted daughter cells to undergo a differentiative path, which blocked cell proliferation leading to suppression of brain tumor growth. In addition, disruption of protein-protein interaction (PPI) within the ERKS axis by competitive inhibition with protein binding domains could block the growth of brain tumor stem cells. These results thus indicate that the ERKS axis proteins can serve as targets for developing novel differentiation therapy for brain tumor treatment. In this study, we propose to develop inhibitors targeting specific interactions within the ERKS axis. We will employ a PPI- based high throughput screening (HTS) assay to isolate small molecule inhibitors from compound libraries and further validate candidate hits using additional secondary and tertiary cell free and cell-based protein binding assays as well as cellular functional assays. We anticipate that the proposed studies will identify and validate candidate hit inhibitors of the ERKS axis, providing a foundation for further developing the lead molecules into potential therapeutics for clinic use in brain tumor treatment.

NCI - National Cancer Institute

Title: Second-generation new-chemical-entity nanomedicine to target treatment resistance in pancreatic cancer Project Summary Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with treatment resistance posing a major challenge to effective clinical management. Cells that survive therapy—such as pancreatic cancer stem- like cells (PCSCs) and drug-tolerant persister (DTP) cells—play a critical role in driving drug resistance, tumor recurrence, and metastasis. Notably, both cell populations depend heavily on elevated autophagy, a self- digestion process that enables survival under stress. Therefore, targeting autophagy pathways holds significant promise for improving treatment outcomes in PDAC. Autophagy inhibition with aminoquinoline drugs, such as chloroquine (CQ) or hydroxychloroquine (HCQ), have limited potency for autophagy inhibition, and the concentrations of CQ/HCQ required to inhibit autophagy are not consistently achievable in the clinic. The overall goal of this application is to develop a second-generation new-chemical-entity nanomedicine as an effective autophagy inhibitor to improve the treatment of PDAC in preclinical animal models, providing validation regarding the feasibility for clinical translation. Recently, we have developed an Autophagy inhibitor Self-delivered Nanodrug (AiSN) that offers superior potency for autophagy inhibition and specific drug delivery to improve PDAC treatment to HCQ. AiSN is a self-therapeutic nanoparticle that contains pure bisaminoquinoline (BAQ) derivative as the building block which has outstanding autophagy inhibiting- and lysosomal disrupting- capabilities. AiSN (BAQ13 nanoparticle, BAQ13 NP) is 20-30 times more effective than HCQ in a panel of PDAC cell lines. It preferentially accumulated at PDAC tumor sites with dense fibrotic stromal tissue. It was efficacious in various PDAC models and prevented cancer stem-like cell mediated tumorigenesis in mice. The FDA has recently approved our Investigation New Drug (IND) application (IND#165331) for moving the AiSN (BAQ13 NP) into clinical trials. The FDA has also granted Orphan Drug Designation for BAQ13 for the treatment of pancreatic cancer. Using BAQ13 as the lead compound, we have recently designed and synthesized 30 new compounds as the second-generation AiSNs, among which BAQ42 and BAQ152 have shown better potency than BAQ13, improving the IC50 value from micromolar to nanomolar levels. Furthermore, our study demonstrated that autophagy is significantly upregulated in DTP cells of PDAC. Although DTP cells exhibit resistance to gemcitabine, they can be effectively eliminated by BAQ42. These results have laid a strong foundation for this R01 application, where we plan to: 1) optimize the structure and formulation of second-generation AiSNs to enhance their anti-PDAC potency and nanoparticle-forming properties; 2) characterize their pharmacokinetics and spatiotemporal distribution; and 3) validate their pharmacology and toxicology in various PDAC models. Successful completion of this research will make this new generation AiSN ready for IND-enabling studies seeking IND approval. The novel design of AiSNs, with significantly improved potency and targeted delivery capabilities, is expected to greatly enhance efficacy while minimizing toxicity in PDAC treatment.

U.S. National Science Foundation

Our world is at a pivotal moment where the boundaries dividing the physical and social worlds from the cyber world have become blurred. Cyberspace has evolved from an interconnected digital environment into a complex and interdependent cyber ecosystem that involves hardware, software, networks, data, people, organizations, countries, and the physical world. Critical functions of everyday life are deeply intertwined with computing, including health, government, commerce, the public sphere, education, critical infrastructure, interpersonal communication, and transportation. The complexity and inter-dependencies in cyberspace can be misused and exploited by malicious actors. These in turn can trigger adverse outcomes such as disruption of critical infrastructure and systems; theft of intellectual property and sensitive data; amplification of inequalities; disclosure of private information of individuals, organizations, and governments; and threats to lives, livelihoods, and reputations. Furthermore, constant attacks on the data and assets of corporations, governments, and individuals undermine people s trust in decision-making and processes that depend critically on these cyber systems. The Security, Privacy, and Trust in Cyberspace (SaTC 2.0) program aims to build trust in global cyber ecosystems. Trust is the core tenet of this program and, for the purposes of this solicitation, is broadly defined to include our confidence in the security, privacy, and resilience of cyberspace, particularly in the face of malicious intent. Achieving this level of confidence in cyberspace requires not only understanding the vulnerabilities in a system that could be exploited and how they can be addressed, but also understanding the social and technical dimensions of trust in cyber systems, along with the educational efforts needed to increase public awareness of risks in cyberspace, and building a well-trained corps of privacy and security professionals. SaTC 2.0 spans the interests of NSF's Directorates for Computer and Information Science and Engineering (CISE), Mathematical and Physical Sciences (MPS), Social, Behavioral and Economic Sciences (SBE), and STEM Education (EDU). Proposals must be submitted pursuant to one of the following designations, each of which may have additional requirements: RES: The Research (RES) designation is the focus of the multidisciplinary SaTC 2.0 research program. RES projects are limited to $1,200,000 in total budget, with durations of up to four years. Proposals with a total budget of more than $600,000 have additional requirements including Broadening Participation in Computing and collaboration plans. RES proposals may include an optional Transition to Education (TTE) plan with a budget up to $50,000 (within the RES total budget request) to co-evolve novel educational initiatives in the context of the proposed research. EDU: The Education (EDU) designation is used to identify proposals focusing on education and workforce training in building trust in security, privacy, and resilience of cyberspace. EDU proposals are limited to $500,000 in total budget, with durations of up to three years. EDU proposals that primarily focus on education research with demonstrated collaboration, as reflected in the PI team between cybersecurity subject matter experts and education researcher(s), may request an additional $100,000 beyond the $500,000 limit. SEED: The Seedling (SEED) category is intended for special topics defined by accompanying Dear Colleague Letters. SEED projects are limited to $300,000 in total budget, with durations of up to two years.

Advanced Research Projects Agency Energy

<p>The purpose of this modification is to clarify the meaning of the Program Policy Factors in Section V.C.</p> <p><br></p> <p>To obtain a copy of the Notice of Funding Opportunity (NOFO) please go to the ARPA-E website at https://arpa-e-foa.energy.gov.&nbsp;To apply to this NOFO, Applicants must register with and submit application materials through ARPA-E eXCHANGE (<a href="https://arpa-e-foa.energy.gov/Registration.aspx" target="_blank">https://arpa-e-foa.energy.gov/Registration.aspx</a>).&nbsp;For detailed guidance on using ARPA-E eXCHANGE, please refer to the ARPA-E eXCHANGE User Guide (https://arpa-e-foa.energy.gov/Manuals.aspx).&nbsp;ARPA-E will not review or consider concept papers submitted through other means. For problems with ARPA-E eXCHANGE, email ExchangeHelp@hq.doe.gov (with NOFO name and number in the subject line).</p> <p>Questions about this NOFO? Check the Frequently Asked Questions available at <a href="http://arpa-e.energy.gov/faq" target="_blank">http://arpa-e.energy.gov/faq</a>.&nbsp;For questions that have not already been answered, email ARPA-E-CO@hq.doe.gov.&nbsp;&nbsp;</p> <p><br></p> <p>AGENCY OVERVIEW</p> <p>The Advanced Research Projects Agency – Energy (ARPA-E), an organization within the Department of Energy (DOE), is chartered by Congress in the America COMPETES Act of 2007 (P.L. 110-69), as amended by the America COMPETES Reauthorization Act of 2010 (P.L. 111-358), as further amended by the Energy Act of 2020 (P.L. 116-260):</p> <p>“(A) to enhance the economic and energy security of the United States through the development of energy technologies that—</p> <p>(i) reduce imports of energy from foreign sources;</p> <p>(ii) reduce energy-related emissions, including greenhouse gases;</p> <p>(iii) improve the energy efficiency of all economic sectors;</p> <p>(iv) provide transformative solutions to improve the management, clean-up, and disposal of radioactive waste and spent nuclear fuel; and</p> <p>(v) improve the resilience, reliability, and security of infrastructure to produce, deliver, and store energy; and</p> <p>(B) to ensure that the United States maintains a technological lead in developing and deploying advanced energy technologies.”</p> <p>ARPA-E issues this Notice of Funding Opportunity (NOFO) under its authorizing statute codified at 42 U.S.C. § 16538. The NOFO and any cooperative agreements or grants made under this NOFO are subject to 2 C.F.R. Part 200 as supplemented by 2 C.F.R. Part 910.</p> <p>ARPA-E funds research on, and the development of, transformative science and technology solutions to address the energy and environmental missions of the Department. The agency focuses on technologies that can be meaningfully advanced with a modest investment over a defined period of time in order to catalyze the translation from scientific discovery to early-stage technology. For the latest news and information about ARPA-E, its programs and the research projects currently supported, see: http://arpa-e.energy.gov/.</p> <p>ARPA-E funds transformational research. Existing energy technologies generally progress on established “learning curves” where refinements to a technology and the economies of scale that accrue as manufacturing and distribution develop drive improvements to the cost/performance metric in a gradual fashion. This continual improvement of a technology is important to its increased commercial deployment and is appropriately the focus of the private sector or the applied technology offices within DOE. In contrast, ARPA-E supports transformative research that has the potential to create fundamentally new learning curves. ARPA-E technology projects typically start with cost/performance estimates well above the level of an incumbent technology. Given the high risk inherent in these projects, many will fail to progress, but some may succeed in generating a new learning curve with a projected cost/performance metric that is significantly better than that of the incumbent technology. ARPA-E will provide support at the highest funding level only for submissions with significant technology risk, aggressive timetables, and careful management and mitigation of the associated risks.</p> <p>ARPA-E funds technology with the potential to be disruptive in the marketplace. The mere creation of a new learning curve does not ensure market penetration. Rather, the ultimate value of a technology is determined by the marketplace, and impactful technologies ultimately become disruptive – that is, they are widely adopted and displace existing technologies from the marketplace or create entirely new markets. ARPA-E understands that definitive proof of market disruption takes time, particularly for energy technologies. Therefore, ARPA-E funds the development of technologies that, if technically successful, have clear disruptive potential, e.g., by demonstrating capability for manufacturing at competitive cost and deployment at scale.</p> <p>ARPA-E funds applied research and development (R&amp;D). The Office of Management and Budget defines “applied research” as an “original investigation undertaken in order to acquire new knowledge…directed primarily towards a specific practical aim or objective” and defines “experimental development” as “creative and systematic work, drawing on knowledge gained from research and practical experience, which is directed at producing new products or processes or improving existing products or processes.”0F1 Applicants interested in receiving financial assistance for basic research (defined by the Office of Management and Budget as “experimental or theoretical work undertaken primarily to acquire new knowledge of the underlying foundations of phenomena and observable facts”)1 should contact the DOE’s Office of Science (http://science.energy.gov/). Office of Science national scientific user facilities (http://science.energy.gov/user-facilities/) are open to all researchers, including ARPA-E Applicants and awardees. These facilities provide advanced tools of modern science including accelerators, colliders, supercomputers, light sources and neutron sources, as well as facilities for studying the nanoworld, the environment, and the atmosphere. Projects focused on early-stage R&amp;D for the improvement of technology along defined roadmaps may be more appropriate for support through the DOE applied energy offices including: the Office of Energy Efficiency and Renewable Energy (http://www.eere.energy.gov/), the Office of Fossil Energy and Carbon Management (https://www.energy.gov/fecm/office-fossil-energy-and-carbon-management), the Office of Nuclear Energy (http://www.energy.gov/ne/office-nuclear-energy), and the Office of Electricity (https://www.energy.gov/oe/office-electricity).</p> <p>ARPA-E encourages submissions stemming from ideas that still require proof-of-concept R&amp;D efforts as well as those for which some proof-of-concept demonstration already exists. Submissions can propose a project with the end deliverable being an extremely creative, but partial solution.</p> <p>PROGRAM OVERVIEW</p> <p>The Seeding Critical Advances for Leading Energy technologies with Untapped Potential (SCALEUP) Ready program provides a vital mechanism for the support of innovative energy R&amp;D that complements ARPA-E’s primary focus on early-stage transformational energy technologies that require proof of concept.</p> <p>Technologies that achieve substantial technical advancement under ARPA-E support may still face significant technical and commercial challenges upon completion of an award's funding period, and thus are at risk of being stranded in their development path once ARPA-E funding ends. Experience across ARPA-E’s diverse energy portfolios, and input from a wide range of investors and industry stakeholders, indicate that pre-commercial scaling projects are critical to establish practical performance and cost parameters. These pre-commercial scaling projects aim to 1) translate the performance achieved at bench scale to commercially scalable versions of the technology, 2) integrate the technology with broader systems, 3) provide extended performance data, and 4) validate the manufacturability and reliability of new energy technologies. Successful scaling projects should enable industry stakeholders to justify the substantial commitments of financial resources, personnel, manufacturing facilities, and materials necessary to subsequently deploy the technologies at a commercial scale.</p> <p>SCALEUP Ready seeks to scale the most promising technologies previously funded by ARPA-E. The possibility of ARPA-E-funded technologies becoming stranded along their development pathways leaves substantial intellectual property developed with American taxpayer dollars vulnerable to adoption by foreign competitors, who capture it for continued development and economic benefit overseas. This harms national competitiveness, as U.S. industries often fall behind on the development, scaling, and manufacturing of technologies necessary to compete in rapidly evolving global energy markets. Thus, projects selected for SCALEUP Ready will meet ARPA-E’s statutory goals by “accelerating transformational technological advances in areas that industry by itself is not likely to undertake because of technical and financial uncertainty."</p>

Advanced Research Projects Agency Energy

The purpose of this modification is to clarify the meaning of the Program Policy Factors in Section V.C. To obtain a copy of the Notice of Funding Opportunity (NOFO) please go to the ARPA-E website at https://arpa-e-foa.energy.gov. To apply to this NOFO, Applicants must register with and submit application materials through ARPA-E eXCHANGE (https://arpa-e-foa.energy.gov/Registration.aspx). For detailed guidance on using ARPA-E eXCHANGE, please refer to the ARPA-E eXCHANGE User Guide (https://arpa-e-foa.energy.gov/Manuals.aspx). ARPA-E will not review or consider concept papers submitted through other means. For problems with ARPA-E eXCHANGE, email ExchangeHelp@hq.doe.gov (with NOFO name and number in the subject line). Questions about this NOFO? Check the Frequently Asked Questions available at http://arpa-e.energy.gov/faq. For questions that have not already been answered, email ARPA-E-CO@hq.doe.gov. AGENCY OVERVIEW The Advanced Research Projects Agency Energy (ARPA-E), an organization within the Department of Energy (DOE), is chartered by Congress in the America COMPETES Act of 2007 (P.L. 110-69), as amended by the America COMPETES Reauthorization Act of 2010 (P.L. 111-358), as further amended by the Energy Act of 2020 (P.L. 116-260): (A) to enhance the economic and energy security of the United States through the development of energy technologies that (i) reduce imports of energy from foreign sources; (ii) reduce energy-related emissions, including greenhouse gases; (iii) improve the energy efficiency of all economic sectors; (iv) provide transformative solutions to improve the management, clean-up, and disposal of radioactive waste and spent nuclear fuel; and (v) improve the resilience, reliability, and security of infrastructure to produce, deliver, and store energy; and (B) to ensure that the United States maintains a technological lead in developing and deploying advanced energy technologies. ARPA-E issues this Notice of Funding Opportunity (NOFO) under its authorizing statute codified at 42 U.S.C. 16538. The NOFO and any cooperative agreements or grants made under this NOFO are subject to 2 C.F.R. Part 200 as supplemented by 2 C.F.R. Part 910. ARPA-E funds research on, and the development of, transformative science and technology solutions to address the energy and environmental missions of the Department. The agency focuses on technologies that can be meaningfully advanced with a modest investment over a defined period of time in order to catalyze the translation from scientific discovery to early-stage technology. For the latest news and information about ARPA-E, its programs and the research projects currently supported, see: http://arpa-e.energy.gov/. ARPA-E funds transformational research. Existing energy technologies generally progress on established learning curves where refinements to a technology and the economies of scale that accrue as manufacturing and distribution develop drive improvements to the cost/performance metric in a gradual fashion. This continual improvement of a technology is important to its increased commercial deployment and is appropriately the focus of the private sector or the applied technology offices within DOE. In contrast, ARPA-E supports transformative research that has the potential to create fundamentally new learning curves. ARPA-E technology projects typically start with cost/performance estimates well above the level of an incumbent technology. Given the high risk inherent in these projects, many will fail to progress, but some may succeed in generating a new learning curve with a projected cost/performance metric that is significantly better than that of the incumbent technology. ARPA-E will provide support at the highest funding level only for submissions with significant technology risk, aggressive timetables, and careful management and mitigation of the associated risks. ARPA-E funds technology with the potential to be disruptive in the marketplace. The mere creation of a new learning curve does not ensure market penetration. Rather, the ultimate value of a technology is determined by the marketplace, and impactful technologies ultimately become disruptive that is, they are widely adopted and displace existing technologies from the marketplace or create entirely new markets. ARPA-E understands that definitive proof of market disruption takes time, particularly for energy technologies. Therefore, ARPA-E funds the development of technologies that, if technically successful, have clear disruptive potential, e.g., by demonstrating capability for manufacturing at competitive cost and deployment at scale. ARPA-E funds applied research and development (R&amp;D). The Office of Management and Budget defines applied research as an original investigation undertaken in order to acquire new knowledge directed primarily towards a specific practical aim or objective and defines experimental development as creative and systematic work, drawing on knowledge gained from research and practical experience, which is directed at producing new products or processes or improving existing products or processes. 0F1 Applicants interested in receiving financial assistance for basic research (defined by the Office of Management and Budget as experimental or theoretical work undertaken primarily to acquire new knowledge of the underlying foundations of phenomena and observable facts )1 should contact the DOE s Office of Science (http://science.energy.gov/). Office of Science national scientific user facilities (http://science.energy.gov/user-facilities/) are open to all researchers, including ARPA-E Applicants and awardees. These facilities provide advanced tools of modern science including accelerators, colliders, supercomputers, light sources and neutron sources, as well as facilities for studying the nanoworld, the environment, and the atmosphere. Projects focused on early-stage R&amp;D for the improvement of technology along defined roadmaps may be more appropriate for support through the DOE applied energy offices including: the Office of Energy Efficiency and Renewable Energy (http://www.eere.energy.gov/), the Office of Fossil Energy and Carbon Management (https://www.energy.gov/fecm/office-fossil-energy-and-carbon-management), the Office of Nuclear Energy (http://www.energy.gov/ne/office-nuclear-energy), and the Office of Electricity (https://www.energy.gov/oe/office-electricity). ARPA-E encourages submissions stemming from ideas that still require proof-of-concept R&amp;D efforts as well as those for which some proof-of-concept demonstration already exists. Submissions can propose a project with the end deliverable being an extremely creative, but partial solution. PROGRAM OVERVIEW The Seeding Critical Advances for Leading Energy technologies with Untapped Potential (SCALEUP) Ready program provides a vital mechanism for the support of innovative energy R&amp;D that complements ARPA-E s primary focus on early-stage transformational energy technologies that require proof of concept. Technologies that achieve substantial technical advancement under ARPA-E support may still face significant technical and commercial challenges upon completion of an award's funding period, and thus are at risk of being stranded in their development path once ARPA-E funding ends. Experience across ARPA-E s diverse energy portfolios, and input from a wide range of investors and industry stakeholders, indicate that pre-commercial scaling projects are critical to establish practical performance and cost parameters. These pre-commercial scaling projects aim to 1) translate the performance achieved at bench scale to commercially scalable versions of the technology, 2) integrate the technology with broader systems, 3) provide extended performance data, and 4) validate the manufacturability and reliability of new energy technologies. Successful scaling projects should enable industry stakeholders to justify the substantial commitments of financial resources, personnel, manufacturing facilities, and materials necessary to subsequently deploy the technologies at a commercial scale. SCALEUP Ready seeks to scale the most promising technologies previously funded by ARPA-E. The possibility of ARPA-E-funded technologies becoming stranded along their development pathways leaves substantial intellectual property developed with American taxpayer dollars vulnerable to adoption by foreign competitors, who capture it for continued development and economic benefit overseas. This harms national competitiveness, as U.S. industries often fall behind on the development, scaling, and manufacturing of technologies necessary to compete in rapidly evolving global energy markets. Thus, projects selected for SCALEUP Ready will meet ARPA-E s statutory goals by accelerating transformational technological advances in areas that industry by itself is not likely to undertake because of technical and financial uncertainty."

NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development

Project Summary: The goals of this project are to determine how sex chromosome dosage (SCD) influences allelic gene regulation in the context of placental development and how SCD imbalance leads to impaired trophoblast differentiation and placental health and function. One fundamental difference between males and females is the sex chromosome content (46,XY and 46,XX), which causes imbalances in X/Y expression. While X chromosome inactivation (XCI) specifically silences one X chromosome in females to restore balanced expression, some genes escape XCI and thus have female-biased expression. In addition, Y-linked genes are only expressed in males. Prior to the onset of sex hormones, the effects of SCD on sex differences in autosomal gene expression and phenotypes are largely mediated by the dosage of sex-linked genes, especially X- and Y- paralogs. Notably, there is a marked effect of fetal sex on pregnancy outcomes. For example, carrying a male fetus is associated with increased risk of gestational diabetes and placental abruption, while carrying a female fetus is associated with increased risk of fetal growth restriction and preeclampsia. Allelic gene expression in males and females contributes to fetal sex differences. However, whether SCD contributes to allele-biased gene expression in placental development remains unknown. We previously showed that manipulation of X-linked gene dosage in mouse results in dysregulation of allelic gene expression. To determine the overall impact of differential SCD on allelic gene regulation and identify sex- linked candidate genes in human placental development as well as during trophoblast differentiation, we will use complementary ex vivo and in vitro approaches to leverage integrated multi-omics and functional studies. First, we will determine the effects of X- and Y-chromosome gene dosage on allelic gene regulation by single- nuclei and single cell assays performed in human 1st trimester placental tissue with varied sex chromosome content (Aim 1) and in trophoblast cell models derived from a unique collection of isogenic human induced pluripotent stem cells (hiPSCs) with different numbers of sex chromosomes (Aim 2). Second, we will investigate mechanisms controlling allelic gene expression by modulating the expression of sex-linked candidate X/Y paralogs and using allelic transcriptomic and epigenomic analyses to identify critical pathways (Aim 3). Third, functional assays will be carried out to evaluate phenotypic effects of differential SCD on trophoblast and trophoblast organoid function (Aims 2 and 3). Overall, this work will provide a comprehensive view of the effects of differential SCD on allele-specific gene regulation and on placental health and function. Results from this project will address a gap in our knowledge of the mechanisms underlying sex differences in allelic gene regulation at the fetal-maternal interface.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY Islet transplantation is a promising treatment for insulin-dependent forms of diabetes, including type 1 diabetes and surgical diabetes induced by total pancreatectomy. In the U.S., total pancreatectomy with islet autotransplantation (TPIAT)—which is performed to relieve pain in patients with chronic pancreatitis-- has been the most prevalent form of islet transplant to date. At the same time, islet allotransplantation for type 1 diabetes is growing, and will continue to grow with the success of stem-cell derived islets and future approaches to reduce immunosuppression risks via technological advancements, genetic editing, or newer immunomodulation. Islet autotransplant is a useful research model to study adjunctive therapies for glycemic control and islet graft survival because it is free of the confounding factors of alloimmune rejection and recurrent type 1 diabetes. In TPIAT, about 70% of patients require exogenous insulin despite having some endogenous islet function, and attrition of islet function over time occurs in both auto and allografts. This attrition appears to be at least in part driven by metabolic stress on the transplanted beta cells. This pilot clinical trial, submitted in response to PAS-25-102, is designed to gather preliminary data on the efficacy and safety of SGLT2 inhibitor therapy (SGLT2i) in islet autotransplant recipients who have partial islet function. Our rationale for studying SGLT2i in this population is: (1) SGLT2i reduces blood glucose levels through increased glucosuria and do not directly stimulate islets (avoiding extra metabolic stress), nor does the benefit depend on presence of insulin resistance, which is often absent in islet transplant; (2) in both T1D and total pancreatectomy, there is evidence of reduced prandial glucose excursions with SGLT2i, which in turn may reduce metabolic beta-cell stress on transplanted islets in TPIAT; (3) SGLT2i are acceptable to patients as a once-daily oral medication. However, safety of these agents is unknown in TPIAT, and in theory they may increase risk for diabetic ketoacidosis in this population of patients who have partial insulin deficiency. We will enroll 30 patients with partial islet function >1 year after TPIAT, randomized to a standard care control arm (n=10) or one of 2 doses of empagliflozin (n=10 on 10 mg; n=10 on 25 mg) for 3 months, followed by a 3 month extension during which all patients will receive empagliflozin (25 mg daily). Specific Aim 1 will determine if empagliflozin improves glycemic control and reduces beta-cell specific endoplasmic reticulum stress after islet autotransplant. Specific Aim 2 will assess safety and feasibility of empagliflozin in islet autotransplant recipients. If results from this pilot study are promising, we will conduct a larger randomized blinded study. PI Bellin has led two multicenter TPIAT studies and has relationships with other centers to build a larger randomized trial. Importantly, we expect that results from this study will also inform the field of islet allotransplant for type 1 diabetes.

NCI - National Cancer Institute

SHP2 (PTPN11) has attracted much attention, because unlike most protein-tyrosine phosphatases (PTPs), it functions as a “positive” component of receptor tyrosine kinase (RTK) signaling. Germline mutations in PTPN11 are the most frequent cause of the “RASopathies” Noonan Syndrome (NS) and NS with multiple lentigines, somatic mutations contribute to benign and malignant neoplasms, and global SHP2 deficiency in mice leads to trophoblast stem cell (TSC) death/peri-implantation lethality. SHP2 has two N-terminal SH2 domains, a central catalytic (PTP) domain, and two C-terminal tyrosine phosphorylation (pY) sites and acts as an elegant molecular switch, residing in a closed, inactive form in the absence of pY-peptide ligands for its N-SH2 domain. Binding by such ligands, found in receptors and scaffolding adapters (e.g., GAB1, 2), activates SHP2. This mechanism was exploited to develop allosteric inhibitors (SHP2i) now in clinical trials. We know that SHP2 acts upstream of the RAS guanine nucleotide exchange factors SOS1/2 to promote RAS/ERK pathway activation, yet despite much progress, key knowledge gaps persist. How SHP2 signals to SOS1/2 is unclear, as are the precise roles of PTP activity and tyrosine phosphorylation in vitro and in mice. Our new Preliminary Data show that SHP2 is required for the assembly of large SOS1 clusters in response to RTK stimulation. Moreover, the PTP domain and Cterminal pY sites play distinct roles downstream of different RTKs, and neither all PTP-inactive nor tyrosine phosphorylation site mutants phenocopy the effects of global SHP2 deficiency. Most surprisingly, we recently found that PTP activity is dispensable for RAS activation. Instead, a specific conformation of the PTP domain, involving movement of a b-sheet is required. This conformation is mimicked by certain catalytic cysteine (Cyscat) mutants and induced by in vitro oxidation of Cyscat. We propose to (1) use super-resolution microscopy to determine how RTKs and SHP2 regulate SOS1 and GRB2/SOS1 clusters, correlate clusters with RAS activation, and define the involvement and requirement of other early components in RTK signaling, (2) determine whether SHP2 pYs all signal via GRB2, use redox probes/proteomics and SHP2 monobodies (Mb) to define the RTKinduced PTP domain oxidation state, test our “conformational switch” model for RAS activation via a structureinformed genetic approach, use SHP2C459D, which is full capable of RAS activation, and the signaling inactive mutant SHP2C459S in affinity purification/proximity MS proteomics to identify SHP2-interacting proteins critical for RAS activation/inactivation and validate them using reverse genetics, and test the effects of SHP2 sub-domain mutants/Mb on SOS1 and GRB2/SOS1 clusters, and (3) use Ptpn11 mutant knock-in mice to test the effects of SHP2 sub-domains on FGF-induced signaling, transcription, proliferation, differentiation, and survival of TSCs, test whether SHP2C459D mediates “adaptive resistance” to RAS/ERK pathway inhibitors, and ask if it causes “RASopathy” and/or myeloproliferative neoplasm/leukemia. Mice are essential to model these complex defects seen in humans with germline and somatic PTPN11 mutations and to develop new treatments.

NIDA - National Institute on Drug Abuse

Neurogenomic studies by the SCORCH (Single Cell Opioid Response in the Context of HIV) consortium strongly suggest that brains of individuals living with HIV in the context of opioid or (polys)substance use disorder (OUD/SUD) comorbidity harbor a molecular environment permissive for HIV viral replication and risk for cytotoxic damage. This conclusion also applied to donors who showed systemic, antiretroviral drug- mediated suppression of the virus. There was a stepwise progression of transcriptomic dysregulation in OUD+HIV+ brain, culminating in widespread neuronal pathology and pronounced inflammatory signatures in microglia from individuals with poor viral suppression. The goals of the current project are two-fold. First, we aim for single molecule validation of SCORCH single cell results, by analyzing~12-20kb single molecule fiber- seq libraries from cingulate cortex of SCORCH brains carefully annotated for OUD/SUD and systemic (HIV) suppression status. We will embark on single fiber-level multiomic profiling with differential analyses to uncover effects of HIV infection on nucleosome phasing, positioning and offset at transcription start sites, together with endogenous m5CpG methylation and transcription factor footprints. Integrating single cell (RNA+ATAC-seq) data already generated from the same set of SCORCH brain cohort, with our new single molecule multiomic fiber-seq mappings is expected to provide unprecedented neurogenomic insights into the HIV and substance-exposed brain. Second, we aim for additional functional validation of SCORCH data, by employing HIV-induced lineage tracing (HILT) in human induced pluripotent stem cell (hiPSC)-derived Neuron-Astrocyte-Microglia (hiPSC N-A-Mg) tricultures, in conjunction with CRISPRi for multiplexed microglial promoter repression focused on genes that are both (i) dysregulated in SCORCH SUD+ postmortem brain and (ii) implicated in HIV expression or replication. We will assess viral integration frequency, numbers and proportions of infected microglia, and compare transcriptomes and chromatin of infected/integrated HIV+ microglia with those from exposed bystander cells. This project is a first step to validate SCORCH genomic discoveries on the single molecule level, followed by the design of novel therapeutic tools targeting opioid/substance-dysregulated genes that could foster HIV infection and spread in the brain.

NHLBI - National Heart Lung and Blood Institute

ABSTRACT Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative therapy for myelodysplastic syndromes (MDS), a heterogenous group of clonal hematopoietic stem cell disorders. Its curative potential is primarily attributed to the graft-versus-leukemia (GVL) effect, mediated by donor T cells. However, disease relapse after allo-HCT continues to be a major clinical challenge and the leading cause of HCT failure. Multiple lines of evidence – including preliminary data from the PI’s K01 award – indicate that both genomic and non- genomic factors contribute to immune escape and posttransplant relapse. Despite these insights, the transcriptional programs orchestrated by these mechanisms remain poorly understood. To elucidate the molecular drivers of relapse, the proposed study will leverage longitudinal samples from 20 MDS patients enrolled in the Bone Marrow Transplant Clinical Trials Network Study #1203. Using paired single-cell RNA sequencing (scRNA-seq) and T cell receptor (TCR) sequencing (scTCR-seq), along with targeted gene sequencing of MDS-associated somatic mutations, we aim to map the dynamic immune landscape following allo-HCT. The study cohort will be comprised of 10 MDS patients who relapsed within one-year post-HCT (cases) and 10 patients who remained relapse-free for at least one year (controls). Peripheral blood mononuclear cells (PBMCs) were collected longitudinally at days 35, 100, 180, and 365 post-HCT. Paired scRNA-seq and scTCR- seq will be performed on all available PBMC samples from controls and on pre-relapse samples from cases. We will profile the single-cell landscape and temporal dynamics of T cells and TCR repertoires at each time point and assess how pre-HCT treatment regimens and donor type influence post-HCT T cell composition, functional states, and TCR clonality (Aim 1). Deep targeted sequencing of 31 MDS-associated genes included in the molecular prognostic model (IPSS-Molecular) will be performed on preconditioning samples to identify MDS- associated somatic mutations that can serve as markers of measurable residual disease (MRD). We will identify T cell subsets and functional states that contribute to relapse after allo-HCT and evaluate how the presence of specific mutations or MRD status influences donor T cell phenotypes, functional states, and clonal architecture (Aim 2). This study will generate preliminary data to identify T cell phenotypes, clonal dynamics, and gene signatures associated with posttransplant relapse, while also examining their interplay with MDS-associated somatic mutations. By integrating high-resolution single-cell and genomic approaches, this R03 project represents a focused and innovative extension of the PI’s ongoing K01 research. It leverages institutional resources and prior insights to advance mechanistic understanding of relapse biology, while supporting the PI’s trajectory toward becoming an independent investigator committed to precision medicine approaches for relapse prediction and prevention in MDS.

NIA - National Institute on Aging

PROJECT SUMMARY This application seeks partial support for the upcoming Society for Muscle Biology (SMB) conference entitled, "Skeletal Muscle Stem Cells in Development, Regeneration, and Adaptations", which will be held July 19-24, 20256 in Victoria, BC, Canada. This will be the 13th edition of this conference since 1998 focusing on skeletal muscle stem cells (MuSCs) and the 2nd sponsored by the SMB. This biennial meeting has traditionally been operated by FASEB, but shifted in 2024 to be organized under SMB to allow the organizers and participants more autonomy. This change facilitates a more robust and vibrant conference and a greater focus on supporting trainees. We expect approximately 125 attendees from around the world with at least ~60% junior researchers. No other scientific meeting has a primary focus on MuSCs. The need for a conference with this focus is demonstrated by the steady increase in attendance since the meeting's inception and the consistently excellent post-meeting evaluations provided by meeting attendees. This meeting attracts all leading MuSC researchers from around the world, further demonstrating its value for established and future leaders in the field. The overall objectives of this meeting include to: 1) provide a comprehensive analysis of recent discoveries in the field, with the goal of understanding the regulatory mechanisms controlling normal and abnormal functions of MuSCs in muscle development, homeostasis, regeneration, hypertrophy, aging, and myopathy; 2) create and foster an interactive environment for the exchange of ideas and unpublished data, so as to hasten discoveries and facilitate new and existing collaborations; 3) provide opportunities for junior investigators to present their work and network with senior investigators; and 4) facilitate career development of all career stages by ensuring representation in all aspects of the conference program. Our keynote speaker will be Dr. Peter Zandstra, a renowned engineer and stem cell biologist. Scientific sessions are planned, presenting 48 speakers (23 confirmed invited speakers and at least 25 selected from submitted abstracts) at all career levels. Session topics include: (i) Molecular regulation of MuSCs; (ii) Spatial and modeling innovation in MuSC analysis; (iii) MuSC epigenetics and transcriptional regulation; (iv) Engineering and translating muscle stem cells; (v) MuSC dynamics during development and muscle regeneration; (vi) MuSC niche biology; and (vii) MuSCs and other cell interactions in disease. Invited speakers have been selected for their scientific excellence, with particular attention to discipline, encompassing all trainee levels and geographical diversity. Speakers are explicitly required to present unpublished work, to ensure scientific discussion is at the forefront of the field. We will have poster sessions, each preceded by a “posters blitz” where poster presenters will give a one-minute talk to highlight their work, and career-oriented workshops and “meet-the-speaker” breakfast and lunch sessions. This meeting will provide a forum to foster discussion and cross-fertilization from diverse areas of research, to advance our understanding of muscle regeneration and aid in the development of therapeutics.

NIA - National Institute on Aging

Project Summary Osteoarthritis (OA) is a degenerative disease resulting in irreversible, progressive destruction of hyaline cartilage lining articular joints. A critical challenge for OA management is the development of an effective treatment that reverses cartilage damage. Our previous work indicates the existence of adult skeletal stem cells (SSCs) in postnatal cartilage. These SSCs are dormant yet can potentially repair damaged cartilage when stimulated by surgical procedures such as Microfracture (MF). While MF typically results in the formation of inferior fibrocartilage, we have demonstrated that MF-activated tissue-resident SSCs can be expanded and directed towards the formation of healthy chondrocytes and hyaline cartilage to regenerate full-thickness cartilage defects by pharmacologically modulating SSC activity and the microenvironment surrounding them. This method we termed Growth-factor Enhanced Microfracture (GEM). Our published studies and preliminary data demonstrate that GEM works well in young animals but is less effective in aged mice. Our data supported by recent findings of others further suggest that FGF7 (Fibroblast Growth Factor 7) expression in the SSC lineage is induced by an inflammatory aged and osteoarthritic bone marrow niche, which leads to pro-fibrotic lineage-skewing resulting in cartilage loss. We now build on additional preliminary results showing that direct and indirect blockade of FGF7 during GEM can reinstate stem cell-based cartilage formation in joints of aged and OA mice. The gained insights from the proposed study will help us to develop strategies to efficiently apply GEM even in impaired settings with a cellular microenvironment less conducive to articular cartilage regeneration. To that end, we are elucidating the cellular dynamics and molecular mechanisms that underlie SSC mediated cartilage repair. In Aim 1, we will expand our preliminary findings to confirm and mechanistically dissect how inhibiting FGF7 locally during GEM in aged and osteoarthritic mice can promote hyaline cartilage formation. In Aim 2, we will determine if epigenetic rewiring of local SSCs by a novel therapeutic compound is sufficient to overcome age-related impairments of GEM mediated cartilage regeneration. Our experiments will use state-of-the-art structural and functional readouts at the tissue level as well as latest technology to unravel cellular and molecular changes at the single cell level to assess regenerative properties and provide new biological insights into OA. Our team brings together expertise in skeletal stem cell biology, in-depth basic science and clinical knowledge of OA as well as bioengineering competency. We are using cutting-edge methods to pursue hypothesis-driven questions aimed at unlocking endogenous stem cells for cartilage repair. By taking advantage of a therapeutic window to skew local MF-activated SSC fate we want to generate new cartilage for the resurfacing of OA joints independent of age and disease state. Eventually, we wish to translate these preclinical studies.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY: SKIN-TARGETED METAL-ORGANIC FRAMEWORK-BASED SUBUNIT VACCINES Driven by their affordability, manufacturability, and safety benefits over traditional vaccines, subunit antigens are an important component of modern vaccinology. However, they exhibit poor immunogenicity and efficacy, and thus, new and rational strategies are required to improve their immunogenicity and efficacy. We propose a novel skin immunization platform (SIP) to address the limitations of vaccine development with subunit antigens. Our innovative and globally deployable SIP leverages emerging vaccine technologies, including (1) metal-organic framework (MOF) nanovaccine constructs; (2) a clinically de-risked adjuvant, and (3) needle-free, thermostable, and self-applied microneedle arrays (MNAs), as well as highly immunoresponsive skin niche for the development of effective and accessible subunit vaccines. The central hypothesis of our project is that in situ harnessing of the immunologically rich milieu of skin with our SIP in a spatially and temporally controlled manner will drive the generation of robust, durable antigen-specific humoral and cellular responses in a well-tolerated manner. Our SIP is engineered in the form of rapidly separable MNAs (rsMNAs) that consist of high-quality obelisk-shaped microneedles comprising dissolving polymer matrix tips loaded with MOF vaccine constructs and non-dissolvable stems with filleted bases attached to the backing layer. Unlike traditional MNAs that require relatively longer wear times (minutes), our rsMNA design, which is enabled by the unique ability of biodegradable MOFs in protecting vaccine components against denaturing organic solvents needed to form non-dissolvable stems of microneedles, facilitates the implantation of MOF vaccines into the skin in less than 10 s via shear force. Our SIP offers the superior vaccine delivery and immunogenicity characteristics compared to needle-and-syringe (N&S) vaccines and conventional MNA-based vaccines. As such, our SIP unlocks the true potential of the skin immune system for improved cutaneous vaccination strategies with subunit antigens. Ultimately, this project will yield a rapidly translatable SIP that will provide unparalleled flexibility and efficacy for vaccination with subunit antigens, which is unattainable with the state-of-the-art immunization platforms.

U.S. National Science Foundation

NSF invests in scientific discoveries, technological breakthroughs, and transformative innovations that strengthen economic growth, enhance security, and improve the lives of Americans and people around the world. Our ability to support that mission requires a robust scientific and engineering (S&amp;E) enterprise in the United States that allows scientists to innovate at the frontier. In addition to funding scientists, America needs next-generation scientific instrumentation that allows scientists to pursue new innovations. In many fields, it is critical that this new scientific instrumentation is developed in the United States. In support of this mission, NSF is initiating a pilot emphasis area for itsSBIR/STTR programs to invest in startups and small businesses that are specifically developing enabling technologies that include next-generation instrumentation, novel experimental platforms, and other scientific equipment to advance the frontiers of scientific discovery and strengthen the American scientific and engineering enterprise. This encompasses novel instrumentation necessary for the coming era of AI-driven discoveries. This pilot will prioritize investing in the necessary infrastructure to support entirely new fields of scientific discovery, making new technological breakthroughs and transformative applications possible. Through this approach, NSF will continue to lead in propelling the scientific enterprise to new frontiers. This pilot emphasis area for the NSF SBIR/STTR programs funds across enabling technology areas and market sectors in alignment with the above goals; the programs do not solicit specific technologies for the purpose of procuring goods and services for the agency from startups and small businesses. NSF will continue to invest in other deep-tech ventures through the historic NSF SBIR/STTR programs available here. Funding opportunities are available through the NSF SBIR/STTR programs: Phase I, Phase II, Fast-Track, and Supplements. Each company can receive up to $2.0 million for R&amp;D. Separately, NSF welcomes Strategic Breakthrough proposals, upon recommendation from the Program Officer, for Phase II awardees. NSF takes no equity and awardees keep full ownership of their company and intellectual property. Expanding Participation in STEM and Gold Standard Science: NSF prioritizes cutting-edge discovery science and engineering research, advancing technology and innovation, and creating opportunities for all Americans. NSF also expects the highest standards of scientific rigor, integrity and adherence to tenets ofGold Standard Sciencein proposals, as appropriate for the field of science and research modality.

NCI - National Cancer Institute

PROJECT SUMMARY Glioblastoma (GBM) is an aggressive form of primary brain tumor, characterized by high malignancy and genetic heterogeneity, and standard treatment for GBM has remained unchanged in the last decade. A feature of GBM that makes it particularly difficult to treat is its heterogeneity, in part created by glioma stem cells (GSCs) within the solid tumor. GSCs have high plasticity and the ability to self-renew and differentiate into various heterogenic cancer cell populations. GSCs are kept in a ‘stem’- like state with unlimited self-replication without differentiation and maturation, which helps maintain tumor heterogeneity and growth. This state also prevents them from being targeted effectively by traditional therapeutics. Histone modifications keep late-glial genes unreachable by transcription factors, promoting transcription of replication and early-glial genes, maintaining stem-ness. A major player in this process is the imitation switch (ISWI) family of ATP-dependent chromatin remodelers, which have been found to have widespread aberrant expression in cancers, including gliomas. The ISWI complex can change the spacing of histones on the chromatin, and is primarily involved in the repression of gene expression. It contains two catalytic subunits, SMARCA1 and SMARCA5, which can have disparate expression patterns and modifications. SMARCA5 in particular is a drug-able target and has been shown to be more highly expressed in GBM than SMARCA1, and miRNA silencing of SMARCA5 has been shown to limit GSC stem-ness. If SMARCA5 is successfully inhibited and doing so enables transcription factor machinery to access the late-glial genes blocked by ISWI, resulting chromatin modification and gene expression would end the GSC cycle of self-replication and inhibit associated malignancies. We hypothesize that SMARCA5 is vital to maintaining a stem-like state in GSCs and to promoting tumor growth, and is therefore a promising therapeutic target. To test this, we will manipulate SMARCA5 expression through genetic knockdowns and pharmacological inhibition. Aim 1: Test the hypothesis that SMARCA5 is essential to maintaining GSC stem-ness, looking in vitro at measure of stem-like state and heterogeneity. Aim 2: To interrogate the effects of SMARCA5 on chromatin and on changes to gene expression in GSCs using sequencing like RNAseq, ATACseq, and CUT&TAG. We will examine differential expression of differentiation- related genes and other changes created by SMARCA5 depletion. Aim 3: To test the hypothesis that SMARCA5 inhibition in vivo extends animal survival and is an effective treatment strategy in mice models. Showing that SMARCA5 depletion is also effective at targeting GSCs in vivo will further confirm it as a potential therapeutic target for GBM.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Patients with diabetes mellitus (type 1 or 2) have a total lifetime risk of a diabetic foot ulcer (DFU) complication as high as 25%; 14-24% of them suffer from amputation. People with T1D develop DFU at a younger age and are at a much greater risk of amputation and hospitalization secondary to a DFU compared to T2D. The difference between pathophysiology and outcomes for individuals with T1D versus T2D is poorly understood and understudied. Family and twin-based studies have identified significant genetic components especially single nucleotide variations (SNV) in T1D as compared to T2D subjects. However, systematic patient-based genetic studies of T1D DFU are scanty, and the proposed work is aimed at seeding a novel paradigm in wound healing research. The originality and strength of our study stems from the genome-wide genotyping feasibility studies on robust quality controlled and parametrically qualified genotyped data of 149 chronic wound patients with diabetes status. This study identified 20576 SNV significantly associated with human chronic wounds (p- value<0.01, CR>97%, MAF>0.01). Majority (>60%) of these SNP were predicted to be causative for truncated or nonfunctional proteins using Variant Effector Prediction analysis were identified. To investigate the clinical significance of wound associated SNV, a meta-analysis against the phenotypes annotated in GWAS catalog was conducted as reported. These SNVs were intersected with manually curated >270,000 GWAS SNPs annotated with ~900 GWAS phenotypes collected from ~2500 studies. Enrichment analysis of the above intersected SNVs was performed against these GWAS phenotypes and respective odds ratio, and level of significance were calculated using Fisher’s exact test. These analyses identified “obesity” as the most significantly enriched GWAS-phenotype (log2 odds ratio = 4.06, p-value= 4.94E-12) for wound associated SNPs predominantly present in fat mass and obesity-associated (FTO) gene. This proposal is responsive to RFA-DK-26-009 for the New Investigator Gateway Award for collaborative type 1 diabetes (T1D) Research through Diabetic Foot Consortium (DFC). The objective of the proposed work is to determine SNV T1D and T2D that contribute to diabetic wound closure. This study will investigate the wound tissue already collected from patients with open DFU (N=50 with T1D and n=100 T2D) enrolled in the DFC Master Protocol. The following specific aims are proposed: 1.0 Aim 1. Identify SNV uniquely associated with T1D non-healing phenotype. T1D vs T2D will identify T1D-specific SNV (SNVT1D). Healing vs non-healing will identify SNVT1D-NH. SNVT1D-NH will be shortlisted to obtain candidate SNVT1D- NH (cSNVT1D-NH) based on overlap with obesity-associated SNP. 2.0 Aim 2. Test the functional significance of cSNVT1D-NH in wound healing mechanisms in vitro. Gene editing to specifically induce risk to non-risk alleles of specific cSNVT1D-NH using CRISPR/Cas9 genome editing improves: 2.1 epidermal keratinocyte migration in an in vitro scratch model; 2.2 formation of well-perfused and non-leaky vessels by microvascular endothelial cells using 3D-angiogenesis assay; and 2.3 augmentation of collagen deposition and maturation by dermal fibroblasts.

U.S. National Science Foundation

<div class="WordSection1"> <div class="WordSection1"> The Social Psychology Program at NSF supports theoretically focused empirical investigations that advance fundamental social psychological explanations of human behavior, attitudes, and experience. Synopsis The Social Psychology Program invites research and infrastructure proposals that advance knowledge of how human behavior is influenced by macro- and micro-level social forces, including how thought, motivation, emotion, neural, and physiological processes explain ways of thinking about and relating to self and others. Proposed research should carry strong potential for groundbreaking discoveries about the power of social dynamics to shape peoples&rsquo; attitudes, behavior, and experience. Basic research that connects to emerging and ongoing global challenges is especially encouraged. </div> Proposals that develop new theories or methods are highly encouraged. Proposals involving non-human animals are considered only if the research offers clear and direct contributions to understanding human social behavior. Note: Proposals may be returned without review if the primary goal of the research is to improve clinical practice as its primary outcome, or contains disease-related goals, including work on the etiology, diagnosis or treatment of physical or mental illness or disease, medical abnormality, or clinical interventions. In assessing intellectual merit, the Social Psychology Program places highest priority on research that is theoretically grounded, based on empirical observation and validation, and with designs appropriate to the questions asked (including but not limited to experiments, naturalistic observations, field studies, longitudinal analyses, and computational modeling). In assessingbroader impacts, the Social Psychology Program places highest priority on proposals that offer strong potential to benefit society, strengthen national security interests, improve the quality of life, build STEM talent, enhance infrastructure for research and education, increase public engagement with science, and include a proactive plan for sharing the results with a wide variety of audiences. PIs are encouraged to review the <a href="https://new.nsf.gov/funding/learn/broader-impacts">NSF resources on broader impact</a>. The Social Psychology Program expects the methods, measures and data that result from NSF support to be openly shared with other researchers and the public. For further guidance proposers should consult <a href="https://www.nsf.gov/sbe/DMP/SBE_DataMgmtPlanPolicy_RevisedApril2018.pdf">Data Management for NSF SBE Directorate Proposals and Awards</a>. The Data Management and Sharing Plan (DMSP) should articulate how the proposed research will engage with best practices of open science. Researchers are expected to engage in open science practices and deviations from that should be well-justified. The Social Psychology Program accepts regular research proposals, including Faculty Early Career Development (CAREER) proposals, proposals for research in undergraduate institutions (RUI), rapid response research proposals (RAPID) and early-concept grants for exploratory research (EAGER). The program also accepts small conference proposals for events (including workshops) being planned one year or more after submission. The Social Psychology Program doesnotaccept proposals for doctoral dissertation improvement awards or mid-career advancement (MCA) awards. Principal Investigators should selectPD 22-1332 in the program announcement/solicitation block on the proposal cover sheet for submission of regular research projects to the Social Psychology program. <a href="https://new.nsf.gov/funding/learn/research-types/learn-about-convergence-research">Interdisciplinary, multidisciplinary and convergent research</a> approaches are encouraged, and PIs are encouraged to identify possible other programs for co-review. PIs are strongly encouraged to submit the Single Copy Document titled &ldquo;List of Suggested Reviewers&rdquo; with their full proposal. Investigators are encouraged to contact a Social Psychology program director before submitting a proposal to confirm its fit with the scope and priorities of the Social Psychology Program. Such contact is most productive when a one-page (maximum) summary of the planned proposal is sent ahead of a meeting. This summary should include a description of the proposed intellectual merit and broader impacts, as well as an additional page of references cited. The Social Psychology program is always interested in identifying new reviewers. Potential reviewers should have a Ph.D. in psychology or related field and have a demonstrated area of basic research expertise relevant to social psychology. Individuals interested in reviewing for the program should complete a short survey to indicate their area of expertise and contact information. </div>

U.S. National Science Foundation

The Social Psychology Program at NSF supports theoretically focused empirical investigations that advance fundamental social psychological explanations of human behavior, attitudes, and experience. Synopsis The Social Psychology Program invites research and infrastructure proposals that advance knowledge of how human behavior is influenced by macro- and micro-level social forces, including how thought, motivation, emotion, neural, and physiological processes explain ways of thinking about and relating to self and others. Proposed research should carry strong potential for groundbreaking discoveries about the power of social dynamics to shape peoples attitudes, behavior, and experience. Basic research that connects to emerging and ongoing global challenges is especially encouraged. Proposals that develop new theories or methods are highly encouraged. Proposals involving non-human animals are considered only if the research offers clear and direct contributions to understanding human social behavior. Note: Proposals may be returned without review if the primary goal of the research is to improve clinical practice as its primary outcome, or contains disease-related goals, including work on the etiology, diagnosis or treatment of physical or mental illness or disease, medical abnormality, or clinical interventions. In assessing intellectual merit, the Social Psychology Program places highest priority on research that is theoretically grounded, based on empirical observation and validation, and with designs appropriate to the questions asked (including but not limited to experiments, naturalistic observations, field studies, longitudinal analyses, and computational modeling). In assessingbroader impacts, the Social Psychology Program places highest priority on proposals that offer strong potential to benefit society, strengthen national security interests, improve the quality of life, build STEM talent, enhance infrastructure for research and education, increase public engagement with science, and include a proactive plan for sharing the results with a wide variety of audiences. PIs are encouraged to review the NSF resources on broader impact. The Social Psychology Program expects the methods, measures and data that result from NSF support to be openly shared with other researchers and the public. For further guidance proposers should consult Data Management for NSF SBE Directorate Proposals and Awards. The Data Management and Sharing Plan (DMSP) should articulate how the proposed research will engage with best practices of open science. Researchers are expected to engage in open science practices and deviations from that should be well-justified. The Social Psychology Program accepts regular research proposals, including Faculty Early Career Development (CAREER) proposals, proposals for research in undergraduate institutions (RUI), rapid response research proposals (RAPID) and early-concept grants for exploratory research (EAGER). The program also accepts small conference proposals for events (including workshops) being planned one year or more after submission. The Social Psychology Program doesnotaccept proposals for doctoral dissertation improvement awards or mid-career advancement (MCA) awards. Principal Investigators should selectPD 22-1332 in the program announcement/solicitation block on the proposal cover sheet for submission of regular research projects to the Social Psychology program. Interdisciplinary, multidisciplinary and convergent research approaches are encouraged, and PIs are encouraged to identify possible other programs for co-review. PIs are strongly encouraged to submit the Single Copy Document titled List of Suggested Reviewers with their full proposal. Investigators are encouraged to contact a Social Psychology program director before submitting a proposal to confirm its fit with the scope and priorities of the Social Psychology Program. Such contact is most productive when a one-page (maximum) summary of the planned proposal is sent ahead of a meeting. This summary should include a description of the proposed intellectual merit and broader impacts, as well as an additional page of references cited. The Social Psychology program is always interested in identifying new reviewers. Potential reviewers should have a Ph.D. in psychology or related field and have a demonstrated area of basic research expertise relevant to social psychology. Individuals interested in reviewing for the program should complete a short survey to indicate their area of expertise and contact information.

Society for Science

Funds science fairs, research competitions, and STEM education programs.

U.S. National Science Foundation

The Sociology Program supports basic research on all forms of human social organization<span>&mdash;</span> societies, institutions, groups and demography<span>&mdash;</span> and processes of individual and institutional change. The program encourages theoretically focused empirical investigations aimed at improving the explanation of fundamental social processes. This includes research on organizations and organizational behavior, population dynamics, social movements, social groups, labor force participation, stratification and mobility, family, social networks, socialization, and the sociology of science and technology. The program supports both original data collection and secondary data analysis that use the full range of quantitative and qualitative methodological tools. Theoretically grounded projects that offer methodological innovations and improvements for data collection and analysis are also welcomed. Principal Investigators should selectPD 98-1331in the program announcement/solicitation block on the proposal cover sheet for submission of regular research projects to the sociology program. Projects are evaluated using the two foundation-wide criteria, intellectual merit and <a href="https://www.nsf.gov/pubs/2021/nsf21059/nsf21059.jsp">broader impacts</a>. In assessing the intellectual merit of proposed research, four components are key to securing support from the Sociology Program: (1) the issues investigated must be theoretically grounded; (2) the research should be based on empirical observation or be subject to empirical validation or illustration; (3) the research design must be appropriate to the questions asked; and (4) the proposed research must advance our understanding of social processes, structures and methods. NSF also offers a number of specialized funding opportunities through its crosscutting and cross-directorate activities; some of the sociology-related opportunities are listed below. Crosscutting Research &amp; Training Opportunities: <ul type="disc"> <li>ADVANCE: Increasing the Participation and Advancement of Women in Academic Science and Engineering Careers</li> <li>Faculty Early Career Development (CAREER) Program</li> <li>Graduate Research Fellowship Program (GRFP)</li> <li>Major Research Instrumentation (MRI) Program</li> <li>Mid-scale Research Infrastructure Programs</li> <li>SBE Postdoctoral Research Fellowships (SPRF)</li> <li>Research Experiences for Undergraduates (REU)</li> <li>Research at Undergraduate Institutions (RUI)</li> <li>Small Business Innovation Research (SBIR) Program</li> </ul> To get information about these programs and others, please visit the<a href="http://www.nsf.gov/funding/pgm_list.jsp?type=xcut">cross-cutting and NSF-wide active funding opportunities</a>search page. NSF's mission calls for the broadening of opportunities for and expanding participation of groups, institutions and geographic regions that are underrepresented in STEM disciplines, which is essential to the health and vitality of science and engineering. NSF is committed to this principle of diversity and deems it central to the programs, projects and activities it considers and supports. NSF is also committed to public access to publications and data, unless there are countervailing interests that prohibit or limit public access to data, including matters of personally identifiable information of research participants, privacy or other issues of vulnerability such as economic, social or other security interests, etc.). See<a href="https://www.nsf.gov/news/special_reports/public_access/">Public Access to Results of NSF-Funded Research</a>and<a href="https://www.nsf.gov/sbe/DMP/SBE_DataMgmtPlanPolicy_RevisedApril2018.pdf">Data Management for NSF SBE Directorate Proposals and Awards</a> for more information.