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NIGMS - National Institute of General Medical Sciences

Project Summary My laboratory investigates epigenetic mechanisms in health and disease. In 1R01GM141349-01A1, we proposed to investigate the mechanisms by which the E3-ligase RING1B, a core member of the Polycomb Repressive Complex 1 (PRC1), positively regulates the expression of oncogenic pathways in breast cancer. In 1R01GM146409-01, we proposed to study how the epigenome is remodeled, and genome instability is regulated, by the loss of H3K36me and Polycomb complexes (PRC1/2) in head and neck squamous cell carcinoma (HNSCC). By converting both R01s to a MIRA-R35 under the unifying umbrella of “Non-canonical functions of Polycomb complexes,” we intend to continue working on the aims we proposed in both grants and expand our research program. New research programs include to determine the role of the RING1B paralog RING1A in gene regulation in breast cancer (both in the settings of sensitive and resistance to current therapies) and the identification and characterization of the first set of non-histone substrates of RING1A and RING1B. To address these questions, we will use multiple model systems including new and established breast and HNSCC cellular models, knock-in (KI) and knock-out (KO) cell lines, patient-derived organoids (PDO), xenografts (PDX), and orthotopic xenograft models, biochemistry and mass spectrometry assays. These efforts aim to unravel novel epigenetic mechanisms deregulated in cancer to develop novel targeted therapeutic strategies, encompassing potential combinations with anti-epigenetic compounds. We also propose another original research program aiming to decode the role of novel de novo missense mutations on PRC1 genes that drive neurodevelopmental disorders. This is particularly significant because the prevalence of neurodevelopmental disabilities in children has risen sharply in recent years, while their underlying causes remain largely unknown and insufficiently studied. To address this, we generated the first set of mouse models, along with human and mouse embryonic stem cells, engineered to carry PRC1 variants newly identified by us in individuals with neurodevelopmental disorders. Our research into genetic disorders not only will provide clinical insights but also reveal fundamental mechanisms by which chromatin regulates brain development and neuronal networks underlying cognition. Overall, our program will uncover fundamental mechanisms of gene regulation that profoundly influence cell identity, differentiation, and oncogenesis, while paving the way for precision medicine and enhanced interventions for cancer and developmental disabilities.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY The initiating factor for opioid use disorder often stems from comorbid neuropsychiatric conditions including anxiety, depression, and post-traumatic stress disorder. Experience of extreme or traumatic stress is often the underlying factor responsible for these neuropsychiatric conditions and, thus, investigation into the neural mechanisms by which stress impacts the brain is essential for determining the mechanisms responsible for the initiation of substance use disorders. Our preliminary data demonstrates that stress exposure leads to increased cytokine release and heightened activity of the noradrenergic locus coeruleus (LC), a key region responsible for the integration of stress signaling that projects norepinephrine to numerous downstream brain areas. The prelimbic cortex of the medial prefrontal cortex (PrL) is one such region that receives over 90% of its noradrenergic innervation from the LC and plays a major role in drug seeking and reward-related behaviors. Thus, the overall goal of this project is to establish the circuit mechanisms of stress-related norepinephrine release in the PrL and the role of these projections in oral oxycodone seeking behaviors. These experiments will use cutting edge techniques including chemogenetics, in vivo electrophysiology, and fiber photometry with GRAB sensors to monitor neuronal activity and transmitter release across this circuit in response to stress and drug stimuli. Three main experiments have been designed to address the hypothesis that stress-evoked increases in neuroimmune activity in the LC initiate neuronal activation and downstream NE release to mediate stress- induced drug seeking behavior. First, chemogenetic suppression of neuroimmune activity in the LC will be paired with in vivo electrophysiology during stress to monitor the impact of microglial reactivity on neuronal activity within this region (Aim1, K99). The second experiment will utilize GRABNE sensors in the PrL to determine the time-course of norepinephrine release in response to stress cues. These studies will also use adrenergic receptor antagonists microinjected into the PrL during stress-cue reinstatement to determine the mechanisms by which NE is acting in this region to impact drug seeking behaviors (Aim2, K99). The final experiment will use translationally relevant compounds to determine if the reversal of stress-induced neuroimmune reactivity can prevent the deleterious effects observed as a consequence of stress (Aim3, R00). Taken together, these studies will expand our understanding of the circuit mechanisms responsible for stress-related opioid seeking behaviors and determine the therapeutic potential of clinically available pharmaceuticals all while providing extensive training in innovative preclinical techniques. The combined technical training and career development opportunities supported by this application will facilitate further independent projects designed to address unanswered questions regarding the neural mechanisms responsible for opioid use to develop novel treatment targets for comorbid stress and substance use disorders.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

Project Summary The purpose of this ‘A1 Single-Year NIAMS/NCI R13 Research Conference Grant’ is to host the highest impact scientific and mentoring conference on “Bone: Musculoskeletal Tumor Perspectives’ that will bring together translational and clinical investigators from diverse specialties. Musculoskeletal Tumor Society (MSTS) is the primary host organization that will partner with OREF, ORS, AAOS, and JOR. Musculoskeletal Oncology is a distinct hybrid clinical and research field that requires the solution to 3 distinct problems: ‘Diagnosing’ and ‘Treating’ molecular oncogenesis of MSK tissues and ‘Reconstructing’ afflicted tissue structures to restore limb function. Due to underlying oncological pathophysiology and massive skeletal defects, traditional orthopaedic treatments using trauma or arthroplasty disciplines were associated with high rate of complications. Furthermore, no cross-disciplinary research and mentoring endeavors on bone tumors have not been offered. Many bone and osteoclast-associated molecules were discovered from bone diseases and tumors such as the giant cell tumor of bone. The last AAOS-initiated R13 Conference was in 2017. There is a serious issue of discontinuation of clinician scientists and basic scientists who conduct cross-disciplinary research on bone and reconstruction science from a perspective of musculoskeletal tumors. There is an urgent need to host a R13 conference to offer mentorship for emerging investigators and to develop new collaborations. Our innovative meeting format features sessions addressing challenging clinical problems with plenary overview talks by experts on state-of the art techniques (spatial biology, artificial intelligence, novel signaling & targeted therapies, novel skeletal stem cells, RNA/DNA therapeutics, 3D printed custom device, and mixed reality). We will invite junior surgeon-scientists to present their innovative solutions in mentoring sessions where a panel of established investigators will critique proposed strategies and Specific Aims in a live multi-disciplinary “study section”. ESI selection criteria are based on one-page Specific Aims that summarizes clinical barriers, hypothesis-/technology-driven scientific and clinical investigation plans, and specific needs for mentorship. A meet-the-mentors session will be set up to foster multi-disciplinary collaboration among mentors and emerging surgeon-scientists, engineers, and basic scientists. In order to facilitate networking and matching mentors- mentees, the meeting phone Apps and website will list mentors and participants with well-prepared research ideas (Specific Aims) and other scientific abstracts. Two Specific Aims are Aim 1. Innovative Mentorship for Emerging Clinicians and Scientists; and Aim 2. Dissemination of Cross-Disciplinary New Knowledge and Techniques for New Collaborations and Enhanced Patient Care. A stand-alone R13 conference could be ideal but too costly for meeting space rent, audio/visual services, and support for young investigators. The R13 Conference will be strategically held immediately prior to the 50th MSTS Annual Meeting for cost reduction and improved participation from clinicians, scientists, allied health care workers, and industry R&D staffs.

National Energy Technology Laboratory

The U.S. Department of Energy (DOE) National Energy Technology Laboratory (NETL) intends to issue an Administrative and Legal Requirements Document (ALRD) on behalf of the DOE Office of Fossil Energy and Carbon Management (FECM) and in collaboration with U.S. Environmental Protection Agency (EPA), entitled IRA: Mitigating Emissions from Marginal Conventional Wells. NETL anticipates issuing the ALRD in August 2023 with an application availability period of 30 days. The ALRD will be funded by the Clean Air Act (CAA), as amended by the Inflation Reduction Act (IRA). DOE is partnering with EPA to make funds available to States for the purpose of working with operators to voluntarily and permanently plug marginal conventional wells on non-Federal lands, supporting environmental restoration of the well pad, and enhancing industry s and States capacities to monitor methane and other air pollutants from wells. If released, this ALRD is expected to make available up to $350 million for financial assistance in the form of grants to States via a formula. Note: The revised Notice of Intent (NOI) document (stemming from synopsis/version 5) can be found under the RELATED DOCUMENTS tab.

National Institutes of Health

The purpose of this funding opportunity announcement (FOA) is to encourage the submission of applications for research to enhance animal stem cells as model biological systems. Innovative approaches to isolate, characterize and identify toti-potent and multi-potent stem cells from nonhuman biomedical research animal models, as well as to generate reagents and techniques to characterize and separate those stem cells from other cell types is encouraged. Studies involving human subjects are not allowed under this FOA. Because the nature and scope of the proposed research may vary from application to application, it is anticipated that the size and duration of each award may also vary. The total amount awarded and the number of awards will depend upon the numbers, quality, duration, and costs of the applications received. Mechanism of Support. This FOA will use the NIH Exploratory/Developmental (R21) grant mechanism and runs in parallel with a FOA of identical scientific scope, PA-07-303, that solicits applications under the R01 grant mechanism. Funds Available and Anticipated Number of Awards. Awards issued under this FOA are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications. Budget and Project Period: The total project period for an application submitted in response to this funding opportunity may not exceed two years. Direct costs are limited to $275,000 over an R21 two-year period, with no more than $200,000 in direct costs allowed in any single year.The R21 is not renewable. Eligible Organizations: Public/State Controlled Institution of Higher Education; Private Institution of Higher Education; Hispanic-serving Institution; Historically Black Colleges and Universities (HBCUs); Tribally Controlled Colleges and Universities (TCCUs); Alaska Native and Native Hawaiian Serving Institutions; Nonprofit with 501(c)(3) IRS Status (Other than Institution of Higher Education); Nonprofit without 501(c)(3) IRS Status (Other than Institution of Higher Education); Non-domestic (non-U.S.) Entity (Foreign Organization); Small Business; For-Profit Organization (Other than Small Business).

Food and Drug Administration

<p>The purpose of this program is to support new approaches that can be applied to facilitate therapeutic development in ultra-rare pediatric and adult cancers, including molecularly-defined subsets of more common cancers.&nbsp;</p><p><br></p><p>Specific areas of interest include, but are not limited to, the following examples:</p><p>• Development of infrastructure for a coordination network and data repository for patient-level data across institutions and internationally to support drug development and regulatory decision-making for one or more ultra-rare cancers.</p><p>• Investigations to explore opportunities to develop and validate early clinical endpoints and other novel efficacy endpoints for evaluation of treatments for ultra-rare cancers.</p><p>• Development and implementation of a collaborative multi-stakeholder effort to support generation and use of real-world data leveraging a registry framework for use in development of new therapies for pediatric patients with diffuse midline glioma (DMG) (including diffuse intrinsic pontine glioma, DIPG).&nbsp;</p><p>• Innovative approaches to identify new biologically-driven opportunities for clinical development of previously approved drugs or biologics (hereafter referred to as drugs), including drugs for which development has been discontinued, in ultra-rare cancers.</p><p>• Research to develop novel approaches to preserve the availability of drugs for which commercial developers have discontinued adult development that have strong potential in ultra-rare cancers but lack financial incentives for commercial development</p><p>• Development of methods to incorporate use of telemedicine and/or pragmatic trial design elements&nbsp;(e.g., collecting laboratory and/or imaging data from local facilities) for patient assessments to facilitate enrollment of patients with ultra-rare cancers</p><p>• Development of nanoparticle-based delivery approaches for therapeutic nucleic acids targeting onco-fusion transcription factors in metastatic tumor animal models using targeted bioPROTAC degradation or genomic editing strategies. Successful efforts should demonstrate effective delivery and expression in-vivo to tumor cells, and downregulation of the target transcription factor protein while minimizing off-target effects and limiting sequestration of the nanoparticle by the liver, spleen, and lungs.</p><p>• Research to exhaustively characterize the plasma-membrane protein expression (surfaceome) of an ultra-rare cancer and the presumed healthy tissue of origin, as well as the resident-tissue stem cells, by single-cell transcriptomics and proteomics. These studies, and available correlative database analyses, should be designed to identify possible combinatorial signatures of plasma membrane proteins unique to the ultra-rare tumor. Tumors of interest include Sclerosing epithelioid fibrosarcoma and atypical teratoid rhabdoid tumors (ATRT).</p><p><br></p>

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Summary Obesity is characterized by visceral fat accrual and lipid spillover to liver and heart, driven largely by systemic insulin resistance. Key drivers of obesity are excessive feeding and reduced energy expenditure. Consequently, understanding the mechanisms that control feeding and/or energy expenditure will help develop strategies to combat obesity and metabolic diseases. At the whole organismal level, the central nervous system (CNS), in particular the hypothalamus and hindbrain, sense signals of nutrient availability and coordinate energy metabolism. While cell-types in the arcuate and their functions are well-characterized, how different cell-types and neuronal populations in the paraventricular nucleus of the hypothalamus (PVH), a deep-seated region in the hypothalamus, coordinate peripheral energy metabolism remains poorly studied. In particular, it is unclear how the PVH integrates physiological nutrient-related cues to control peripheral energy and lipid metabolism, and how these processes are disrupted to cause obesity and insulin resistance. My studies using brain-wide imaging of c-Fos, a defined neuron activation marker, revealed that dietary triglycerides administered via an oral gavage activates diverse regions across the brain, with greatest activation in discrete regions of the hypothalamus, including the PVH. Comparative bulk-RNA sequencing of multiple regions with the greatest response to lipids revealed Zinc Finger and BTB Domain Containing 16, a transcription factor required for stem cell maintenance and cell differentiation, as a key ubiquitously upregulated gene in response to corn oil gavage, including the PVH. Based on hypothalamic single-nuclei RNA sequencing, and PVH spatial transcriptomics, we reveal that this lipid-driven induction of ZBTB16 expression occurs in a small cluster of a poorly-characterized PVH neurons. On this basis, I hypothesize that these lipid-responsive PVH neurons play a role in regulating systemic lipid metabolism. Consistently, my preliminary studies in a small group of mice revealed that deletion of ZBTB16 in these PVH neurons leads to weight gain and adiposity when compared to controls. Taken together, in this K01 Mentored Research Scientist Career Development Award, I will test the hypothesis that lipid-driven induction of ZBTB16 in these novel PVH neurons facilitates energy expenditure in peripheral fat depots and maintains energy balance; and that sustained high fat diet feeding alters the activity of these neurons to cause obesity. I will test this hypothesis via three specific aims: Aim 1 will characterize the changes that occur in these poorly studied PVH neurons as mice transition from lean to obesity states; Aim 2 will determine the role of ZBTB16 in PVH neurons in the pathophysiology of obesity; while Aim 3 will evaluate the effect of stimulation of these PVH neurons on the reversal of obesity phenotypes. I expect that the completion of these studies will not only reveal novel roles of an uncharacterized neuronal population in combating obesity, but this K01 grant will also serve as a critical mechanism for my career development into an independent neuroscience-focused obesity researcher.

U.S. National Science Foundation

The main goal of the S-STEM program is to enable academically talented, low-income students to pursue successful careers in promising STEM fields. Ultimately, the S-STEM program seeks to increase the number of academically promising low-income students who graduate with an S-STEM eligible degree and contribute to the American innovation economy with their STEM knowledge. Recognizing that financial aid alone cannot increase retention and graduation in STEM, the program provides awards to institutions of higher education (IHEs) not only to fund scholarships, but also to adapt, implement, and study evidence-based curricular and co-curricular[a] activities that have been shown to be effective in supporting recruitment, retention, transfer (if appropriate), student success, academic/career pathways, and graduation in STEM. To be eligible, scholars must be domestic low-income students with academic ability, talent, or potential and demonstrated unmet financial need who are enrolled in an associate, baccalaureate, or graduate degree program in an S-STEM eligible discipline. Proposers must provide an analysis that articulates the characteristics and academic needs of the population of students they are trying to serve. NSF is particularly interested in supporting the attainment of degrees in fields identified as critical needs for the Nation. It is up to the proposer to make a compelling case that such a field serves a critical need in the United States. [a] an activity at a school or college pursued in addition to the normal course of study. S-STEM Eligible Degree Programs Associate of Arts, Associate of Science, Associate of Engineering, and Associate of Applied Science Bachelor of Arts, Bachelor of Science, Bachelor of Engineering and Bachelor of Applied Science Master of Arts, Master of Science, and Master of Engineering Doctoral (Ph.D. or other comparable doctoral degree) S-STEM Eligible Disciplines Disciplinary fields in which research is funded by NSF, including technology fields associated with the S-STEM-eligible disciplines (e.g., biotechnology, chemical technology, engineering technology, information technology, etc.). The following degrees and disciplines areexcluded: Clinical degree programs, including medical degrees, nursing, veterinary medicine, pharmacy, physical therapy, and others not funded by NSF, are ineligible degrees. Programs for STEM teacher certification or licensure currently covered by the Robert Noyce Teacher Scholarship program (NOYCE) are ineligible for S-STEM funding. Business school programs that lead to Bachelor of Arts or Science in Business Administration degrees (BABA/BSBA/BBA) are not eligible for S-STEM funding. Masters and Doctoral degrees in Business Administration are also excluded. Proposers are strongly encouraged to contact Program Officers before submitting a proposal if they have questions concerning degree or disciplinary eligibility. The S-STEM program particularly encourages proposals from 2-year institutions, predominately undergraduate institutions, and urban, suburban, and rural public institutions.

U.S. National Science Foundation

NSF STEM K-12

U.S. National Science Foundation

The NSF STEM K-12 program in the Division of Research on Learning in Formal and Informal Settings (DRL) in the Directorate for STEM Education (EDU) supports fundamental, applied, and translational research that advances STEM teaching and learning and improves understanding of education across the human lifespan and a range of formal and informal settings.

U.S. National Science Foundation

In 2016, the National Science Foundation (NSF) unveiled a set of Big Ideas, 10 bold, long-term research and process ideas that identify areas for future investment at the frontiers of science and engineering (see https://www.nsf.gov/news/special_reports/big_ideas/index.jsp). The Big Ideas represent unique opportunities to position our Nation at the cutting edge of global science and engineering leadership by bringing together diverse disciplinary perspectives to support convergence research. As such, when responding to this solicitation, even though proposals must be submitted to the Directorate for STEM Education (EDU) / Division of Equity for Excellence in STEM (EES), once received, the proposals will be managed by a cross-disciplinary team of NSF Program Directors. The INCLUDESInitiative is a comprehensive, national effort to enhance U.S. leadership in science, technology, engineering, and mathematics (STEM) discovery and innovation, focused on NSF s commitment to ensuring accessibility and inclusivity in STEM fields, as communicated in the NSF Strategic Plan for Fiscal Years (FY) 2022 - 2026. The vision of the INCLUDES Initiative is to catalyze the STEM enterprise to work collaboratively for inclusive change, resulting in a STEM workforce that reflects the Nation s population. More specifically, the INCLUDES Initiative seeks to motivate and accelerate collaborative infrastructure building to sustain systemic change to broaden participation in STEM fields at scale.Significant advancement of the INCLUDES Initiative's goalswill result in a new generation of STEM talent and leadership to secure the Nation s future and long-term economic competitiveness. With this solicitation, NSF offers support for five types of projects that connect and contribute to the National Network: (1) Design and Development Launch Pilots, (2) Collaborative Change Consortia, (3) Alliances, (4) Network Connectors, and (5) Conferences. The INCLUDES National Network is a multifaceted collaboration of agencies, organizations, and individuals working collectively to broaden participation in STEM. The INCLUDES National Network serves as a testbed for designing, implementing, studying, refining, and scaling collaborative change modelsand is composed of: INCLUDES funded projects Other NSF funded projects Subcommittee on Federal Coordination in STEM Education (FC-STEM) agencies Scholars engaged in broadening participation research and evaluation, and Organizations that support the development of talent from all sectors of society to build an inclusive STEM workforce. All INCLUDES funded projects must operationalize five design elements of collaborative infrastructure - (1) shared vision, (2) partnerships, (3) goals and metrics, (4) leadership and communication, and (5) expansion, sustainability, and scale- to create systemic change that broadens participation in STEM.

Ohio Department of Education and Workforce

STEM education initiative grants for OH to expand science, technology, engineering, and mathematics programs in K-12 and postsecondary institutions.

U.S. Mission to Bangladesh

The U.S. Department of State s Embassy Dhaka announces an open competition to manage and operate the Edward M. Kennedy Center for Public Service. The EMK Center advances U.S. foreign policy and national security objectives by engaging young Bangladeshi professionals, and U.S. exchange alumni in high-impact programs that showcase American excellence in trade, commerce, technology, and education, while promoting U.S. culture and society through strategic campaigns, workshops, and curated events. As part of the global American Spaces network, the EMK Center supports U.S. foreign policy objectives by countering adversarial narratives, engaging U.S. exchange alumni, promoting U.S. innovation, expanding access to English language and professional skills training, and providing EducationUSA advising that significantly contributes to the U.S. economy. In addition, the EMK Center serves as a whole-of-mission platform where the Foreign Commercial Service, Economic Section, and Foreign Agricultural Services collaborate to advance U.S. commercial objectives through joint programming, business engagement, and showcasing American brands. The selected recipient will manage the EMK Center in close partnership with the Embassy s Public Diplomacy Section (PD). Key responsibilities include supervising professional local staff; delivering comprehensive EducationUSA services; designing and implementing programs in STEM, videography, photography, and related fields; maintaining all technology and equipment; and executing a flexible monthly program calendar that sustains strong in-person and virtual participation in EMK, American Spaces Bangladesh network programs, and Embassy-sponsored activities. Eligible ApplicantsThe following organizations are eligible to apply: Not-for-profit organizations, including think tanks and civil society/non-governmental organizations, trust Private educational institutions Public International Organizations For-profit entities, even those that may fall into the categories listed above, are not eligible to apply for this NOFO. Organizations may sub-contract with other entities, but only one, non-profit, non-governmental entity can be the prime recipient of the award. When sub-contracting with other entities, the responsibilities of each entity must be clearly defined in the proposal. For more information on the difference between sub-contract and sub-recipient, please refer to 2 CFR 200.331. Individuals are not eligible to apply for this NOFO

U.S. Mission to Bangladesh

<p>The U.S. <span style="color: black;">Department of State’s Embassy Dhaka announces </span>an open competition to manage and operate the Edward M. Kennedy Center for Public Service.&nbsp;The EMK Center advances U.S. foreign policy and national security objectives by engaging young Bangladeshi professionals, and U.S. exchange alumni in high-impact programs that showcase American excellence in trade, commerce, technology, and education, while promoting U.S. culture and society through strategic campaigns, workshops, and curated events.</p> <p>As part of the global American Spaces network, the EMK Center supports U.S. foreign policy objectives by countering adversarial narratives, engaging U.S. exchange alumni, promoting U.S. innovation, expanding access to English language and professional skills training, and providing EducationUSA advising that significantly contributes to the U.S. economy.&nbsp;In addition, the EMK Center serves as a whole-of-mission platform where the Foreign Commercial Service, Economic Section, and Foreign Agricultural Services collaborate to advance U.S. commercial objectives through joint programming, business engagement, and showcasing American brands.</p> <p>The selected recipient will manage the EMK Center in close partnership with the Embassy’s Public Diplomacy Section (PD). Key responsibilities include supervising professional local staff; delivering comprehensive EducationUSA services; designing and implementing programs in STEM, videography, photography, and related fields; maintaining all technology and equipment; and executing a flexible monthly program calendar that sustains strong in-person and virtual participation in EMK, American Spaces Bangladesh network programs, and Embassy-sponsored activities.&nbsp;&nbsp;</p> <p><strong><em>Eligible Applicants</em></strong><span style="color: black;">The following organizations are eligible to apply</span><em style="color: black;">:</em><em style="color: red;">&nbsp;</em></p> <p><span style="color: black;">●&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Not-for-profit organizations, including think tanks and civil society/non-governmental organizations, trust</span></p> <p><span style="color: black;">●&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Private educational institutions</span></p> <p><span style="color: black;">●&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Public International Organizations</span><em style="color: black;"> </em></p> <p><span style="color: black;">For-profit entities, even those that may fall into the categories listed above, are </span><strong style="color: black;"><u>not</u></strong><span style="color: black;"> eligible to apply for this NOFO.&nbsp;Organizations may sub-contract with other entities, but only one, non-profit, non-governmental entity can be the prime recipient of the award. When sub-contracting with other entities, the responsibilities of each entity must be clearly defined in the proposal. For more information on the difference between sub-contract and sub-recipient, please refer to </span><a href="https://www.ecfr.gov/current/title-2/section-200.331" target="_blank" style="color: black;">2 CFR 200</a><a href="https://www.ecfr.gov/current/title-2/section-200.331" target="_blank" style="color: rgb(70, 120, 134);">.331</a><span style="color: black;">. </span></p> <p><span style="color: black;">Individuals are not eligible to apply for this NOFO</span></p>

NCI - National Cancer Institute

PROJECT SUMMARY Our overall goal is to develop a human bone marrow organoid culture method that sustains both normal and leukemic hematopoiesis. A historic inability to culture hematopoietic stem cells (HSC), progenitors, and leukemic blasts beyond days to weeks has hindered fundamental investigations and therapeutic development for hematopoietic pathologies. Notably, a complex bone marrow microenvironment vitally sustains HSC and their leukemic derivatives, containing diverse endothelium, mesenchymal stem cells and osteoid, and providing an essential niche during homeostasis and neoplasia. Conceivably, prior culture systems have been limited by insufficient recapitulation of the structurally and cellularly complex bone marrow microenvironmental niche. In response, we developed an air-liquid interface (ALI) primary bone marrow organoid (BMO) system for acute myeloid leukemia (AML) that propagates intact fragments of bone marrow, preserving osteoid, vascular, and mesenchymal niche components in native spatial orientations. When generated from normal bone marrow, BMO maintain hematopoietic stem cells (HSC) and expand progenitors for >60 days (longest examined), support erythroid, myeloid (including neutrophils) and megakaryocyte differentiation, while BMO transplantation rescues lethally irradiated mice. When applied to leukemia, ALI BMO allow ex vivo expansion of human AML blasts from intact fragments of PDX or primary human bone marrow biopsies, preserving histology, surface markers and mutations for >60 days (longest examined), and undergo successful in vivo transplantation. Our proposal responds to PAR-22-242: Bioengineering Research Grants (BRG), that requests “promising tools, methods and techniques”, “design-directed research” and “organoids that closely mimic physiological conditions”. To exploit this broadly enabling leukemia organoid method, Aim 1 conducts BMO-based live imaging of the bone marrow microenvironment in AML BMO during homeostasis and drug treatment to obtain spatially and time-resolved insights into interactions between AML blasts and the bone marrow microenvironment and modulation by therapies. Aim 2 pursues AML BMO as a tool to define and functionally test AML microenvironmental paracrine signals that are evaluated by pharmacologic blockade for effects on leukemic blasts. Lastly, Aim 3 develops human leukemic BMO as a drug evaluation platform, creating human AML BMO from transplanted PDX models and patient core biopsies, and multiplexing for drug testing, which is correlated to therapy effects on conventional short-term cultures, PDX and prospective clinical outcomes. Importantly, Aim 3 develops methods to enable non-expert institutions to receive live or cryopreserved AML PDO, and to create these cultures themselves. We pursue these goals via a synergistic team of the Multi-PIs Calvin Kuo and Kathy Sakamoto, and Co-investigator Ravi Majeti, towards developing a primary human AML organoid method that leverages a fully native bone marrow microenvironment, with application to studies of leukemia pathogenesis, therapy and precision medicine, and broad potential extension to hematologic diseases in general.

Pennsylvania Department of Education

STEM education initiative grants for PA to expand science, technology, engineering, and mathematics programs in K-12 and postsecondary institutions.

National Institutes of Health

-Purpose. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), invites applications to understand how endogenous pancreatic beta cells are made by studying pancreatic development, with the goal of making pancreatic islets in culture, to explore the potential of animal or human stem/progenitor cells (embryonic or adult; if human embryonic, only NIH-approved human embryonic stem cell lines may be used) as a source for making pancreatic islets, and to determine the basic mechanisms underlying beta cell regeneration in the adult as a basis for producing new cellular therapies for diabetes. This Funding Opportunity Announcement (FOA) is intended to stimulate the application of advances made in developmental biology, stem cell biology, and diabetes to develop new strategies for diabetes therapy, either through cell replacement or regeneration. This FOA is intended to intensify investigator-initiated research, to attract new investigators to the field, and to encourage interdisciplinary approaches to research in this area. -Mechanism of Support. This FOA will utilize the NIH Research Project Grant (R01) award mechanism. -Funds Available and Anticipated Number of Awards. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. The total amount awarded and the number of awards will depend upon the mechanism numbers, quality, duration, and costs of the applications received.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary/Abstract This proposed research project focuses on understanding the pathogenesis of papillomavirus infection in WHIM syndrome and how one can use the mechanisms to develop curative treatment to alleviate papillomavirus infection in WHIM syndrome. The proposed studies will form the foundation for a future research program that focuses on investigating underlying mechanisms of papillomavirus pathogenesis in WHIM and developing curative treatment for them to alleviate papillomavirus-related malignancies. Research: Mouse papillomavirus (MmuPV1) models high-risk human papillomavirus (HPV) infection and associated cancers in mice. This project will use MmuPV1 and a WHIM mutation knock-in mice to understand keratinocyte-intrinsic mechanism of WHIM mutation contributing to papillomavirus pathogenesis, as well as to test whether reversing leukopenia caused by the mutation will clear infection. To determine if rescuing leukopenia is sufficient to clear pre-existing infection, CRISPER/Cas9 will be used to inactivate WHIM allele in hematopoietic stem cells and test if edited hematopoietic stem cell transfer can cure or slow down papillomavirus-induced disease in infected unconditioned WHIM hosts. MmuPV1 and WHIM mutant mice become powerful pre-clinical disease model for WHIM patients and can provide informative data guiding future clinical testing. In addition to pre-clinical testing, this model will also be used to answer whether there is crosstalk between myeloid cells and lymphoid cells that are contributing to infection clearance. This question has been raised from a reported case of chromothriptic cure of WHIM syndrome where the patient spontaneously cleared warts with only recovered myeloid cell count while remained lymphopenia. It is hypothesized that mutation corrected myeloid cells can interact with lymphoid cells bearing WHIM mutation, recruiting them to infected sites to overcome lymphoid cell shortage to clear viral infection. In addition to immune cells, this project also aims to understand how WHIM mutation contributes to papillomavirus life cycle in infected keratinocytes. This project will use in vitro culture of primary mouse keratinocytes derived from WHIM mice and investigate how WHIM mutation affects newly infected MmuPV1 entry, maintenance and amplification. Drugs targeting affected pathways will be tested in vivo to determine if current approved drug for WHIM syndrome is sufficient to treat papillomavirus-related malignancies. The data generated by proposed studies will provide insights into how current CXCR4 inhibitor works, and help design strategies to cure papillomavirus-related malignancies, which is a significant cause of fatality in WHIM syndrome.

NHLBI - National Heart Lung and Blood Institute

Doxorubicin is a highly effective chemotherapeutic agent used for treating a wide range of malignancies, including breast cancer and pediatric cancers. However, its clinical utility is often limited by life-threatening cardiotoxicity, which can lead to irreversible heart failure. While clinical risk factors such as cumulative dose and age are well-established, individual genetic susceptibility plays a critical role in doxorubicin-induced cardiotoxicity (DIC). Currently, predicting which patients will develop DIC remains challenging. The longterm goal of this project is to identify genetic determinants of DIC to enable precise risk stratification and cardioprotection. During the K99 phase, the Principal Investigator (Pl) successfully established a highthroughput CRISPR interference/activation (CRISPRi/a) screening platform in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). In the R00 independent phase, the Pl will transition from gene-level perturbation to the characterization of specific genetic variants or single nucleotide polymorphisms (SNPs). Specifically, Aim 3 (R00 Phase) will utilize Prime Editing 7 (PE?), a precise genome editing technology, to install a library of 116 clinically implicated genetic variants into human iPSCCMs. This "in vitro GWAS" approach will quantify the functional impact of each variant on cardiomyocyte survival under doxorubicin stress. Top candidate variants will be further validated using high-throughput 3D engineered heart tissues (EHTs) to assess physiological contractility and automated live-cell imaging to determine cytotoxicity kinetics. Finally, these functional biological scores will be integrated with clinical GWAS data to generate Integrated Risk Scores. This research will bridge the gap between clinical genetics and functional biology, establishing a foundation for the personalized prediction and prevention of chemotherapy-induced heart failure.

Parker Hannifin Foundation

Funds STEM education, community vitality, and social services in Parker operating communities.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY/ABSTRACT Urinary tract infections (UTIs) are the second most common infectious disease worldwide, primarily caused by pathogenic bacteria that ascend from the bladder to the kidneys. In severe cases, UTIs can progress to urosepsis, the leading cause of hospital-acquired sepsis, with mortality rates as high as 40%. Understanding the mechanisms that drive UTI pathogenesis, disease progression, and resulting kidney injury is therefore critical. This R21 is based on the emerging role for amyloid-β (Aβ) as a novel innate immune effector that drives deleterious inflammation in the context of bacterial infection. Aβ has been studied almost exclusively in the context of neurocognitive disorders and neuroinflammation, where its aggregation into insoluble plaques is a hallmark of disease. However, a growing body of evidence highlights a role for Aβ as an antimicrobial peptide and pro-inflammatory signal molecule. Our recent findings have shown that intensive care unit (ICU) patients with sepsis have elevated levels of Aβ in their plasma, and that Aβ correlates with outcome severity. Strikingly, a control ICU cohort with no suspicion of infection did not display elevated plasma Aβ levels, indicating a requirement for infection. Moreover, we present new preliminary data indicating that Aβ accumulates in the kidney in a mouse UTI model and is directly correlated with bacterial burden. While published and preliminary data support the idea that Aβ is an antimicrobial peptide, it is unknown as to whether Aβ is capable of transitioning from a host-protective role to a detrimental one during bacterial infection. Our innovative study aims to explore the novel hypothesis that bacterial infection triggers the accumulation of Aβ peptides in the kidney to drive deleterious inflammation and UTI pathophysiology. This is an early conceptual stage project that may lead to a breakthrough in the current understanding of kidney damage in pyelonephritis and urosepsis. Given that treatments to enhance Aβ clearance are already in use for other diseases, our findings may pave the way for novel therapeutic approaches to UTIs, especially in cases that progress to severe kidney involvement. Our discovery that Aβ is elevated in the context of infection and is a potential driver of deleterious inflammation in the kidney is a highly significant conceptual advance with broad impact across the fields of infectious disease and renal biology. Gram-negative cystitis and pyelonephritis are highly prevalent in hospital and community settings, and the most severe cases progress to sepsis, and multi-organ failure. Importantly, survivors often suffer long-term sequelae such as post-intensive care syndrome that reduce overall quality of life. Thus, future studies stemming from the work proposed herein may reveal potentially transformative links between a pathogen-mediated dysfunctional Aβ response and organ dysfunction.

U.S. National Science Foundation

The Directorate for Geosciences (GEO) supports the Pathways into the Geosciences - Earth, Ocean, Polar and Atmospheric Sciences (GEOPAths) funding opportunity. GEOPAths invites proposals that specifically address the current needs and opportunities related to education, learning, training and professional development within the geosciences community through the formation of STEM Learning Ecosystems that engage students in the study of the Earth, its oceans, polar regions and atmosphere. The primary goal of the GEOPAths funding opportunity is to increase the number of students pursuing undergraduate and/or postgraduate degrees through the design and testing of novel approaches that engage students in authentic, career-relevant experiences in geoscience. In order to broaden participation in the geosciences, engaging students from historically excluded groups or from non-geoscience degree programs is a priority.This solicitation features three funding tracks that focus on Geoscience Learning Ecosystems (GLEs): 1. GEOPAths:Informal Networks(IN).Collaborative projects in this track will support geoscience learning and experiences in informal settings for teachers, pre-college (e.g., upper level high school) students, and early undergraduates in the geosciences. 2. GEOPAths:Undergraduate Preparation(UP).Projects in this track will engage pre-college and undergraduate students in extra-curricular experiences and training in the geosciences with a focus on service learning and workplace skill building. 3. GEOPAths:Graduate Opportunities(GO).Projects in this track will improve research and career-related pathways into the geosciences for undergraduate and graduate students through institutional collaborations with a focus on service learning and workplace skill building.

U.S. National Science Foundation

The Pathways to Enable Open-Source Ecosystems (POSE) program aims to harness the power of open-source development for the creation of new technology solutions to problems of national and societal importance. Many NSF-funded projects result in publicly accessible, modifiable, and distributable open-source products, including software, hardware, models, specifications, programming languages, or data platforms that catalyze further innovation. In some cases, an open-source product that shows potential for wide adoption forms the basis for a self-sustaining open-source ecosystem (OSE) that comprises a leadership team; a managing organization with a well-defined governance structure and distributed development model; a cohesive community of external intellectual content developers; and a broad base of users across academia, industry, and/or government. The overarching vision of POSE is that proactive and intentional formation of managing organizations will ensure adoption of open-source products; increased coordination of external intellectual content developer contributions; and a more focused route to technologies with broad societal impact. Toward this end, the POSE program supports the formation of new OSE managing organizations based on anexisting open-source product or class of products, whereby each organization is responsible for the creation and management of processes and infrastructure needed for the efficient and secure development and maintenance of an OSE. POSE constitutes a new pathway to translate scientific innovations, akin to the Lab-to-Market Platform that NSF has pioneered over many decades. Whereas programs like theNSF Innovation Corps (NSF I-Corps )andAmerica s Seed Fund[Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR)]represent an integrated set of programs to provide researchers with the capacity to transform their fundamental research into deep technology ventures, POSE is specifically focused on another translational pathway supporting the transition from open-source research artifacts to OSEs. Importantly, the POSE program isnotintended to fund thedevelopmentof open-source products, including tools and artifacts. The POSE program is alsonotintended to fund existing well-resourced, open-source communities or ecosystems. Instead, the program aims to supportnewmanaging organizations to catalyze distributed, community-driven development and growth ofnewOSEs. The expected outcomes of the POSE program are to grow the community of researchers and innovators who develop and contribute to OSE efforts, and to enable pathways for the safe and secure development of OSEs that have broad societal impacts. OSEs can emerge from any areas of Science, Technology, Engineering, and Mathematics (STEM) research and development. This solicitation seeks two types of proposals, allowing teams to propose specific activities toscope and planthe establishment of an OSE (Phase I), and toestablisha sustainable OSE based on a robust open-source product that shows promise in the ability to both meet an emergent societal or national need and build a community to help develop it (Phase II). Phase I: OSE Scoping and Planning Proposals Phase I projects are for open-source research products with a small community of external users though the product may not necessarily have external content developers. The objectives of Phase I projects are to: (1) enable scoping activities that will inform the transition of promising research products that are already available in open-source formats into sustainable and robust OSEs that will have broad societal impacts, and (2) provide training to teams interested in building such an OSE. Phase I awardees are not obligated to submit Phase II proposals in the future. Phase II: Establishment and Expansion Proposals Phase II projects are for open-source research products with small, existing communities of external usersandexternal content developers. The objective of Phase II projects is to support the transition of a promising open-source product into a sustainable and robust OSE. Phase II proposal teams are expected to have already conducted the scoping activities needed to develop a detailed project plan to support the community-driven distributed development and deployment of successful open-source tools into operational environments (not necessarily via a Phase I award). An NSF POSE Phase I award is not required for the submission of a Phase II proposal.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Suicide is the second leading cause of death among young adults ages 15-241, with rates continuing to rise2. While research has identified some broad predictive factors3, our ability to predict who will experience suicidal thoughts and behaviors (STB) and when these crises will occur remains limited4. This challenge stems from the fact that suicide risk fluctuates dramatically in response to emotional and interpersonal distress5,6, with social threats often acting as precipitating events7,8. The tendency to respond impulsively to negative emotions (e.g., negative urgency9) may help explain why some individuals engage in STB as a maladaptive attempt to escape emotional pain following social threat or rejection. Evidence from neuroscience indicates that social- affective circuitry reflects subjective affective sensitivity to social threat10,11, and overlaps with putative neural correlates of negative urgency12,13, suggesting a potential neural profile that may drive associations between social threat and STB. To test this, I will utilize data from an ongoing R01 including 6 months of ecological momentary assessment (EMA), a personalized peer social feedback fMRI task, and self-report questionnaires from 150 young adults (ages 18-30) with chronic STB to examine how function in social-affective systems and real-world experiences of social threat interact to predict STB. The Specific Aims of this study are to: (1) test associations between negative urgency and STB using both baseline and prospective EMA assessments; (2) investigate associations between functional connectivity of social-affective systems during social threat and trait-level negative urgency; and (3) examine whether individual differences in neural response to social threat moderate same-day relationships between social rejection-generated negative affect and suicidal thoughts. This project, and the associated F31 fellowship at the University of Pittsburgh, will provide critical training for the applicant to become an independent researcher investigating how neural and behavioral responses to social contexts influence suicide risk during key developmental periods. To accomplish the proposed research, this application includes a comprehensive training and mentorship plan that builds on the applicant’s prior clinical psychology and developmental neuroscience training. These Training Goals will focus on expanding the applicant’s knowledge and/or skills in: (1) neurodevelopmental pathways to suicide; (2) negative urgency as a mechanism of suicidal thoughts; (3) task-based fMRI methods, with an emphasis on functional connectivity analyses; and (4) implementing mixed-effects modeling for intensive longitudinal data. These goals will be accomplished through mentorship meetings, workshops, conferences, and coursework with a committed interdisciplinary team. Complemented by support from a dedicated research environment at the University of Pittsburgh, this fellowship will accelerate the applicant’s trajectory toward becoming an independent researcher focused on using multimodal research to identify how individual neurobiology interacts with one’s social environment to create enduring risk for STB.