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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.

NHLBI - National Heart Lung and Blood Institute

Duchenne muscular dystrophy (DMD) is a rare X-linked genetic disorder affecting 1 in 3,500 male births worldwide. In DMD, cardiomyopathies are highly prevalent and the leading cause of death in the disease. DMDassociated cardiomyopathies include myocardial fibrosis and dilated cardiomyopathy that subsequently results in heart failure. Corticosteroids may increase the life expectancy of a DMD patient until the age of 30 by postponing heart failure, but more than 25% of DMD patients are unable to be treated with corticosteroids due to side effects or lack of response. To date, there are no specific treatments available for myocardial fibrosis and dilated cardiomyopathy in DMD. This proposal for the NHLBI Catalyze (R61/R33) will build on promising preliminary studies by Greenstone Biosciences to advance drug discovery for myocardial fibrosis in two phases. The R61 Phase will be to (i) perform unbiased proteomics to elucidate pathogenic crosstalk in DMD induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and cardiac fibroblasts (iPSC-FBs) as alternative testing models to identify drug targets, (ii) utilize artificial intelligence (AI) with molecular docking and molecular dynamics simulations to computationally screen a large library of compounds that bind to the drug target, (iii) apply a new generative AI SyntheMol to generate novel and easily synthesizable compounds out of a chemical space of ~30 billion molecules, and (iv) perform a drug screen using bioactive compound library that includes different nutritional and dietary supplements using DMD iPSCs that may prevent cardiac fibrosis. The R33 Phase will be to (v) synthesize and evaluate compounds to characterize physicochemical properties, including lipophilicity, pKa, and solubility, (vi) perform validation and replication studies to confirm the safety and efficacy of drug candidates identified from AI/ML and small molecule drug screen using DMD iPSCderived cardiac organoids for the prevention of myofibroblast activation, and (vii) evaluate the safety and efficacy in vivo using DMD mouse model (D2-mdx) along with an assessment of initial pharmacokinetic parameters for absorption, distribution, metabolism, excretion, and toxicity (ADMET). The successful outcome of this proposal will advance a drug candidate for cardiac fibrosis into the next stages of preclinical studies, including Investigational New Drug (IND) enabling studies and ultimately into clinical trials to address an unmet need for DMD patients. This drug would also be anticipated to be broadly applicable to dilated cardiomyopathies and other diseases with prevalent myocardial fibrosis. In doing so, our approach utilizes in silico (i.e., AI) and in vitro (i.e., iPSCs) approaches as New Alternative Methods (NAMs) and testing models, which will advance the replacement, reduction, and refinement of animal studies and clinical trials, especially to address urgent health needs and chronic health issues that affect many Americans, such as chronic childhood diseases like DMD.

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.

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 societies, institutions, groups and demography 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 broader impacts. 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: ADVANCE: Increasing the Participation and Advancement of Women in Academic Science and Engineering Careers Faculty Early Career Development (CAREER) Program Graduate Research Fellowship Program (GRFP) Major Research Instrumentation (MRI) Program Mid-scale Research Infrastructure Programs SBE Postdoctoral Research Fellowships (SPRF) Research Experiences for Undergraduates (REU) Research at Undergraduate Institutions (RUI) Small Business Innovation Research (SBIR) Program To get information about these programs and others, please visit thecross-cutting and NSF-wide active funding opportunitiessearch 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.). SeePublic Access to Results of NSF-Funded ResearchandData Management for NSF SBE Directorate Proposals and Awards for more information.

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.

NIGMS - National Institute of General Medical Sciences

Project Summary Growing evidence suggests that stem cells are crucial to the success and transmission of many helminths. As helminths cause a wide variety of symptoms from intestinal distress and lethargy to organ failure, seizures and even death, discoveries in helminth biology have the potential to lessen human and animal suffering. Tapeworms have enormous capacity to grow, regenerate and reproduce in a stem cell-dependent manner, but pathologically significant tapeworm species are extremely difficult to study in the laboratory. We have performed foundational work on establishing Hymenolepis diminuta (rat tapeworm) into a tractable and modern model organism. Our long-term goal is to use H. diminuta to elucidate the molecular regulation of stem cells with potential application to helminths in general. Previous work shows that H. diminuta is a prolific regenerator, but the ability to regenerate is confined to the most anterior tissue of the neck/germinative region (GR). As tapeworms can regenerate fully reproductive structures from this tissue, fundamental somatic and germline fate transitions must occur here. Intriguingly, we find that a known reproductive regulator in flatworms: nonribosomal peptide synthetase (nrps) is strongly expressed in a spatially distinct region toward the anterior GR. Together, these observations suggest that there is a level of spatial regulation of stem cells that we can leverage. Our central hypothesis is that heterogeneous stem cell subpopulations and their niches are spatially restricted in the GR of H. diminuta. We propose to describe the distribution of stem cell subpopulations within the GR and perform functional studies to ascertain how these subpopulation states/types are determined. Our work is innovative because it exploits biological features of H. diminuta in combination with state-of-the-art methods in spatial transcriptomics and cell transplantations to functionally interrogate this parasite in ways that are near impossible in other tapeworms. We will test our hypothesis using three specific aims: Aim 1) Identify spatially distinct subpopulations of somatic and germline stem cells, Aim 2) Functionally determine stem cell hierarchies in the regeneration- competent GR and Aim 3) Explore nrps+ cells as a putative stem cell/germ cell niche. The expected outcome is that we will successfully determine somatic, germline and potentially pluripotent stem cell states that are spatially segregated within the GR. We will also determine if nrps serves as a bona fide stem cell or germ cell niche. Our proposal is significant because the gaps in our knowledge of how all important soma-germline stem cell transitions are regulated means that we are blind to potential vulnerabilities of these parasite or points of robustness for their success. Elucidating these mechanisms will strengthen our arsenal to target parasitic helminths.

NIGMS - National Institute of General Medical Sciences

Spatiotemporal Regulation of DNA Metabolism Pathways PROJECT SUMMARY/ABSTRACT Myriad DNA lesions occur continuously, and they necessitate distinct DNA damage repair mechanisms for removal. DNA double stranded breaks (DSBs) are potentially deleterious lesions that can trigger extensive loss of genetic information, chromosome fusions, and other gross chromosome rearrangements. DSBs are repaired mostly by homology-driven (Homologous Recombination: HR) or homology-independent (Non-Homologous End Joining, NHEJ) mechanisms. The choice of the repair pathway is dictated by the cell cycle phase, with HR being the more accurate (conservative) mechanism. Pathologies, such as meiotic defects and infertility, developmental syndromes, and cancer could stem from defects in HR. In addition to their involvement in DSB repair, many HR proteins fulfill key roles in the resolution of stalled replication forks or difficult-to-replicate DNA structures such as centromeres, telomeres, or DNA-RNA hybrids (R-loops). Importantly, HR proteins must be selectively activated to only perform repair functions at DNA lesions and differentially regulated to fulfill their crucial functions at other DNA structures such as stalled or collapsed replication forks. Timely activation/deactivation of HR proteins is thus a pre-requisite for maintaining genomic stability and avoidance of pathologies. There is a major gap of knowledge in understanding how the activity of HR proteins is dampened at DNA structures that resemble DNA lesions but activated at pathological structures, and how they fulfill unique roles at DNA breaks and replication forks. We postulate that phosphorylation and dephosphorylation of tyrosine residues, an under-studied subject as compared to serine/threonine modifications, contribute to the dynamic regulation of HR proteins. In our effort to fill this crucial knowledge gap, we have provided compelling evidence that EYA4, a dual activity protein phosphatase, acts on key HR and NHEJ factors to exert seminal impact on DNA repair efficiency and pathway choice. Over the past several years, we have devised biochemical procedures for the expression and purification of EYA4, and have identified RAD51 and 53BP1, central components of HR and NHEJ, respectively, as substrates of this poorly characterized protein phosphatase. We have made considerable progress in delineating the contributions of key phospho-residues in RAD51 to its role in HR, and in 53BP1 to NHEJ. We will now conduct mechanistic studies to understand the cellular regulation of EYA4, and whether its role in DNA repair pathway choice impacts the preservation of stressed and damaged replication forks and affects the maintenance of telomeres.

National Institutes of Health

Through this funding opportunity announcement (FOA), the National Cancer Institute (NCI) invites applications for P50 Research Center Grants for Specialized Programs of Research Excellence (SPORE). The program will fund P50 SPORE grants to support state-of-the-art investigator-initiated translational research that will contribute to improved prevention, early detection, diagnosis, and treatment of an organ-specific cancer or a highly related group of cancers. For the purpose of this FOA, a group of highly related cancers are those that are derived from the same organ system, such as gastrointestinal, neuroendocrine, head and neck, and other cancers. Other programmatically appropriate groups of cancers may include those centered around a common biological mechanism critical for promoting tumorigenesis and/or cancer progression in organ sites that belong to different organ systems. For example, a SPORE may focus on cancers caused by the same infectious agent or cancers promoted and sustained by dysregulation of a common signaling pathway. In addition, a SPORE may focus on cross-cutting themes such as pediatric cancers or cancer health disparities. The research supported through this program must be translational and must stem from research on human biology using cellular, molecular, structural, biochemical, and/or genetic experimental approaches. SPORE projects must have the goal of reaching a translational human endpoint within the project period of the grant.

National Institutes of Health

Through this funding opportunity announcement (FOA), the National Cancer Institute (NCI) invites applications for P50 Research Center Grants for Specialized Programs of Research Excellence (SPORE). The program will fund P50 SPORE grants to support state-of-the-art investigator-initiated translational research that will contribute to improved prevention, early detection, diagnosis, and treatment of an organ-specific cancer or a highly related group of cancers. For the purpose of this FOA, a group of highly related cancers are those that are derived from the same organ system, such as gastrointestinal, neuroendocrine, head and neck, and other cancers. Other programmatically appropriate groups of cancers may include those centered around a common biological mechanism critical for promoting tumorigenesis and/or cancer progression in organ sites that belong to different organ systems. For example, a SPORE may focus on cancers caused by the same infectious agent or cancers promoted and sustained by dysregulation of a common signaling pathway. In addition, a SPORE may focus on cross-cutting themes such as pediatric cancers or cancer health disparities. The research supported through this program must be translational and must stem from research on human biology using cellular, molecular, structural, biochemical, and/or genetic experimental approaches. SPORE projects must have the goal of reaching a translational human endpoint within the project period of the grant.

National Institutes of Health

Through this Notice of Funding Opportunity (NOFO), the National Cancer Institute (NCI) invites applications for P50 Research Center Grants for Specialized Programs of Research Excellence (SPORE). This is a re-issuance of PAR-23-284. The program will fund P50 SPORE grants to support state-of-the-art investigator-initiated translational research that will contribute to improved prevention, early detection, diagnosis, and treatment of an organ-specific cancer or a highly related group of cancers. For the purpose of this NOFO, a group of highly related cancers are those that are derived from the same organ system, such as gastrointestinal, neuroendocrine, head and neck, and other cancers. Other programmatically appropriate groups of cancers may include those centered around a common biological mechanism critical for promoting tumorigenesis and/or cancer progression in organ sites that belong to different organ systems. For example, a SPORE may focus on cancers caused by the same infectious agent or cancers promoted and sustained by dysregulation of a common signaling pathway. In addition, a SPORE may focus on cross-cutting themes such as pediatric cancers or epigenetics. The research supported through this program must be translational and must stem from research on human biology using cellular, molecular, structural, biochemical, and/or genetic experimental approaches. SPORE projects must have the goal of reaching a translational human endpoint within the project period of the grant.

National Institutes of Health

<p>Through this Notice of Funding Opportunity (NOFO), the National Cancer Institute (NCI) invites applications for P50 Research Center Grants for Specialized Programs of Research Excellence (SPORE). This is a re-issuance of <a href="https://grants.nih.gov/grants/guide/pa-files/PAR-23-284.html">PAR-23-284</a>. The program will fund P50 SPORE grants to support state-of-the-art investigator-initiated translational research that will contribute to improved prevention, early detection, diagnosis, and treatment of an organ-specific cancer or a highly related group of cancers. For the purpose of this NOFO, a group of highly related cancers are those that are derived from the same organ system, such as gastrointestinal, neuroendocrine, head and neck, and other cancers. Other programmatically appropriate groups of cancers may include those centered around a common biological mechanism critical for promoting tumorigenesis and/or cancer progression in organ sites that belong to different organ systems. For example, a SPORE may focus on cancers caused by the same infectious agent or cancers promoted and sustained by dysregulation of a common signaling pathway. In addition, a SPORE may focus on cross-cutting themes such as pediatric cancers or epigenetics. The research supported through this program must be translational and must stem from research on human biology using cellular, molecular, structural, biochemical, and/or genetic experimental approaches. SPORE projects must have the goal of reaching a translational human endpoint within the project period of the grant.</p>

NIAID - National Institute of Allergy and Infectious Diseases

ABSTRACT Type 1 diabetes is an autoimmune disease where the immune system mistakenly attacks and destroys insulin-producing beta cells in the pancreas. Our research has discovered unique hybrid molecules, called Hybrid Insulin Peptides (HIPs), that form in beta cells when fragments of insulin fuse with other protein fragments. Various HIPs contributing to disease in humans and mice are generated by an enzyme called Cathepsin D and serve as key targets for the immune system’s attack on beta cells. Interestingly, while HIPs are consistently detectable in laboratory mice used to study diabetes, they are harder to detect in human tissue samples even when analyzing larger amounts. We discovered this difference stems from how HIPs are made: the human version of Cathepsin D requires more acidic conditions to function compared to the mouse version. This could explain why human and mouse diabetes look different under the microscope - mice show widespread inflammation throughout the pancreas, while humans show more localized damage. To better understand how HIPs form in human disease, we propose to create a new mouse model where we replace the mouse version of Cathepsin D with the human version. We expect these “humanized” mice will form HIPs less readily, similar to humans. This model will help us understand how environmental factors influence HIP formation and disease development, potentially identifying new ways to prevent or treat type 1 diabetes. This research could reveal important insights into why type 1 diabetes develops and how environmental factors might influence disease progression through their effects on HIP formation, potentially leading to more effective prevention strategies.

OD - NIH Office of the Director

Vesicating (blister-forming) chemical-threat agents such as sulfur mustard (SM) or mustard gas, nitrogen mustard (NM), lewisite, and phosgene oxime can cause moderate to severe injuries and pain to the skin, eyes, and lungs. SM and NM are highly reactive bifunctional alkylating agents that can covalently modify all major cellular biomolecules, such as DNA, proteins, and lipids; thus, they are highly toxic. The eyes are particularly vulnerable to vesicant injuries, which cause a biphasic pathology of an acute response of photophobia, corneal erosions and inflammation, and chronic or late effects with significant deterioration of corneal structure and function from neovascularization, epithelial defects, fibrosis, and opacity. No therapeutic drugs are available as Medical Countermeasures (MCMs) for vesicant damage to the eye, eyelid or other organs. The major obstacle in developing potential MCMs is our limited understanding of the complex pathophysiological response of the eye after vesicant exposure. In this application, we propose to test the hypothesis that vesicating ocular injury pathology involves bioactive sphingolipid (SPL) pathways for acute and chronic inflammation and subsequent cornea, conjunctiva, and eyelid damage, causing significant vision impairment and dry-eye symptoms. In preliminary studies, we developed and characterized an NM-induced ocular surface injury (NMOSI) in mice, exposing the entire ocular surface to NM instead of only the cornea. We observed a severe acute inflammatory response that resolves in a month and cause damage to the cornea, atrophied eyelid glands, almost complete loss of vision, and apparent dry-eye symptoms. We found increased activity of acid sphingomyelinase, concurrent reduction in the sphingomyelin, and increased ceramides, suggesting sphingomyelinase activation in ocular surface tissue at three days post-exposure. Here, we propose to characterize NMOSI models in mice and rabbits, focusing on conjunctival goblet cells and epithelial stem cells and how NM affects the eyelids and their glands and causes dry-eye symptoms (SA #1). We will determine the temporal and spatial relationship of NM to SPL pathway for acute toxicity in ocular surface tissue of mice and rabbits separately from the cornea, conjunctiva-sclera, and eyelids at different time points (SA #2). It is unknown whether NM or SM-induced SPL pathways are overlapping. Hence, we propose to study if the NM- induced SPL pathway activation is similar to SM exposure (SA #3). Lastly, we plan to map out the pathway of SPL activation and lipid signaling using in vitro assays with meibomian gland epithelial and corneal cell lines (SA #4). We expect to identify novel associations of bioactive lipids in the inflammatory and wound-healing pathways of vesicating ocular injury, which will aid in improving our understanding of pathophysiological mechanisms of the injury and aid in developing potential MCMs in the future.

NCI - National Cancer Institute

Despite tremendous advances in cancer detection, diagnosis and treatment, many gaps remain, and cancer continues to be a chronic disease and the second leading cause of death in the US. To further advance the health and longevity of all Americans, it is of paramount importance to train the next generation of biomedical scientists by providing the high-quality research experiences and mentorship. Studies suggest that undergraduate research experiences can support trainee career development to pursue research careers.  The goal of this new R25 program, Stanford’s Cancer Research Education Program (SCREP) is to provide necessary research experiences to undergraduate trainees enabling them to persist in STEM fields by cultivating a scientific identity by building their confidence in their ability to succeed in cancer research setting.  SCREP will provide undergraduate trainees with the opportunity to actively engage in cancer relevant research within the stellar scientific and educational environment at Stanford University and the mentors from the Stanford Cancer Institute (SCI). The SCREP is a fully funded 10-week summer cancer research program, during which undergraduate trainees will work in cancer laboratories of the SCI and receive training in a wide range of cancer research concepts and techniques combined with curated programming that includes career and research seminars, skill building workshops and social events to complement the research components of the program. Trainees will be provided with a multi-layered supportive ecosystem where Mentors, Program Administrator and a Peer Mentor will provide individualized support. Another layer of support will be provided through leveraging existing Stanford University Resources and career enhancement partnership programs to ensure trainees continue their profession growth. This supportive ecosystem that SCREP provides is intended to help undergraduates trainees cultivate a scientific identity by building their confidence in their ability to succeed in cancer research setting. Together, SCREP will create research and career development opportunities for all undergraduates to explore, experience and pursue cancer research and careers in medicine. SCREP’s impact and effectiveness will be measured longitudinally by tracking trainees’ persistence in STEM, level of confidence in their abilities, and educational and career trajectories post program. The program ultimately supports the National Cancer Plan to develop future biomedical scientists in cancer research and clinical care workforce.

National Park Service

In cooperation with the University of Georgia, this project supports the development of statistically sound long-term natural resource monitoring, including sampling designs and data analysis approaches, to ensure that recommendations stemming from the monitoring are based on statistically sound analyses that support management needs.

Kids and Paper

Kids and Paper has served children ages 5-12 with afterschool and summer program through homework help, SEL development through creative arts, healthy meals, and recreational activities at Magnuson Community Center, located at 7110 62nd Ave NE Seattle, WA. We are now looking to expand our educational impact by adding a new element to our program, specific STEM focused activities and tutoring that expose children to topics and hands-on learning. This will help students connect what they are learning with real-world applications. We will offer the new STEM program through the summer of 2023 and anticipate closing this project on September 30, 2023.

Xbot Robotics

Xbot Robotics will organize a series of free STEM robotics workshops for youth. They will be held from fall 2017 to spring 2018 at the Beacon Hill Library located at 2821 Beacon Avenue S. Recruitment for the workshops will be targeted towards youth who may lack access to STEM activities and robotic kits at home or in their communities.

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

PROJECT SUMMARY The Stem Cell & Developmental Biology Early Career Symposium, jointly organized by the Society for Developmental Biology (SDB), the International Society for Stem Cell Research (ISSCR) and the Allen Institute, aims to catalyze scientific exchange and professional development at a pivotal moment for the fields of developmental and stem cell biology. Stem cell research increasingly depends on developmental principles to understand cell behavior in complex, three-dimensional environments, while developmental biology has rapidly incorporated organoid, stem-cell–based, and reprogramming technologies to model development and disease in vitro. These converging trajectories present unprecedented opportunities to uncover the molecular, cellular, and biophysical mechanisms underlying embryogenesis, morphogenesis, tissue regeneration, and human disease. This in-person symposium will be held September 23–25, 2026, at the Allen Institute in Seattle, WA. Designed as an intimate, highly interactive forum of approximately 150 participants, the meeting elevates early-career scientists at a formative stage of their careers and provides meaningful opportunities for scientific visibility, leadership, and community building. This symposium is the first of its kind: a scientific meeting created, led, and shaped primarily by early-career investigators. Its trainee-centered design ensures that emerging scientists lead discussions and set the intellectual direction. At the same time, senior investigators and society leaders actively participate in planning and remain engaged throughout the symposium, enriching, but not overshadowing, the meeting by providing perspective, mentorship, and continuity with broader community efforts. The scientific sessions of the symposium are organized around four conceptual themes that cut across organisms, technologies, and research communities: Data Analysis Across Scales, Model Systems and the Organism, Spatial Awareness, and Cell Fates and Traits. Each session features four invited talks and two trainee talks selected from submitted abstracts, with ample time for discussion to promote deep, cross- disciplinary dialogue. Workshops on career development and emerging technologies, together with a strategic working session focused on future directions and workforce needs, further strengthen the program. Overall, the symposium will deliver high-quality science, foster interdisciplinary collaboration, and provide essential leadership and professional development opportunities.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY This investigator’s proposal describes a 5-year project of vertebral body derived mesenchymal stem cells within a Thread Reinforced Encapsulation Device (THRED) to treat the acute and long-term effects of mesenteric ischemia. The proposal evaluates intestinal organ recovery after treatment with cellular therapy and evaluates the metabolic and cellular host responses to massive surgical small bowel resection. The proposal provides basic and translational applications of emerging technologies relevant to the surgical treatment of intestinal ischemia. Investigators hypothesize that H2S is a critical component of VB-MSC mediated intestinal protection during mesenteric ischemia treatment, and that encapsulated MSCs can provide a stable source of H2S via an implantable, retrievable delivery system. They have developed a novel mouse with a mutation to test their hypothesis that VB-MSCs release hydrogen sulfide that then reacts at Cysteine440 on eNOS to bring about improved mesenteric blood flow. Through additional models, they investigate how VB-MSCs can be safely delivered within an implantable, retrievable, nanoporous device that allows cells to release their beneficial paracrine mediators while protecting them from host immune deletion. They propose three Specific Aims: 1) Develop a novel cellular delivery system to effectively deploy hydrogen sulfide from VB-MSCs in mesenteric ischemia, 2) Evaluate the interaction of THRED packaged VB-MSCs, H2S, and Nitric Oxide (NO) on chronic mesenteric vasodilation and long-term intestinal adaptation, and 3) Deploy THRED packaged VB-MSCs in a porcine model of mesenteric ischemia as final preclinical testing of scalability and effectiveness. The investigator is a pediatric surgeon scientist who completed his K08 funding through the NIDDK and was previously awarded an Early Stage Investigator R01 through the NIDDK. His career goals are to use this R01 to develop novel therapies and diagnostic tools for intestinal ischemia. He has collaborated with Dr. Minglin Ma at Cornell University who has extensive experience with implantable devices. Dr. Ma’s group has invented the THRED device, which is an electrospun nanoporous membrane that allows stem cells to interact with their local environment, while also containing them in a specific anatomical location and protecting them from immune destruction. Dr. Markel has also collaborated with Dr Tim Lescun, a large animal veterinarian at Purdue University which is approximately 45 minutes away from Dr. Markel’s institution. Additional collaborators include Dr. Erik Woods from Ossium Health, who will supply the VB-MSCs. In summary, this research aims to understand the mechanism that VB-MSCs use to provide acute and chronic protection in mesenteric ischemia. It also looks to identify appropriate delivery strategies so that cells can be delivered in an implantable, retrievable device for therapeutic use. The proposal is highly innovative and the investigator has the appropriate support, collaborations, and infrastructure in place to carry out the study.