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NIAID - National Institute of Allergy and Infectious Diseases

Abstract CD8+ T cells are unique in effective sensing and killing of intracellular pathogen-infected cells and tumor cells. Because current vaccines are designed to induce high titer pathogen-specific antibodies for host protection, new vaccines focused on promoting effective memory CD8+ T cells are needed. Since a single naive CD8+ T cell has the potential to give rise to multiple types of progenies, it is essential to understand how naive T cells are primed to form distinct effector and memory cells. It is generally accepted that the strength of cognate antigen (Ag) stimulation determines the size of the primary response and of the memory cell pool, and that strong cognate Ag signals coupled with robust co-stimulation and cytokines altogether drive naive CD8+ T cells towards an effector rather than a memory cell fate. The current dogma also states that cognate Ag stimulation does not lead to functionally distinct subsets of memory CD8+ T cells. In contrast, however, we recently discovered that the strength and the stability of cognate Ag/MHC interactions with the T cell receptor (TCR) determine the development of memory cell functional characteristics, in particular stem-cell associated characteristics, through epigenetic imprinting. Stem cell memory CD8+ T (TSCM) cells have been shown to exhibit superior functional features, progeny potential, self-renewal capacity and longevity. Using state of the art conditional mouse models, high dimensional spectral flow cytometry, lentiviral-based inducible gain or loss of function experiments, and computational modeling approaches, we will define the features of T cell epitopes, key TCR structural modes of recognition, TCR signaling pathways, genetic and epigenetic regulators that enhance the differentiation of TSCM cells in vivo. We will validate our findings in models of chronic infections and tumors. This research directly impacts the rational design of more effective vaccines and adoptive T cell transfer therapies.

NCI - National Cancer Institute

Project Summary/Abstract Somatically acquired mutation in the E1 ubiquitin-activating enzyme UBA1 within hematopoietic stem and progenitor cells (HSPCs) was recently identified as the cause of the adult-onset autoinflammatory syndrome VEXAS (vacuoles, E1 enzyme, X linked, autoinflammatory, somatic). Most VEXAS-associated mutations occur at Met41 in UBA1 and lead to clonal expansion within the HSPC and myeloid compartments, and frequently cause myelodysplastic syndrome (MDS) in addition to multi-organ inflammation. Despite the severity and prevalence of VEXAS, the mechanisms whereby UBA1 mutations cause multiorgan autoinflammation and myeloid malignancy are unknown. Our preliminary work utilizes newly developed and genetically controlled primary cell-based models of VEXAS to show that UBA1 mutant HSCs are primed towards myeloid differentiation and that their myeloid progeny undergo aberrant inflammatory cell death upon engagement of innate immune receptors. We hypothesize that aberrant inflammatory cell death underlies VEXAS pathogenesis. To build upon our preliminary work, this career development program will address 2 specific aims: (1) to determine cell-intrinsic and -extrinsic factors that promote clonal expansion and myeloid skew of UBA1 mutant HSPCs, and (2) to evaluate the role of inflammatory cell death as a therapeutic target in VEXAS. The proposed studies are part of the candidate’s developing research program at the intersection of myeloid malignancy and innate immune signaling and build upon his clinical expertise in MDS and AML. Dr. Narendra will develop a research program under the close supervision of his mentor Dr. Alexander Gitlin, an expert in the molecular basis of innate immune signaling, and co-mentor Dr. Scott Lowe, an expert in cancer biology, mouse models and functional genetics. Dr. Narendra will additionally be supported by members of his advisory committee including Drs. Omar Abdel- Wahab, Caleb Lareau, and Alexander Rudensky, experts in experimental and computational approaches to the study of hematopoiesis and immunity. Under the guidance of his mentors and advisory committee, the candidate will continue to gain expertise in immunology, malignant hematopoiesis, and single cell analytics. Dr. Narendra’s training environment will ideally position him to achieve his goal of becoming an independent physician-scientist, working at the convergence of innate immunity and cancer.

NCI - National Cancer Institute

SUMMARY Basal-like breast cancer (BLBC) is an aggressive cancer subtype that disproportionally affects younger women and women of African ancestry, contributing to cancer disparity. Additionally, women with BRCA1 germline mutations have an extremely high risk of developing BLBC. BLBC precancer tends to be high-grade and likely to progress to malignant cancer. Understanding immune escape mechanisms in BLBC precancer is crucial for developing immunoprevention strategies to intercept its progression to aggressive breast cancer. Recent studies have showed that the generation of embryonic multipotent stem-like cells (referred to as pre-CSCs) through de- differentiation is critical for BLBC precancer progression in mouse models. Importantly, de-differentiation to multipotent cells has also been observed in patients with germline BRCA1 mutations. Similar de-differentiation processes occur in other breast cancer subtypes, suggesting a broad strategy for cancer prevention by targeting pre-CSCs. However, how pre-CSCs escape immunosurveillance remains poorly understood. In our preliminary studies, we have discovered that BLBC pre-CSCs express high levels of the stem cell transcription factor SOX9, which greatly induce the expression of the immune checkpoint B7x (also known as B7-H4, B7S1 or VTCN1). These cells also upregulate multiple cancer testis antigens. We found that the SOX9- B7x pathway is necessary for inhibiting T cell infiltration and protecting pre-CSCs from T cell-mediated elimination. SOX9 or B7x knockout blocks the progression of BLBC precancer. These findings strongly support the hypothesis that BLBC pre-CSCs are unexpectedly immunogenic due to upregulation of cancer testis antigens, and the upregulation of immune checkpoint B7x by stem cell factor SOX9 in these cells are required for establishing an immuno-suppressive microenvironment crucial for safeguarding pre-CSCs from immune elimination. This hypothesis will be tested by pursuing the following specific aims: (1) Dissect the mechanisms by which SOX9 regulates B7x and other immunosuppressive pathways in in precancer stem cells; (2) Determine the mechanistic interactions between precancer stem cells and their reactive immune cells; and (3) Develop anti- B7x therapy, either alone or in combination, as new immunoprevention strategies targeting pre-cancer stem cells in breast cancer. The most effective strategies will be further tested in mouse models of other breast cancer subtypes. To accomplish our goals, we have generated a number of novel tools and resources. The outcomes of this project will elucidate new immunosuppressive mechanisms of pre-CSCs and develop anti-B7x therapy, either alone or in combination, as immunoprevention approaches against breast cancer.

NCI - National Cancer Institute

This application is focused on the study of bioengineered plant virus-based adjuvant and vaccine technology. We discovered that some plant viruses serve as potent adjuvants in the context of infectious disease and cancer vaccines/immunotherapy. Cowpea mosaic virus (CPMV) was identified as a uniquely potent adjuvant with distinct mechanism of immunomodulation compared to small molecule agonists, other plant viruses, or oncolytic viruses. Recently we discovered that systemic CPMV administration prior to tumor challenge protects mice from onset of tumor growth. Data indicate that the innate immune stimulation by CPMV is durable and lasts for weeks after CPMV exposure when innate cells would have returned to a homeostasis state – therefore data are consistent with induction of trained immunity. Single cell sequencing analysis of human PBMCs after CPMV adjuvant exposure indicates stimulation of interferon signaling pathways along with metabolic changes, and epigenetic rewiring – also consistent with a mechanism involving trained immunity. Together our data suggest that CPMV could act as an inducer of trained immunity – to date there are no reports on the study of plant viruses in trained immunity. Proposed studies will help elucidate the foundational principles that make CPMV a uniquely potent immunomodulator. We will fulfil the following specific aims: (1) We will establish the mechanism of CPMV as a training agent in vitro using immune cells followed by LPS challenge; longitudinal studies will be carried out and analysis will include measure of pro- inflammatory cytokine as well as CHiP and ATAC sequencing to confirm epigenetic rewiring and metabolic cell changes. Structure-function studies of bioengineered viruses will provide foundational insights into differential potency. (2) We will establish the mechanism of CPMV as a training agent using the B16F10 tumor model using WT and Rag 1 vs CCR2 knockout (KO) mice to delineate the role of adaptative vs. innate immune cells (β-glucan will serve as benchmark). Hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) will be analyzed by single cell sequencing, CHiP and ATAC sequencing to delineate the mechanism of action. Studies will be paralleled with safety and biodistribution studies. (3) We will test the ability of the CPMV training agent to facilitate protection from influenza virus challenge; protection from influenza virus infection and pathology from CPMV will be benchmarked against FLUMIST and β-glucan. These studies could lay the foundation for continued and deeper studies of CPMV as an adjuvant technology towards the development of more broadly protective and efficacious vaccine formulations and immunoprevention strategies.

NINDS - National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY BCL11A is a zinc-finger transcription factor that has been well-studied in erythroid biology, but evidence for an important role in the brain is beginning to emerge. Patients with heterozygous loss-of-function BCL11A mutations present with clinical features that can include intellectual disability (ID), autism spectrum disorder (ASD), and epilepsy. BCL11A is identified as a high confidence ASD risk gene in the SFARI database, and multiple lines of evidence also support potential roles in the etiology of schizophrenia (SZ) and Alzheimer’s disease (AD). However, the mechanisms that link BCL11A to these clinically challenging disorders are poorly understood. To better understand the neuronal function of BCL11A, we performed a series of preliminary behavioral analyses following the selective heterozygous deletion of Bcl11a from excitatory and/or inhibitory neurons in the mouse brain. Surprisingly, we found that Bcl11a deletion from inhibitory GABAergic interneurons (GINs) resulted in social deficits, hyperactivity, and increased seizure susceptibility. Furthermore, we observed increasing levels of BCL11A expression and physical occupation at predicted binding motifs during differentiation and maturation of GINs derived from human induced pluripotent stem cells (iPSCs). Additionally, we found that GIN-enriched ventral forebrain organoids derived from BCL11A-null iPSCs display differential gene expression signatures that overlap with pathological changes in the prefrontal cortex of postmortem brains of individuals with ASD and SZ. Taking these observations together, we hypothesize that the clinically challenging neurological phenotypes associated with BCL11A mutations likely reflect the specific impact of altered BCL11A function on different classes of neurons, with GINs being particularly vulnerable. We will test this hypothesis through a comprehensive series of in vitro (Aim 1) and in vivo (Aim 2) approaches. In Aim 1, we will identify and compare the gene targets of BCL11A in human iPSC-derived excitatory neurons and GINs. We will also employ single-nucleus (sn)RNA-seq and snATAC-seq along with whole-cell patch clamp electrophysiology and histology to establish the overlapping and distinct roles of BCL11A in human neuron populations. In Aim 2, we will further explore the in vivo function of Bcl11a by determining the behavioral and physiological effects of deleting Bcl11a in a neuron type-specific manner in mice. We will also use a chemogenetic approach to further interrogate GIN subtype-specific contributions to BCL11A disease mechanisms. Our long-term goal is to translate these findings into a better understanding of the role of BCL11A in the brain, which will help guide treatment development for patients with BCL11A dysfunction and other GIN-associated disorders.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Abstract Intestinal stem cells (ISCs) play pivotal roles in intestinal epithelium renewal during homeostasis and after injury. The metabolic demands faced by ISCs require high mitochondrial oxidative phosphorylation (OXPHOS) activity compared to other differentiated cells. ISCs’ mitochondrial dysfunction has been implicated in the etiopathogenesis of intestinal bowel diseases (IBD), which afflicts over 2 million people in the US. The carbon sources that fuel ISC OXPHOS have been broadly described in the small intestine (SI) but not in the colon. I seek to understand how ISC metabolic demands are met in the colon. The colonic epithelium is organized into the colonic crypt. ISCs localize to the base of the crypt (base-crypt), and this protects them from microbial metabolites and microbe-associated molecular patterns (MAMPs). Top-crypt differentiated colonic epithelial cells (CECs) oxidize microbial-derived short-chain fatty acid (SCFA) butyrate making it inaccessible to base-crypt cells. This shields ISCs, as butyrate suppresses ISC proliferation. This metabolic interaction between CECs and ISCs has focused my interest in CEC-ISC metabolic cross-talk. Ketones (acetoacetate, β-hydroxybutyric acid (βHB), and acetone) are important metabolic substrates. I hypothesize that CECs generate ketones that are used by ISCs as their principal energy source. This hypothesis is supported by the localization of rate-limiting enzymes (RLE) for the generation of ketones to the CECs and my preliminary data demonstrating that loss of these enzymes in CECs compromises ISC self-renewal and differentiation. My proposal focuses on this metabolic cooperation between epithelial cells within the crypt where top-crypt CECs shuttle ketones to base-crypt ISCs thus maintaining their turnover capacity. Understanding colonic ketone biosynthesis and function could lead to new treatments and therapeutic targets for IBD. Beyond defining this proposed metabolic crosstalk between CEC and ISC, I am interested in factors regulating CEC metabolic enzymes. I have identified microbial features that regulate the expression of the CEC RLE for ketone generation. I will determine the receptor and pathways downstream of this receptor by which they regulate the expression of this RLE. This research will help to decipher how microbial signals and metabolites contribute to epithelial repair and regeneration.

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY Stem cells and progenitors are integral for tissue development, homeostasis and regeneration, and their dysfunction underlie development disorders, defective tissue regeneration, aging and cancer. In addition to intrinsic mechanisms, diverse niche cells influence stem/progenitor cell fate. Adult tissues harbor heterogenous stem/progenitor cell subsets which are intricately involved in tissue regeneration and disease. Yet, the fundamental cell types and molecular mechanisms that regulate distinct tissue-specific stem/progenitor cell populations remain poorly understood. Using the murine mammary gland as a model, we were the first to uncover primitive mesenchymal progenitor niche cells that have a remarkable capacity to contribute to a major subset of tissue-specific epithelial progenitors, indicating their potential role in replenishing progenitor cells central to tissue regeneration. We have also observed that sympathetic neurons modulate progenitor subsets in the niche and epithelium to orchestrate tissue regeneration. These niche cell types permeate diverse somatic tissues and thus, understanding their control of tissue-specific progenitors is critical for advancing progenitor- targeted therapies in regenerative medicine and malignancy. The proposed research will investigate how tissue-specific progenitor cell fate is dictated by mesenchymal progenitors and sympathetic neurons during adult tissue regeneration. We will utilize the postnatal mouse mammary gland as a tractable model to study tissue-specific progenitors given that it undergoes extensive morphogenesis directed by progenitors. We will explore niche cell-mediated modulation of progenitors and identify underlying molecular signals and mechanisms. We will employ a variety of strategies that include in vivo genetic reporter, lineage tracing and cell ablation mouse models and ex vivo organoids combined with phenotypic, functional assays and next-generation sequencing. Our findings will bridge key gaps in knowledge of the niche-driven circuitry that impacts tissue progenitors and provide a framework for improving the outcome of diseases attributed to aberrant progenitors.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY Type 1 diabetes (T1D) results from immune-mediated destruction of pancreatic beta cells. Increasing evidence suggests that beta cells actively contribute to their own demise through heightened immunogenicity, stress-induced neoantigen formation, and impaired immune tolerance. Enhancing beta cell resilience under inflammatory conditions remains a major challenge to the success of durable therapies, especially for cell replacement approaches. Our in vivo CRISPR/Cas9 screen identified ZBED3 — a transcription factor previously implicated in type 2 diabetes (T2D) — as a modulator of beta cell survival under autoimmune attack. Analysis of human islet single-cell RNA sequencing data revealed increased ZBED3 expression in beta cell subclusters associated with both T1D and T2D, whereas ZBED2, a related transcription factor with anti-inflammatory properties, is selectively absent in beta cells. Integration of public ZBED2 chromatin immunoprecipitation sequencing (ChIP-seq) and our in-house ZBED3 ChIP-seq datasets identified shared transcriptional targets involved in interferon signaling, FOXO-mediated transcription, and beta cell function. These findings suggest that ZBED family members may exert opposing regulatory effects on beta cell fate during autoimmune diabetes. This proposal aims to elucidate the transcriptional mechanisms underlying beta cell vulnerability by testing the hypothesis that ZBED2 and ZBED3 govern the balance between beta cell function, immune tolerance, and stress adaptation. Using genetically engineered beta cells derived from human induced pluripotent stem cells (iPSCs) and primary islets, we will pursue two specific aims: Aim 1. Define the role of ZBED3 in regulating beta cell immunogenicity, functional maturation, and stress response. Aim 2. Enhance immune tolerance by inducing ZBED2 and investigating its antagonistic effects on inflammatory signaling. This study combines gene editing, transcriptomic profiling, and T cell cytotoxicity assays to elucidate regulatory pathways governing beta cell survival. By establishing ZBED2 and ZBED3 as central regulators of beta cell fate, this work addresses a critical gap in T1D therapy and supports the development of transcription-based strategies to improve the durability of cell replacement interventions.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary Candida spp. are the 4th leading cause of bloodstream infections (BSIs) in the US. C. parapsilosis (CP), the 2nd or 3rd most common cause of candidemia, is designated as a high priority fungal pathogen for research by the World Health Organization. Mortality rates for CP BSIs are ~20% despite treatment with echinocandins (ECHs), the frontline antifungal class. ECH resistance is uncommonly identified among CP clinical strains, and most ECH treatment failures of CP BSIs are not linked to a resistant strain. Antifungal heteroresistance (a low-frequency subpopulation of resistant cells co-existing with susceptible cells) and tolerance (some cells grow better than controls in presence of drug without minimum inhibitory concentration changes) are reported in CP and other spp. The clinical relevance of ECH HR or tolerance is not broadly validated, but recent studies have implicated the phenotypes in at least some patients failing treatment for CP BSIs. The long-standing model is that almost all sterile site infections, including candidemia, stem from a single, clonal organism that passes through a bottleneck to establish disease. Our preliminary data challenge the “single organism” model by demonstrating that blood cultures (BCs) from individual patients with C. glabrata, C. albicans and CP BSIs are comprised of mixed populations of genetically and phenotypically diverse strains, including strains exhibiting differences in antifungal-resistance or tolerance that were not recognized by the clinical lab. Our objectives in this project are to characterize genetic and phenotypic diversity of CP populations in baseline and ECH treatment failure BCs from individual patients, and to implicate specific genetic variants and genes in ECH heteroresistance or tolerance. We hypothesize that certain CP genetic variants or genes enriched in BCs from ECH treatment failures will contribute to ECH heteroresistance or tolerance, and that heteroresistance or tolerant strains are present, but unrecognized in baseline BCs from some pts. We will test these hypotheses by pursuing 2 specific aims. In aim 1, we will perform deep whole genome sequencing on CP populations from baseline and ECH treatment failure BCs from 10 pts. We will prioritize CP genetic variants and genes enriched in treatment failure BCs, and assay strains containing these variants and genes for ECH heteroresistance and tolerance in vitro. In aim 2, we will validate the impact of CP genetic variants and genes on ECH treatment responses during BSIs. We will create isogenic mutant strains for genetic variants and genes. Then, we will test strains for ECH heteroresistance and tolerance in vitro and for ECH treatment responses during mouse BSIs. This study will afford new insights into CP responses to ECH exposure during BSIs and identify novel genetic determinants of ECH heteroresistance and tolerance. Our findings will provide a foundation for future studies of clinical significance of within-pt CP strain diversity during BSIs and mechanisms by which CP genes promote heteroresistance and tolerance. By challenging the single organism model, the study has potential to reshape current clinical and clinical microbiology lab practices.

National Park Service

In order to connect with the next generation of park stewards, the National Park Service (NPS) Natural Resources Stewardship and Science (NRSS) Directorate will partner with the CNS Education & Outreach Center (CNSEOC) at Colorado State University to create curriculum-based materials focused on Science, Technology, Engineering, and Math (STEM) subjects. This expands on a previous pilot project that developed pre-, syn-, and post- park visit STEM kits and curriculum materials centered around pressing park water quality and quantity issues at a specific park in Hawai i. Two cohorts of K-12 teachers received professional development, helped develop and pilot test materials, and are now training new teachers. The goal of this new multi-regional scale project is to create materials about natural resource subjects that best align with K-12 educational standards as well as the needs of the regional culture(s). It will engage students in the scientific research and monitoring being done in the parks and incorporate NPS protocols and data from the Natural Resource Stewardship and Science programs such as Inventory and Monitoring, Night Skies, and Natural Sounds programs. The pre- and post-visit activities developed via this project will be able to be done independently in classrooms or on school grounds and therefore are specifically designed to serve as a public benefit. This project will bring together scientists, park staff, teachers, and community partners to provide K-12 students with learning experiences that inspire them to take action on real-world problems.

NHLBI - National Heart Lung and Blood Institute

SUMMARY The annual Vasculata conference has been convening since 2004, and has been hosted by different academic research institutions throughout the United States. Vasculata is co-sponsored by the North American Vascular Biology Organization (NAVBO), which promotes the study of vascular biology and the dissemination of scientific knowledge and discoveries to the next generation of vascular biologists and bioengineers. The NAVBO Educa- tion Committee has selected the University at Buffalo (UB) – SUNY as the host of Vasculata 2026, marking the first time the meeting will be held in Western New York! Vasculata is an intense “boot camp” that provides foun- dational knowledge in vascular biology, as well as the latest discoveries and technologies, to students and post- doctoral trainees. The meeting has grown considerably since the inaugural meeting in 2004 (a group of about 60 people) to now attracting a group of about 100-120 faculty, students, and fellows. UB, especially the Jacobs School of Medicine and Biomedical Sciences (JSMBS), houses a critical mass of faculty with expertise in various areas of vascular biology including, but not limited to, vascular endothelial cell and mural cell biology, inflamma- tory signaling and molecular mechanisms of vascular cell dysfunction in cardiovascular, cerebrovascular, and other organ-specific diseases, metabolic and hemodynamic regulation of vascular function, intercellular commu- nication, angiogenesis, vascular remodeling in development and pathology, stem cell-driven vascular biology, bioengineered vascular grafts, vascular medicine, aneurysms and other blood vessel disorders. UB is within driving distance from other top tier institutions, such as the University of Rochester (collaborating institution in Vasculata 2026), Case Western Reserve University, Cleveland Clinic, Cornell University, Rochester Institute of Technology, Syracuse University, and the University of Pittsburgh (host of Vasculata 2025). Furthermore, UB is home to the a) world-renowned Canon Stroke & Vascular Research Center that focuses on research related to the diagnosis and treatment of vascular disease through minimally invasive image-guided interventions and im- proved imaging modalities, and b) the Gates Vascular Institute that consists of a team of health care specialists from UB’s JSMBS, who provide state-of-the-art vascular, stroke, and cardiac care under one roof. A key strength of our program is the incorporation of bioengineering-based vascular-focused presentations through the involve- ment of faculty from the Departments of Biomedical Engineering at UB (including the Vasculata 2026 Chair) and the University of Rochester. All training and dissemination of new knowledge through lectures, workshops and poster sessions, as well as faculty, student and trainee networking, align with the education mission of the NHLBI.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Adipose tissue (AT) remodeling plays a key role in metabolic homeostasis and healthy expansion of AT is required to preserve insulin sensitivity. Pathological consequences of dysfunctional AT remodeling include chronic inflammation and fibrosis that contribute to the adverse outcomes of obesity. Beiging (cold-induced recruitment of thermogenic adipocytes in white adipose tissue (WAT) is potentially a healthy means to remodel AT because the newly formed beige adipocytes not only enhance energy expenditure, but they also counteract unhealthy remodeling. For beiging to be a strategy to treat obesity, we need to induce it in obese individuals. Studies show however that beiging declines with obesity and aging. We propose a strategy that inhibits pathways contributing to the unhealthy remodeling of WAT while enhancing beige adipocyte recruitment. We propose that obesity prevents beiging because the pool of beige progenitors is redirected to other fates. In a recent study, we discovered a previously unrecognized population of quiescent mural cells expressing transgelin (SM22) that can rapidly transition into adipocyte progenitors (APCs) in response to cold exposure. We hypothesize that beige progenitors arise from mural cells of the microvasculature during angiogenesis; a process that is significantly attenuated in obese WAT. Serum response factor (SRF) and its associated coactivator, myocardin-related transcription factor A (MRTFA) are regulators of mesenchymal stem cell (MSC) fate decisions and angiogenesis. We and others discovered that inhibition of MRTFA activity promotes conversion of progenitors to beige adipocytes. Furthermore, MRTFA-/– mice are protected from diet-induced obesity and insulin resistance, which leads us to hypothesize that these effects are mediated (at least in part) by a beneficial AT remodeling including beige adipocyte recruitment, enhanced angiogenesis and inhibition of fibrosis. We hypothesize that MRTFA/SRF signaling opposes conversion of vascular mural cells into beige adipocytes while promoting macrophage-driven fibrogenesis. Thus, we predict that mice lacking MRTFA activity in mural cells and macrophages will exhibit enhanced beige remodeling and remain responsive to browning agents even during obesity. Small molecules that attenuate MRTFA activity in combination with agents that mimic cold are, therefore, potential therapeutics for obesity-related disorders. We propose three aims: 1: Deconstruct the beige-associated remodeling of WAT in MRTFA-deficient mice. 2: Establish a role for MRTFA in regulating recruitment of beige progenitors from mural cells in WAT. 3: Define the mechanisms by which MRTFA regulates the conversion of mural cells to beige progenitors. Impact: At the completion of these aims, we will have defined novel mechanisms facilitating beige remodeling during obesity and identified targets for development of anti-obesity therapeutics.

Verizon

Funds digital learning and STEM education programs in underserved schools.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY Many metabolic responses involve the trafficking of proteins within the endomembrane system. A major branch of membrane protein trafficking is vesicle fusion, which entails the merging of membrane-enclosed vesicles with their target membranes. Vesicle fusion mediates key metabolic processes, including the translocation of the glucose transporter GLUT4, insulin secretion, glucagon release, and GLP-1 secretion. Imbalances in these vesicle fusion processes are associated with metabolic disorders such as insulin resistance (IR) and type 2 diabetes (T2D). To devise effective therapeutic strategies for these disorders, it is crucial to understand how protein-protein networks mediate and regulate vesicle fusion in these metabolic pathways. Our research focuses on the vesicle fusion pathway critical for the insulin-dependent translocation of GLUT4 in adipocytes and muscle cells. In our preliminary studies, we developed CRISPR-based genetic platforms and identified new players in the vesicle fusion pathway. Additionally, through biochemical and biophysical assays, we uncovered novel protein-protein and protein-membrane binding modes in GLUT4 vesicle fusion. In this work, we aim to expand these preliminary findings to elucidate how the soluble and membrane proteins act in concert to mediate and regulate the vesicle fusion reaction and to understand how fusion kinetics are affected by changes in lipid composition. Our genetic experiments employ cultured adipose and muscle cells differentiated from progenitor cells, as well as genetically modified mouse strains. We will also use a novel platform of mature human adipocytes derived from differentiation of human pluripotent stem cells. As a crucial step towards grasping the molecular basis of IR, we will use mouse models to explore how a high-fat diet-induced IR condition affects vesicle fusion mediators. The experiments proposed here are expected to provide key mechanistic insights into the molecular basis of metabolic vesicle fusion, and will pave the way for understanding IR and T2D. Ultimately, these findings will likely contribute to the development of new treatments for these metabolic disorders.

National Park Service

This announcement is to provide public notice of the National Park Services intention to fund the following project activities without full and open competition to Seward Association of the Advancement of Marine Science dba the Alaska SeaLife Center (ASLC)for a cooperative agreement in the amount of $42,997 to cooperatively complete the project described below. STATUTORY AUTHORITY: 16 USC 1g, Agreements for the Transfer of Appropriated Funds to Carry Out NPS Programs. STATEMENT OF JOINT OBJECTIVES/PROJECT MANAGEMENT PLAN: OVERVIEW The unique nature of Alaska, with its many rural and remote villages, provides the challenge of getting quality marine science education to students in schools which are usually multi-grade facilities with minimal staff support. Staff members of both Kenai Fjords National Park and the Alaska SeaLife Center have been successfully taking science to these students for the past ten years. In a state with such an abundance of science, natural resources, and students longing to understand them the OASLC Village Outreach Program is a natural fit. With a track record of success and a recent increase in teacher participation and frequency of outreach trips, this program has the potential for continued growth and even greater success as schools are looking for unique, cost-effective, and inquiry-based learning experiences for their students. STATEMENT OF JOINT OBJECTIVES/PROJECT MANAGEMENT PLAN Village outreach trips are conducted jointly by the ASLC and NPS staff. Villages are chosen in collaboration. Content for lessons are contributed by both ASLC and NPS staff and lessons are designed by the ASLC. Staff from both ASLC and NPS travel to the villages and both present lessons and programs related to marine and park resources. NPS staff will give a presentation on jobs and careers opportunities in the NPS. Objectives 1. To share the scientific research and information available at both the Alaska SeaLife Center and Kenai Fjords National Park with teachers and students across Alaska in an effort to create a climate of ocean stewardship through understanding of the natural resources and unique features of our local oceans, seas and coastal communities. 2. To inspire continued education in STEM-related content through exposure to science, technology, and careers related to stewardship of Alaska s oceans and their resources. 3. To provide quality education content on marine research and glaciers from the ASLC and the NPS-KEFJ, who are uniquely qualified on these subjects, to all students in Alaska. 4. Four week-long outreach trips between August 2014 and June 2015: Northwest Arctic Borough School District sites in consultation with NPS office in Kotzebue (2 educators). Goals include 1-4 schools and <750 students. Nome and Bering Strait School District sites, in consultation with the Nome office (2 educators). Goals include 1-4 schools and <500 students. Chatham School District or other area of priority to the Glacier Bay office (1 educator). Goals include 1-3 sites and <120 students. Priority communities in the Lake &amp; Peninsula School District, in consultation with the Katmai and Lake Clark offices (1 educator). Goals include 1-3 sites and <120 students. 5. Two week-long outreach trips to the schools in Port Graham and Nanwalek between August 2014 and June 2015. During the first visit, ASLC educators will begin a dialogue with the students and will work with teachers to establish a long-term project for the school year. Between visits, ASLC educators will stay in touch with classes to continue the dialogue and to use the resources of the aquarium to highlight certain lessons (e.g., mammals swimming in their tanks to discuss different methods of locomotion.) 6. Assessment results that will inform future outreach goals and methods. RECIPIENT INVOLVEMENT The Alaska SeaLife Center will work with NPS to identify villages and schools to visit. The ASLC take the lead on developing marine science lessons focused at appropriate grade levels. Examples of lessons adaptations of marine birds and mammals, comparative anatomy of marine invertebrates, comparative anatomy of vertebrates, and investigative science using the scientific method focused on walruses. The ASLC will also take the lead on delivering lessons in each of the identified villages. The ASLC shall establish long term contact with schools in Port Graham and Nanwalek in order to develop a long term school project and to deliver lessons throughout the school year from their facilities and resources in Seward using distance learning technology. Finally the ASLC will be responsible for conducting evaluations of the village outreach lessons from teachers and students in order to inform future outreach goals and lessons. 3. Collaboratively choose schools and villages for outreach trips with NPS staff. 4. Provide content and develop lessons focused on marine science for K-12 students. 5. Provide staff to travel to villages and deliver lessons. 6. Establish a long term project with students in Port Graham and Nanwalek, maintain contact throughout the school year, and between visits deliver lessons focused on resources present at the ASLC using distance learning technology. 7. Conduct evaluations with teachers and students to inform future outreach goals and lessons. NATIONAL PARK SERVICE INVOLVEMENT Substantial involvement on the part of the National Park Service is anticipated for the successful completion of the objectives to be funded by this award. In particular, the National Park Service will be responsible for the following: 1. Collaboratively choose schools and villages for outreach trips with ASLC staff. 2. Provide content and develop programs focused on park natural and cultural resources for K-12 students. 3. Provide staff to travel to Port Graham, Nanwalek and when possible other villages to deliver lessons and programs (NPS Travel is not part of the cost proposed and will be processed outside this agreement). 4. Develop and present program to inform students and village youth about jobs and career opportunities in the National Park Service. SINGLE-SOURCE JUSTIFICATION: Department of the Interior Policy (505 DM 2) requires a written justification which explains why competition is not practicable for each single-source award . The National Park Service did not solicit full and open competition for this award based the following criteria: (4) Unique Qualifications The applicant is uniquely qualified to perform the activity based upon a variety of demonstrable factors such as location, property ownership, voluntary support capacity, cost-sharing ability if applicable, technical expertise, or other such unique qualifications;The focus of the village outreach program is on ocean science and issues with a strong emphasis on engaging rural schools in Alaska. The Alaska SeaLife Center is a leader in both conducting marine science in the state of Alaska and educating rural pre-K-12 grade students on the results. They are the only educational institution (non-profit, for profit or government) within the state that has a state wide reach to rural pre-K-12 grade schools. This is particularly important for schools not located near the Gulf of Alaska. Since its inception in 1998 the Alaska SeaLife Center has been sharing scientific knowledge to promote understanding and stewardship of Alaska's marine ecosystems through educational programs to all ages. Throughout that time the ASLC has engaged in village outreach efforts like the project described in this task agreement. They have demonstrated both a commitment and excellence in conducting educational outreach to rural schools. The ASLC has demonstrated knowledge and skills that put them in a position of leadership in informal education. Each of the ASLC educational staff are certified informal science educators. In addition, the ASLC provides training to staff at other institutions, for example the Anchorage Museum, on informal education. The ASLC also conducts teacher workshops and training for individuals wishing to become Certified Interpretive Guides through the National Association of Interpreters (NAI). The ASLC has also received three Pinnacle Awards in 2008, 2011 and 2013, along with two honorable mentions in 2009 and 2010. Pinnacle Awards are presented by the Center for Interactive Learning and Collaboration (CILC) to institutions providing content for distance learning and informal education programs. Awardees are selected based on teacher evaluations. There are only four entities in the state of Alaska providing marine science outreach to grade school children: The Sitka Sound Science Center, The Prince William Sound Science Center, the Kachemak Bay Research Reserve, and the Alaska SeaLife Center. The first three are limited in scope and mission to their local areas, and all are on the Gulf of Alaska, in the southern part of the state. The villages in this project are spread out throughout the state. The ASLC is the only institution with both the experience and scope to reach all the villages in this project.Technical contact information: Benjamin Pister, benjamin_pister@nps.gov, 907-422-0501, National Park Service, Alaska Region, End of FOA

Virginia Department of Education

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

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

ABSTRACT Pantothenic acid, also known as Vitamin B5 (VitB5), is a member of the vitamin B family found in diets and gut microbiota and is primarily absorbed by the intestines. VitB5 is a precursor for the biosynthesis of coenzyme A (CoA). As the major carrier of activated acyl groups within cells, CoA is critical in various core metabolic processes, including nutrient catabolism and lipid synthesis. VitB5 has been shown to regulate the functions of different cells and various diseases. Isolated VitB5 deficiency results in metabolic imbalance and gastrointestinal symptoms. A deficiency in VitB5 was recently reported in the blood and feces of IBD patients; accordingly, VitB5 administration enhanced intestinal barrier repair, suggesting a potential correlation between VitB5 reduction and IBD development. However, how VitB5 regulates IBD is still largely unknown. Our preliminary data showed a lower level of VitB5 in the serum of IBD patients and lower expression of pantothenate kinase (PANK), one of the enzymes that catabolize VB5 to CoA, in Foxp3+ Tregs in IBD patients, compared with healthy controls. This suggests a potential role of VitB5 in the regulation of IBD development through Tregs. We further showed that supplementation of VitB5 protects intestinal inflammation with higher levels of Foxp3+ Tregs in the intestines. This indicates a crucial role for VitB5 in regulating Treg and ongoing intestinal inflammation by promoting Foxp3+ Tregs. Thus, the central hypothesis of this project is that VitB5 protects the intestines from inflammation by promoting Treg suppressive function in the intestines. VitB5-SLC5A6 axis induces Foxp3+ Tregs through increased mitochondrial oxidation and epigenetic regulation, limiting intestinal inflammation progression in IBD. We will test our hypothesis in this application to determine (1) the impact of the VitB5-Slc5a6 axis in Tregs in the regulation of colitis.; (2) whether VitB5 promotes Treg function by enhancing Treg stemness; and (3) the mechanisms by which VitB5 promotes Treg stemness and the protection of intestinal inflammation.

VMware Foundation

Funds STEM education, environmental sustainability, and community resilience in global communities.

Washington STEM

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

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY Inflammation is a major culprit of obesity comorbidities including diabetes, cardiovascular disease, and infections, all of which are leading causes of death worldwide. Over 40% of adults in the United States are obese. The most common and effective treatment to alleviate obesity-related inflammation is weight loss. However, weight loss is difficult to maintain and over 60% of adults regain their weight, a process termed weight cycling (WC). WC has been associated with exacerbated inflammation and a greater risk of developing obesity complications such as diabetes and cardiovascular disease, compared to never losing weight, however, the mechanisms remain unknown. The proposed work aims to interrogate the origin of exacerbated inflammation during weight cycling to provide a novel mechanistic basis that can be used to treat obesity-induced inflammation, thus addressing a critical public need and adding fundamental knowledge about metabolic regulation of immunity. Hematopoietic stem and progenitor cells (HSPCs) are critical for the lifelong production of all blood cells. Their ability to self-renew, differentiate into all blood cells, and respond to pathogenic stimuli, places them as major determinants of immune responses. HSPCs are also known to harbor trained immunity, which results in the enhanced inflammatory and metabolic activity of progeny from HSPCs to non-specific stimuli. Studies from our lab show that WC promotes inflammation in a cardiovascular disease mouse model via the transfer of HSPCs that have been exposed to a WC environment. This indicates that WC may induce trained immunity. My preliminary data show that WC increases HSPC frequencies compares to stable-obese mice, illustrating HSPCs are being activated by WC. Additionally, challenging WC mice with stimuli to induce systemic inflammation results in a greater amounts of inflammatory myeloid cells within the bone marrow compared to stable-obesity. Lastly, ex vivo stimulation of mature immune cells from WC bone marrow and adipose tissue result in greater pro-inflammatory gene expression compared to stable-obese cells. The results of my data have led to my central hypothesis that weight cycling reprograms immune progenitors via epigenetic and metabolic changes to produce more myeloid progeny with greater inflammatory potential. To test my central hypothesis I have developed two specific aims: 1) Test the hypothesis that WC promotes myelopoiesis via metabolic alterations and, 2) Identify the mechanisms underlying the heightened inflammatory phenotype of myeloid progeny in WC. This project will uncover mechanisms driving increased inflammation during weight cycling that can be targeted to alleviate obesity-related inflammation. Furthermore, this project will train a highly motivated graduate student with the necessary skills to become an independent investigator and expert in the field of immunometabolism.

NHLBI - National Heart Lung and Blood Institute

ABSTRACT This NHLBI, R13 grant application is to seek partial funding for the 2026 Weinstein Cardiovascular Development and Regeneration Conference in the New York City area, in Jersey City, New Jersey on May 6-8. This conference originated in 1986 as an RFA from Dr. Constance Weinstein at the NHLBI to bring together basic and clinical researchers working in cardiovascular developmental biology and congenital heart disease. Due to its great success, and after the retirement of Dr. Weinstein, the meeting was named the Weinstein Cardiovascular Development Conference, and it was held each year since, and the 2026 Conference will be the 40th year that the conference has been ongoing. With the expansion of technologies and new concepts in biomedical sciences, the field of cardiac regeneration blossomed and because of this, the conference name was modified to be called the Weinstein Cardiovascular Development and Regeneration Conference. Usually there are 350-400 attendees, split evenly between trainees that consist of graduate students and postdoctoral fellows and faculty, at all stages of their careers. The topics are timely and are chosen in large part by the hottest science as identified from the typical, 200-220 submitted abstracts about 2-3 months before the conference. Session topics typically include cardiovascular stem cell models with tissue engineering, heart fields and embryonic morphogenesis, cardiomyocyte development and function, valves and cardiac conduction, genetics of congenital heart disease, heart regeneration, and epigenetic changes during development and disease. In addition to the scientific focus, one of the most unique aspects of the conference is that all the oral talks, besides the two keynote lectures, is given by trainees and early career faculty, selected from submitted abstracts a few months before the meeting. This meeting is well-known for its collegiality and for providing opportunities to impart new knowledge on all attendees, as well as to the next generation of leaders in our field. Our aims are to 1) provide a collegial environment for sharing of innovative and unpublished scientific findings in the cardiovascular field, 2) to increase our understanding of the etiology and genetics of congenital heart disease, explore the developmental mechanisms and regenerative therapies and 3) to .enhance the professional development of a diverse array of trainees by providing a platform for the presentation of their data and an opportunity to network and interact with established cardiovascular researchers. The Weinstein Conference has a mission that directly aligns with the goals and mission of the NHLBI and financial support will make it more feasible for trainees to attend and participate and interact with established faculty to improve health of individuals with human congenital and cardiovascular diseases.

U.S. National Science Foundation

The chief goal of WIDER is to transform institutions of higher education into supportive environments for STEM faculty members to substantially increase their use of evidence-based teaching and learning practices. The first recommendation in the Report of the President's Council of Advisors on Science and Technology (PCAST), "Engage to Excel," is to increase widespread implementation of evidence-based practices in order to increase persistence in STEM and contribute to the goal of producing 1 million additional STEM graduates. Through this process, WIDER seeks to substantially increase the scale of application of highly effective methods of STEM teaching and learning in institutions of higher education, by employing instructional materials and methods that have a convincing evidentiary basis of effectiveness. In particular WIDER seeks this transformation for high enrollment, lower division courses required for many STEM majors and taken by many other students to fulfill general education distribution requirements.Included in our broad definition of effective STEM teaching and learning are not only instructional practices in traditional learning environments, but also modern laboratory methods and field research, proven distance education methods (or hybrid designs incorporating both face-to-face and distance methods), and improved approaches to motivating student interest in STEM. In all cases, the primary goal of WIDER is to increase substantially the scale of these improvements within and across the higher education sector in order to achieve:(1) Improved student learning; (2) Increased numbers of students choosing STEM majors, particularly from demographic groups underrepresented in STEM; (3) Improved retention in the first two years of undergraduate study and to graduation of all STEM majors. Applicants may apply for WIDER grants to begin institutional planning efforts, to support implementation efforts for evidence-based teaching and learning practices, and for research on how to increase the importance placed on evidence-based practices in institutional strategic planning and faculty rewards.

Wisconsin Department of Public Instruction

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

Wisconsin Economic Development Corporation (WEDC)

The Fab Labs Grant program funds the establishment and enhancement of fabrication laboratories in Wisconsin, providing communities with shared access to digital manufacturing tools, STEM education resources, and entrepreneurial training.