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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.

NIGMS - National Institute of General Medical Sciences

The Scientific Excellence and Experiential Development for Scholars T32 (SEEDS-T32) at the University of South Dakota aims to transform how we train the next generation of biomedical scientists, equipping them to lead the future of the biomedical workforce in South Dakota and beyond. Aligning with South Dakota’s “Grow Our Own” STEM initiative, SEEDS-T32 develops scholars who are resourceful, resilient, and workforce-ready, and who are prepared to meet the critical regional and national needs for highly skilled biomedical researchers. USD offers a rare training ecosystem: as the state’s only academic medical center and one of only two Carnegie-classified doctoral universities with high research activity in a rural IDEA state, it provides a powerful nexus for trans-departmental training spanning the Biomedical and Translational Sciences, Biology, and Sustainability Ph.D. programs. SEEDS-T32 blends mentor-guided, hypothesis-driven research with advanced coursework, microcredentialing in high-demand skills, and structured professional development in scientific communication, data analytics, and research rigor. Trainees gain real-world, career-aligned experiences through informational interviews, teaching practicums, industry-embedded internships, shadowing, and Individual Development Plans (IDPs), while cohort-building activities, including graduate student-led retreats, cross-disciplinary workshops and seminars, and collaborative symposia, create a vibrant, supportive scholarly community. Our objectives include: (1) Expand NIH- supported graduate training and trans-departmental integration; (2) Foster excellence in research rigor and independent scholarship; (3) Advance career readiness through experiential learning and personalized IDPs; (4) Develop interdisciplinary communication and in-demand technical skillsets; and (5) Ensure strong, evidence-based mentorship with continuous program improvement by an engaged Executive Committee and external advisors. Trainees will be selected in their first year of doctoral study and supported for up to two years, with continued engagement in the program activities through graduation. By uniting rigorous science with intentional career preparation, SEEDS-T32 will produce resilient, research-ready scientists who will strengthen the region’s biomedical enterprise and drive innovation across academia, industry, government, and beyond.

NHLBI - National Heart Lung and Blood Institute

Project Summary/Abstract Gene regulatory mechanisms are a key driver of the dynamic changes from multipotent progenitor cells into progressively more differentiated cell types during organ development, including cardiac development, and tightly regulated in time and space. Mutations that affect gene regulation often lead to congenital defects or increase risk for complex diseases. However, in most cases, the molecular mechanisms causing these effects remain unknown. This knowledge gap exists because current genomics methods cannot fully capture the coordinated and dynamic gene regulatory processes, including resolving the interactions between transcription factors (TFs), cis-regulatory elements (CREs), DNA methylation, and chromatin. In this proposal we will focus on the gene regulatory mechanisms of cardiomyocyte differentiation and cardiac disease. We will use single molecule footprinting (SMF) which combines methyltransferase-based measurement of chromatin organization with native long-read sequencing, to assess chromatin accessibility, nucleosome positioning, TF binding, and DNA methylation simultaneously on single chromatin fibers from human cells. We will collect both SMF data and single-cell multiome data from induced pluripotent stem cells at multiple time points as they differentiate into cardiomyocytes. Using multimodal data captured from haplotype-resolved individual DNA molecules, we will explore how genetic perturbation of CREs and TFs - including those observed in congenital and complex cardiac diseases - affect chromatin organization and transcription. In this study we aim to develop better models of the gene regulatory mechanisms that drive cardiomyocyte differentiation, providing direct insights into developmental cardiac defects; we aim to establish a novel paradigm for the genome-wide study of dynamic and coordinated gene regulatory processes.

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

Thrombotic complications are responsible for one in four deaths. Current anticoagulation strategies directly target coagulation factors, thereby mitigating thrombosis systemically, but at the cost of increased bleeding risk. However, the distribution of coagulation factors and thrombotic propensity varies across the vascular tree. An improved mechanistic understanding of how thrombus forms locally could inform a new generation of therapeutic targets. Mechanical forces vary across vascular beds; yet, how these heterogeneous forces translate into thrombosis remains unresolved. Mechanosensitive ion channels, particularly Piezo1, transduce mechanical stimuli into cellular responses. In studying Piezo1 and coagulation, we found that endothelial Piezo1 activation counters the prothrombotic shift during inflammation by inducing KLF2/4, increasing thrombomodulin, and reducing tissue factor. Piezo1 protein levels increase from static conditions to laminar flow conditions, yet enhanced agonist concentrations are required to potentiate an anti-coagulant response in the laminar flow conditions. Together, these data support the tuning of Piezo1 sensitivity by shear forces. We propose that Piezo1 is a crucial mediator of thrombotic responses to mechanical forces, and that its influence varies significantly across distinct vascular beds. We will evaluate this overarching hypothesis using a combination of pharmacological and genetic tools to modulate Piezo1 channels in both in vitro mechanical activation models, such as flow chambers and strain models, as well as murine models. We will systematically link heterogeneous mechanical forces to distinct Piezo1 signatures across multiple cell types by monitoring Piezo1 protein levels, calcium transduction properties, and the resulting coagulation-associated changes. In vivo we will evaluate the effect of Piezo1 activation on thrombosis across veins, venules, capillaries, arterioles, and arteries. These findings will initiate discovery at the interface of biochemical signaling and mechanotransduction, identifying endothelial pathways that can be targeted locally to stem thrombosis. This proposal outlines a five-year mentored research training program designed to support Dr. Sack’s career development. The applicant has a strong background in endothelial biology and mechanotransduction. This proposal will expand Dr. Sack’s skill set through didactics, workshops, mentoring sessions, and an investigation into Piezo1 mechanotransduction and thrombosis. Dr. Robert Flaumenhaft, the primary mentor, has a distinguished record of mentorship and innovation in the field of thrombosis research. Dr. Sack will receive additional feedback, mentorship, and training through a scientifically relevant and experienced advisory committee that will critically assess the applicant’s progress. In summary, Dr. Sack has created an outstanding environment that fosters success in her career as an independent physician-scientist, dedicated to investigating how mechanical factors contribute to critical illness-associated hemostatic and thrombotic pathologies.

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.

NCI - National Cancer Institute

Summary: Acral melanoma is associated with a significantly lower survival rate compared to cutaneous melanoma. The goals of this study are to elucidate the early developmental stages of acral melanoma and to develop strategies to prevent its progression. A major barrier to understanding the progression of this deadly cancer lies in the paucity of preclinical models. Our lab recently developed a novel murine model that selectively targets mature melanocytes, thereby allowing for their precise manipulation within the basal layer of acral skin. We have demonstrated that these cells possess acral melanoma-forming capacity and can be used to model melanoma initiation at its earliest stages. This model overcomes a fundamental limitation of other existing models, which target immature melanocyte stem cells in skin appendages (hair follicles or sweat glands), as well as mature melanocytes. Building upon recently innovated technology from our lab, we can now visualize and track the emergence of acral melanoma from single epidermal melanocytes in real-time in vivo. This innovation has created new opportunities to address fundamental, yet unexplored questions in melanoma studies. In Aim1, we aim to answer the following key questions: 1) What percentage of melanocytes give rise to invasive melanoma when given mutations? 2) How many cell divisions occur prior to dermal invasion? 3) What melanoma cell density is required to disrupt the basal lamina? 4) Do melanoma cells invade as single cells or in `collectives? As we currently cannot prospectively identify melanoma-forming melanocytes in human samples before tumor formation becomes evident, our model is uniquely powerful in addressing these crucial questions. Moreover, our new live imaging platform for melanoma initiation has identified the essential role of Sortilin 1 (Sort1) in the initiation of acral melanoma. Sort1 is a cell surface protein known to promote migration and invasion in various cancers has been targeted for clinical trials because it is highly specific to tumor cells and may play an early role in tumor development. A potential function for Sort1 in melanoma has not been investigated. Our preliminary analyses identify Sort1 in early human acral melanoma, and inhibition of Sort1 significantly suppresses acral melanoma formation. Sort1 inhibitors have been actively studied in clinical trials, emphasizing the need to investigate their roles in melanoma. In Aim 2, we will investigate the function of SORT1 in both mouse models and human acral melanoma cell lines. We will investigate the molecular mechanisms underlying the effects of SORT1 inhibitor using spatial transcriptomic analysis. We will also utilize a xenograft assay to begin assessing the effects of its inhibition on a human acral cell line. Together, these studies will establish a framework for detecting its earliest invasive behavior and reveal SORT1 as a promising target for pharmacologic intervention to block melanoma progression at its inception.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

7. Project Summary/Abstract: Studying the hair cycle provides an in vivo model for studying stem cell regulation that can be easily accessed, manipulated, and visualized. Loss of hair follicle stem cells (HFSCs) leads to hair aging and hair loss, while aberrant regulation of these HFSCs contributes to cutaneous squamous cell carcinoma (cSCC). cSCC is costly to treat and leads to metastasis and death. Hair loss leads to significant stigmatization, low self-esteem, anxiety, and reduced quality of life, which are worse in women. HFSC quiescence is essential for their self- renewal. HFSC quiescence is greater in females than males. Estrogen regulates HFSC quiescence in a sex dependent manner. However, we do not understand the complete mechanisms for these sex differences. Retinoids are a family of vitamin A derived compounds, which includes vitamin A (retinol) and its active metabolite retinoic acid (RA). RA regulated HFSC quiescence dose-dependently in vitro. Importantly, our data shows that dietary vitamin A and loss of RA synthesis also regulates HFSCs in vivo. Retinoids prevented or worsened the development of cSCC and hair loss in humans and mouse models, but few of these studies examined an effect of sex. We and others found that sex hormones regulated expression of RA synthesis and signaling genes and RA responses in a sex dependent manner. RA, in turn, affects sex hormone synthesis and signaling, suggesting the existence of an interaction between sex hormones and RA signaling. The objectives in this application are to identify how sex hormones and exogenous retinoids alter endogenous RA synthesis within the HFSC niche to maintain HFSC quiescence and determine how this affects HFSCs and hair loss during aging. Our central hypothesis is that sex hormones regulate RA synthesis to maintain HFSC quiescence to prevent hair aging. The specific aims are to: 1) Identify the vitamin A metabolism and signaling cross talk with sex hormone signaling to maintain quiescent HFSCs in a sex dependent manner; and 2) Identify the role of Sdr16c5 and Sdr16c6 in hair aging in a sex dependent manner. The approach is to treat whole body Sdr16c5-/-/Sdr16c6-/- double knockout mice with sex hormone receptor agonists and antagonists and examine HFSC quiescence. We will also rescue these transgenic mice with synthetic retinoids. In addition, we will analyze hair cycling as these mice age. Understanding how sex hormones and vitamin A metabolism interact in a sex-dependent manner to regulate hair follicle stem cells in vivo is significant because it will lead to the development of alternative sex specific retinoid treatments with more specificity and fewer side effects than current retinoid therapies. Once we identify which vitamin A metabolism enzymes and RARs are involved, we can target therapies to regulate endogenous RA synthesis and/or specific RARs. The proposed research is innovative because it will identify how endogenous RA synthesis is regulated in a sex dependent manner using state of the art retinoid analysis technology.

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.

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

We seek continued support of the Waisman Center Intellectual and Developmental Disabilities Research Center, a comprehensive interdisciplinary program focused on IDD spanning the biological, behavioral, and biomedical sciences. The Waisman IDDRC brings together 61 PIs from 24 academic departments from the UW-Madison’s Schools of Medicine and Public Health, Veterinary Medicine, Agriculture and Life Sciences, Letters and Science, Education, Engineering, Social Work, and Human Ecology. This application requests support for an Administrative Core (Core A), providing scientific leadership, program and faculty development, facilitation of interdisciplinary collaboration, oversight of training programs, biostatistical and bioinformatics expertise; and dissemination of knowledges and best practices; and three innovative scientific core services: Clinical Translational (Core B), providing services, resources, and training in the recruitment of human participants, clinical research coordination/navigation, clinical assessment, behavioral methods development, and production of clinical grade biotherapeutics for use in clinical trials; Brain Imaging (Core C), providing access to state-of- the-art neuroimaging instrumentation for both human and animal studies (3T MRI, PET, and microPET scanners for human, non-human primate, and rodent scanning, an fNIRS, and an EEG recording system), as well as expertise and tools for image acquisition and analysis; and IDD Models (Core D), providing resources, expertise, and technical services in cellular and molecular neuroscience, the generation and manipulation of human pluripotent stem cell (hPSC) lines from humans with IDD conditions, as well as the generation and behavioral phenotyping of mutant or genetically engineered strains of mice and rats as models of IDD conditions. In addition, we request support for a Research Project that addresses a fundamental question on the emergence of ADHD symptoms in children with ASD, using a multidisciplinary approach that combines the power of neurobehavioral, brain imaging, statistical genomics, and machine learning analyses. We propose to provide core support to 59 research projects headed by 42 PIs addressing three broad themes relevant to IDD: 1) neurodevelopment and mechanisms, 2) disorders of the nervous system, and 3) assessments and interventions. Collectively the core services and the research project of the Waisman Center IDDRC will stimulate new interdisciplinary IDD research and enhance existing IDD investigations, with a sharp focus on discovery, prevention, and treatment for IDD conditions, and improvement of the quality of life of individuals with IDD and their families.

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.

NCI - National Cancer Institute

ABSTRACT Glioblastoma, the most common primary malignant brain cancer, remains uniformly fatal despite current standard of care consisting of maximal safe surgical resection followed by chemotherapy and radiation. Glioblastoma is characterized by a high degree of heterogeneity, including the presence of therapeutically resistant cancer stem cells that drive tumor recurrence after therapy. Cancer stem cells are greatly influenced by cues received from the surrounding tumor microenvironment that activate signaling pathways promoting cell growth, self-renewal, and therapeutic resistance. Here, in preliminary data, we observed that glioblastoma cancer stem cells from patient-derived xenografts express the gap junction protein connexin 43 (Cx43), which drives their survival. Mechanistically, Cx43 is required to maintain expression of the proto-oncogene MYC, a critical factor for cancer stem cells that is increased in recurrent GBM. Expression of the kinase WNK lysinedeficient protein kinase 1 (WNK1) occurs downstream of Cx43 and is also required for normal levels of MYC. Interestingly, while WNK1 expression is necessary to preserve both MYC mRNA and MYC protein levels, WNK1 kinase activity appears to only be necessary for MYC mRNA expression and does not affect MYC protein levels. Based on this observation, we hypothesize that WNK1 drives GBM growth and MYC expression through both kinase-dependent and kinase-independent mechanisms. We will test this hypothesis through the following specific aims: 1) that WNK1 is required for MYC mRNA expression in a kinase-dependent manner, 2) that WNK1 regulates MYC protein in a kinase-independent manner, and 3) that a kinase-independent function of WNK1 is essential for GBM growth and therapeutic resistance. The immediate goal of this project is to provide detailed mechanistic insight into the function of kinase-dependent and kinase-independent functions of WNK1 in GBM and interrogate a potentially targetable and novel signaling node. Our longer-term goal is to translate these findings into improved treatments for patients with glioblastoma. We will utilize in vitro and organoid systems where possible for mechanistic studies and integrate these with in vivo preclinical models that better represent the tumor microenvironment. These preclinical models resemble the human condition in that glioblastoma cells do not exist in isolation and are greatly impacted by other cell types within the tumor microenvironment. As these critical interactions cannot be effectively modeled in vitro, it is essential that we use mouse models for preclinical studies to enable meaningful comparisons to human GBM formation and response to therapies.

U.S. National Science Foundation

The Workplace Equity for Persons with Disabilities in STEM and STEM Education solicitation, which is managed by the Division of Equity for Excellence in STEM in the Directorate for STEM Education,supports fundamental, applied, and translational research that advances knowledge and practice about diverse, equitable, inclusive, and accessible STEM and STEM education workplaces and postsecondary training environments for persons with disabilities. Proposals should focus on one or more of the following three research themes: (1) Studying barriers and solutions to diversity, equity, inclusion, and accessibility in STEM and STEM education workplaces and training settings for persons with disabilities; (2) Applying intersectional social identity perspectives to investigate characteristics and conditions of STEM and STEM education workplaces and training environments that limit and/or improve diversity, equity, inclusion, and accessibility for persons with disabilities; and (3) Conducting use-inspired and solution-oriented translational research about diverse, equitable, inclusive, and accessible STEM and STEM Education workplaces and training settings for persons with disabilities. Research proposals must address key project design components: (1) The inclusion of researchers, experts, and organizations with authentic disability experiences; (2) The identification of disability type(s) to be investigated; (3) The specific STEM and/or STEM education workplaces and postsecondary training settings to be studied; (4) The use of theoretical and/or conceptual frameworks and robust research hypotheses, questions, designs, methodologies, data analyses, and data interpretation; (5) A plan to assess the success of the project; and (6) A plan for the accessible dissemination of knowledge and practice outcomes to traditional and new audiences. The amount of funding and duration requested in the Research proposals submitted in response to this solicitation should align with the maturity of the proposed work and the size and scope of the project activities. Research proposals may request a budget up to $1,500,000 and a duration up to five (5) years. All proposals should justify the requested level of funding and duration in the project description.This solicitation also invites Synthesis projects, which are a very specific type of Research proposal. Synthesis projects may propose budgets up to $600,000 and project durations up to three (3) years. This solicitation also invites proposals for Conferences, EArly-concept Grants for Exploratory Research (EAGER), and Rapid Response Research (RAPID). Facilitation Awards for Scientists and Engineers with Disabilities (FASED) are always welcome. The solicitation s Section II, Program Description, provides additional information about each type of proposal.