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NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

Abstract: Chronic inflammation and fibrosis are hallmark pathologies of Duchenne Muscular Dystrophy (DMD), yet current therapies focus on restoring dystrophin in muscle cells and largely overlook the pathological microenvironment. This niche—sustained by pro-inflammatory macrophages and fibrogenic fibro-adipogenic progenitors (FAPs)—impairs regeneration and reduces therapeutic efficacy. Existing gene therapies perform poorly in fibrotic muscle and require high doses that have caused toxicity and patient deaths. To address this critical therapeutic gap, we propose a first-in-class chimeric antigen receptor T cell (CAR-T) therapy for DMD that dually targets both inflammatory macrophages and fibrogenic FAPs to reprogram the dystrophic niche. While CAR-T therapies have revolutionized cancer treatment, they have not been applied to DMD or regenerative medicine. Supported by preliminary data, our goal is to develop a CAR-T cell therapy that can eliminate pro-inflammatory macrophages and fibrogenic FAPs, restore muscle stem cell (MuSC) regenerative potential, and improve both limb and diaphragm function in pre-clinical murine models of DMD. Specifically, we will: (Aim 1) Evaluate the effect of CAR-T therapy on inflammation and fibrosis; (Aim 2) Assess its impact on muscle regeneration and function. This paradigm-shifting approach addresses a major unmet need by targeting the inflamed-fibrotic niche and may enhance the effectiveness of current gene and cell therapies. If successful, it will establish a new therapeutic framework for DMD and other muscle diseases marked by chronic inflammation and fibrosis.

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary/Abstract SCN2A encodes the voltage-gated sodium channel Nav1.2, an important channel mainly expressed in the brain to mediate neuronal action potential firing. Recent large-scale genetic studies in humans have demonstrated that mutations in SCN2A are one of the leading causes of neurodevelopmental disorders. Protein- truncating variants (PTVs), which lead to SCN2A deficiency, represent a sizable proportion. However, there is no effective treatment or cure for these genetic disorders. Our lab has established a “gene trap” Scn2a-deficient mouse model and found that partial restoration of the SCN2A gene expression can rescue key disease phenotypes. Restoration of gene expression by the exogenous supply of functional genes is a demonstrated approach to treating monogenic diseases caused by gene deficiency. Thus, developing a “gene replacement therapy” to restore SCN2A expression could be a potential therapeutic strategy. AAV is an FDA-approved delivery vehicle used in different types of gene therapies. However, one major limitation of AAV is its relatively small packing capacity. The SCN2A gene is beyond the packaging capacity of a single AAV. To overcome this packaging limitation, technologies were developed to separate a single gene into two parts for packing into two AAVs (Dual-AAV), which can then be assembled inside the cells to produce a full-length functional protein. To test the SCN2A replacement strategy in both mouse models and human cells, our lab has also established human induced pluripotent stem cells (hiPSCs) carrying SCN2A PTVs. We differentiated these hiPSCs into 3D brain organoids, and our preliminary study uncovered unique human cell-specific phenotypes, highlighting the utility of human cell-based models. In this application, we propose to test an overarching hypothesis that delivery of functional WT SCN2A via Dual-AAV vectors will rescue behavioral deficits in Scn2a-deficient mice and cellular phenotypes in human brain organoids carrying SCN2A PTVs. Our proposed study is significant because: i) It tackles one of the leading monogenic causes (SCN2A) of neurodevelopmental disorders; ii) Gene replacement is an FDA-approved therapeutic strategy for many genetic disorders. Our proposed Dual-AAV strategy will bypass the packaging limitation of AAV to deliver large genes like SCN2A to treat an expanded list of genetic disorders; iii) We will use both transgenic mouse models that show robust behavioral abnormalities and human cell-based brain organoid models that reveal human cell-specific phenotypes to comprehensively test our novel genetic interventions. By completing this study, we expect to move much closer toward gene replacement therapy for SCN2A disorders. Additionally, our study is also expected to impact other fields that benefit from Dual-AAV, including many neurological diseases caused by the deficiency of large genes.

NEI - National Eye Institute

PROJECT ABSTRACT Cataracts and glaucoma are the two leading causes of blindness worldwide. Crucial ophthalmic procedures to treat cataract, glaucoma, and other vision conditions require precise visualization of anatomy and microsurgical instruments. Visualization in such surgeries has been limited to stereo optical microscopes since the early 20th century. With advancements in optical coherence tomography (OCT), we can now obtain real-time 3D visualization within the eye. Over the past decade, intraoperative OCT (iOCT) systems have become widely researched and integrated into the latest ophthalmic microscopes built by companies such as Zeiss and Leica. These iOCT systems come with the potential to revolutionize ophthalmic surgery, with an unparalleled ability to resolve key anatomic features at micron-level precision. However, there is a crucial challenge that hampers the clinical utility of iOCT. This challenge stems from the fundamental tradeoff between OCT field-of-view and imaging speed. This tradeoff constrains state-of-the-art systems to operate with a relatively small (e.g. 5x5 mm) field of view to achieve the volume update speeds (~10-15 Hz) required for surgical visualization. Consequently, a trained operator on the surgical team must manually reposition the OCT scan throughout the surgery. The current implementation of iOCT results in a “point-and-shoot” approach to imaging, i.e. using OCT as an intermittent snapshot tool, rather than as a continuous surgical visualization technology. With even small movements of the surgical instruments, the OCT image can quickly lose sight of the surgical region of interest (ROI). Manual tracking of iOCT discards a key advantage of OCT, which is real-time 3D data collection. With advances in deep learning methods for image processing and object recognition, there are new opportunities to tackle this problem. The goal of this project is to engineer a novel computational system for automatic, real- time tracking of the surgical ROI in a clinical iOCT system. Our vision is to develop a system that can be readily applied to existing clinical microscopes, and adaptable to future robotic surgical systems. As part of our preliminary work, we have created a lateral tool tracking OCT system using deep learning models applied to the microscope feed. Our current system utilizes a novel synthetic data approach, making use of 3D-rendered models of eyes and tools to accelerate deep learning model development. In the proposed project, we expand on this preliminary work by developing a system for 3D multimodal surgical ROI tracking of iOCT that can be applied to many different types of ophthalmic surgeries. We will then evaluate our platform via ex-vivo porcine and human cadaver eye studies with wet-lab benchmarking and simulated surgeries with our clinical collaborators. Our immediate application is ophthalmic surgery, but the methodology has relevance to a wide range of 3D imaging systems for microsurgical procedures. By developing this system for dynamic OCT surgical tracking, we hope to improve ophthalmic visualization in both training and surgical practice.

NHLBI - National Heart Lung and Blood Institute

Project summary/Abstract Hematopoiesis is a highly regulated process fueled by hematopoietic stem cells (HSCs) and progenitors in response to physiological and pathological changes throughout life. During development, the system quickly expands to provide increasing numbers of blood cells for the growing tissues and organs. In regeneration, HSCs re-establish the hematopoietic hierarchy and supply lost blood cells to restore tissue function. In pathological conditions, dysregulated hematopoiesis drives disease progression. A detailed cellular and molecular understanding of the mechanisms of dynamic hematopoiesis is key to intervening in these processes for therapeutic benefits. Although the niche critically regulates HSCs and hematopoiesis, how the niche is dynamically regulated to adapt to the distinct demands in the ever-changing conditions is not clear. Our previous work has identified key cellular components of the niche in the bone marrow and developing liver, allowing precise studies of niche dynamics in these organs. Our recent work has also revealed surprising cell fate plasticity in the bone marrow niche. The proposed work in this application builds on these findings to 1) define niche dynamics and plasticity in development, regeneration, and hematological disease, 2) uncover the mechanisms that regulate these processes, and 3) harness the mechanisms to enhance niche function and boost blood cell production. We will use several novel mouse models generated in the lab to study the function of key pathways in regulating niche dynamics and cell fate plasticity. We will employ single-cell transcriptomics, imaging, metabolic analysis, functional studies, and other cutting-edge approaches to understand how these key pathways regulate niche dynamics and plasticity. Collectively, these experiments will uncover novel mechanisms that regulate niche cell dynamics and plasticity with broad implications for better treatment of blood diseases. They may lead to transformative strategies for boosting blood cell production by enhancing niche function.

NIGMS - National Institute of General Medical Sciences

Abstract Flagella—motile, hair-like appendages extending from the surface of cells—are ubiquitously present across all three domains of life. These organelles carry out diverse functions of cells, including motility, sensory perception, and fluid transport, through their primary ability to move ambient fluids relative to the cells. Thus, understanding the interaction between flagella and their surrounding fluid, particularly their fluid-transport capability, is crucial to addressing a wide range of fundamental biological questions. While advances in electron microscopy and X-ray crystallography have illuminated the ultrastructures of bacterial and eukaryotic flagella, the dynamics of motile flagella in fluid environments remain poorly understood. The challenges in studying flagellar dynamics in fluid media stem from the lack of suitable experimental tools capable of imaging collective flagellar motions in real time at small length scales and mapping the three-dimensional (3D) fluid flow around rapidly beating flagella with high spatial and temporal resolution. Drawing on my unique training and career path, I lead a research group that develops new physical model systems and advanced novel imaging techniques to elucidate fluid-mediated flagellar dynamics in key biological processes. Specifically, we aim to address two critical questions on flagellar dynamics in this R35 MIRA proposal. 1) Resolving the synchronized dynamics of prokaryotic flagella that enable the formation of a bacterial flagellar bundle, a process essential for bacterial motility and chemotaxis. 2) Imaging the 3D fluid flow generated by beating eukaryotic flagella and their various mutants, a long-standing challenge that is central to the understanding of the functional consequences of normal and dysfunctional flagella and the key step towards the development of treatments for ciliopathies. Specifically, in Goal 1 of our proposed research, we will integrate experiments on peritrichous bacteria Escherichia coli and their genetically engineered mutants with a scaled physical model of a bacterial flagellar bundle constructed in my lab. This unique approach will help to reveal the detailed mechanisms, through which different physical factors, such as hydrodynamic interactions, the elastic properties of flagellar hooks, and motor torque fluctuations, control the synchronization and formation of bacterial flagellar bundles. In Goal 2, we will develop a new imaging technique—high-speed tracking holographic microscopy—to measure the temporal variations of the three-dimensional flow around the beating flagella of a green alga, Chlamydomonas reinhardtii, which serves as a premier model for eukaryotic flagella. Our research will deliver the first comprehensive characterization of the 3D flow field generated by isolated motile eukaryotic flagella in their natural, unperturbed state and directly correlate abnormal flagellar structures with their functional deficiencies in fluid transport. Thus, through the innovative model system and the advanced experimental techniques pioneered in our lab, our study will address crucial open questions on the dynamics of motile prokaryotic and eukaryotic flagella in fluid media.

NIDCR - National Institute of Dental and Craniofacial Research

Project Summary: Cells are sensitive to changes in DYRK1A (Dual-specificity tyrosine-regulated kinase 1A) dosage. Too much DYRK1A occurs with Down Syndrome since it is located within the critical region of chromosome 21. Too little DYRK1A is associated with DYRK1A Syndrome caused by loss of function variants of the gene. Both these syndromes are characterized by a range of birth defects including craniofacial differences. Such differences can pose immense medical and social burdens regardless of intellectual problems. Therefore, the goal of this work is to investigate how alterations of DYRK1A dosage affects face formation. Moreover, we aim to uncover the mechanisms through which changes in the levels of this protein influences developmental processes such as cell cycle, senescence, and cell survival. We propose to integrate experiments in a developmental model Xenopus laevis with Down Syndrome patient derived cells and human stem cells. In Aim 1 we will test the hypothesis that too much DYRK1A causes inappropriate levels of senescent cells which in turn contributes to orofacial differences. We will scrutinize senescence in the developing face of Xenopus embryos and attempt to ameliorate craniofacial malformations in embryos with excess Dyrk1a using anti- senolytics and other agents to reduce senescence. We will also test whether a reduction in DYRK1A can delay or prevent Down Syndrome patient derived fibroblasts from entering senescence. This work could have an enormous impact on Down Syndrome research. In Aim 2 we will test the hypothesis that a reduction in Dyrk1a results in the activation of the intrinsic apoptotic pathway which contributes to orofacial differences. We propose that Dyrk1a is protective in the embryo in that it maintains pathways necessary for cell survival which allows for proper growth and development. Here we will further scrutinize the role for Dyrk1a in cell survival in craniofacial tissues and human mesenchymal iPS cells. Further, we will attempt to rescue craniofacial malformations with antiapoptotic or pro-survival agents. This could present new treatment avenues for DYRK1A Syndrome. In Aim 3 we will work on building the DYRK1A interactome in development. The focus will be on one protein, Lzts2, which preliminary evidence indicates it indeed interacts with Dyrk1a during craniofacial development. We will test the hypothesis that Lzts2 is required for nuclear localization and cell cycle regulatory functions of Dyrk1a. In addition, we will also evaluate whether novel DYRK1A interactors uncovered in a proteomics screen in the Litovchick lab also interact with Dyrk1a in craniofacial development. Understanding DYRK1A interactors could present new ways to modulate the function and levels of DYRK1A in associated syndromes in humans. In summary, the proposed work brings together a developmental biologist and an expert in DYRK1A molecular biology to make major inroads into the roles of this multifunctional kinase during development. Our work also aims to test new methods to ameliorate craniofacial defects caused by altered DYRK1A dosage. Such methods could translate to the development of therapeutics that could be used in both DYRK1A and Down Syndromes.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY/ABSTRACT Radiation-induced intestinal injury is a frequent and debilitating complication of abdomino-pelvic cancer therapy, often resulting in malabsorption, infection, and chronic gastrointestinal dysfunction. The intestinal epithelium regenerates through dedifferentiation events that give rise to revival stem cells (RevSCs), which replenish lost LGR5⁺ intestinal stem cells (ISCs) following injury. While the identity and regenerative potential of RevSCs are increasingly well understood, the earliest chromatin remodeling events and mechanisms that initiate their formation are not. Preliminary scRNA-seq data from our lab show that Bmi1-YFP⁺ epithelial cells, derived from Bmi1-CreERT2; Rosa26eYFP mice, form a distinct RevSC cluster as early as 24 hours post-irradiation, a timepoint significantly earlier than previous reports of RevSCs emerging from 48-96h. Thus, employing this mouse model provides a unique mechanistic window for studying the early emergence and regulation of RevSCs. We observed widespread chromatin accessibility changes at RevSC loci within 3 hours following injury from ATAC-seq data on intestinal epithelial cells (IECs), indicating promoter and enhancer remodeling as a key early event. Given the role of CBP/p300 histone acetyltransferases in maintaining enhancer activity, I hypothesize that injury-induced chromatin remodeling and a transient reduction in CBP/p300-dependent acetylation following injury, direct IECs toward a “pre-RevSC” state, which can be investigated through the lens of the Bmi1-lineage, enabling subsequent RevSC formation. I will test my hypothesis with two SPECIFIC AIMS. Aim 1 will define the transcriptional and chromatin dynamics that drive RevSC emergence by combining single-nucleus multi-ome (snRNA+snATAC-seq) and CUT&RUN profiling in both whole intestinal tissues, capturing broad, lineage- independent changes, and Bmi1-YFP⁺ IECs to investigate drivers of RevSC emergence. Aim 2 will determine how CBP/p300 inhibition alters enhancer accessibility and promotes RevSC formation and lineage plasticity using in vitro organoid models and in vivo pharmacologic and genetic perturbations. This work will generate a high-resolution atlas of early regenerative chromatin states and uncover enhancer-centric mechanisms that govern epithelial reprogramming. Importantly, it will elucidate how enhancer accessibility and histone modifications orchestrate cell fate transitions during intestinal regeneration, uncovering early epigenetic regulators of RevSC formation. These findings will identify molecular markers of regenerative potential and inform strategies to enhance mucosal repair in radiation enteropathy and inflammatory bowel disease. As part of a structured training plan, I will receive hands-on instruction in single-nucleus multi-omics, enhancer mapping, and organoid-based assays, complemented by formal coursework, clinical shadowing, and mentorship from physician-scientists. This integrated approach will provide the technical, analytical, and professional foundation necessary for a successful career as a physician-scientist in gastroenterology.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY Early life stress (ELS), particularly during fetal development, is a critical risk factor for long-term health, including obesity and metabolic disorders. This project investigates how prenatal stress exposure is biologically embedded, leading to increased vulnerability to abdominal adiposity and metabolic dysfunction. Our long-term goal is to eluci- date cellular and molecular pathways that mediate the developmental origins of metabolic disease, supporting early identification and prevention strategies for at-risk children. Despite known associations between ELS and adult dis- ease, current research is limited by inconsistent findings in early life, inadequate biomarkers of fetal stress exposure, and poor measurement of adiposity in infants. Traditional reliance on weight-based metrics fails to capture fat dis- tribution, which is key to metabolic risk. Moreover, stress exposure during pregnancy is typically estimated from basal circulating biomarkers, neglecting dynamic physiological stress responses. To address these gaps, we employ a translational, multi-level design integrating basic science and clinical research. Using umbilical-derived mesenchy- mal stromal cells (MSCs) from human newborns, we will model individualized cellular vulnerability to ELS. In par- allel, we will track in vivo adipose development using serial MRI assessments and metabolic profiling in infants. Our specific aims are: Aim 1: Determine if biological stress during pregnancy predicts infant adiposity, distribution, and metabolic function using state-of-the-art MR imaging at birth and 5–6 months. Aim 2: Test whether MSCs from high-stress exposed infants exhibit greater cellular vulnerability under in vitro adi- pogenic challenge conditions. Stress exposure will be comprehensively quantified using ex vivo glucocorticoid-cytokine stimulation, diurnal sali- vary cortisol sampling, and maternal blood assays during early and late pregnancy. These data will be synthesized into a composite (PCA) biological stress exposure score. We hypothesize that dynamic, functionally derived measures of maternal stress will better predict infant abdominal adiposity and metabolic function than static bi- omarkers, and that stem cells from high-stress-exposed infants will exhibit greater vulnerability—reflected by in- creased lipid accumulation and hypertrophy—especially under in vitro challenge conditions. This integrated ap- proach will illuminate mechanisms of biological embedding and identify novel markers of metabolic risk. Findings will advance precision health by enabling targeted early-life interventions. This project will also establish a scalable human newborn stem cell biobank for future studies of stress-related disease pathways.

U.S. National Science Foundation

Plasma science is a transdisciplinary field of research where fundamental studies in many disciplines, including plasma physics, plasma chemistry, materials science, and space science, come together to advance knowledge for discovery and technological innovation. The primary goal of the ECosystem for Leading Innovation in Plasma Science and Engineering (ECLIPSE) program is to identify and capitalize on opportunities for bringing fundamental plasma science investigations to bear on problems of societal and technological need within the scope of science and engineering supported by the participating NSF programs. The ECLIPSE meta-program has been created to foster an inclusive community of scientists and engineers, an ecosystem spanning multiple NSF Directorates, in the pursuit of translational research at the interface of fundamental plasma science and technological innovation. The ECLIPSE program builds on the long history of NSF leadership in supporting multi-disciplinary research in plasma science and engineering, and is intended to enhance organizational unity within NSF, and potentially with other funding agencies, in considering proposals and supporting projects that may otherwise struggle to find a natural home within the existing hierarchy of Directorates, Divisions, and programs within the Foundation. Examples of topical areas within the scope of the ECLIPSE program include but are not limited to: Plasma surface interactions, with applications to, e.g., advanced manufacturing, materials processing, and catalysis. Atmospheric pressure plasmas and microplasmas with applications to, e.g., microelectronics, plasma agriculture, environmental remediation, and other clean and decarbonized energy goals enabled by electrification of the chemical industry. Dusty plasmas with applications to, e.g., development of nanomaterials, aerosols, and functionalized surface coatings. Novel sensor development for highly non-equilibrium plasmas with applications to, e.g., cubesat-based geospace measurements and industrial plasma diagnostics. Novel computational modeling for multi-component and/or multi-phase plasma systems with applications to, e.g., space weather prediction and plasma reactor design. Novel studies of plasmons in nano-photonics and nano-optics with applications to, e.g., sub-THz wireless communication and photocatalytic chemical processes. New chemical measurement science for characterizing processes occurring in plasmas and using plasmas as part of measurement systems with applications to, e.g., analysis of environmental contaminants or identification of forensic evidence. Study of fundamental chemical reactions and mechanisms in plasmas with applications to, e.g., novel chemical synthesis. Proposals submitted for consideration by this program should address societal or technological needs within the scope of science and engineering supported by the National Science Foundation. Proposals addressing technology development primarily supported by other US government funding agencies are not eligible for consideration and may be returned without review. Proposers are strongly encouraged to contact the cognizant Program Officers if they are unsure of the suitability of a project to this program. Proposals submitted for consideration by the ECLIPSE program should satisfy the following criteria: (1) clearly articulate the fundamental scientific and/or engineering challenge in plasma science and engineering that may be relevant to more than one NSF program; and (2) provide a substantive discussion of how a resolution of the stated scientific and/or engineering challenge will address specific societal and/or technological needs identified as priorities by the research communities, policymakers and/or other stakeholders. Depending on the nature of the proposal, the latter may be described as the Intellectual Merit or the Broader Impact of the proposed activity. The program encourages inclusion of specific efforts to increase the diversity of the ECLIPSE community and to broaden participation of under-represented groups in Science, Technology, Engineering, and Mathematics (STEM) as Broader Impacts of proposed work. The program welcomes proposals from Historically Black Colleges and Universities (HBCUs), other Minority Serving Institutions (MSIs), and institutions in EPSCoR-eligible jurisdictions, along with collaborations between these institutions. Proposers are also encouraged to address how the proposed efforts may enhance workforce development towards STEM careers associated with the field of plasma science and engineering. The ECLIPSE program is not intended to replace existing programs. A proposal that is requesting consideration within the context of ECLIPSE should begin the title with the identifying acronym "ECLIPSE:" and should be submitted to one of the "Related Programs" listed below. In choosing the most relevant program, proposers are advised to read program descriptions and solicitations carefully and to consult with cognizant Program Officers in advance of proposal preparation. Proposal submissions outside of the scientific scope of the receiving program may be transferred to a different program or may be returned without review. Proposers should ask for consideration and review as an ECLIPSE proposal only if the proposal addresses both of the criteria listed above. Proposals marked for consideration by the ECLIPSE program that do not address both of these criteria may be returned without review or reviewed within the context of an individual program. Supplement requests to existing awards within a program that address both of the above criteria may also be considered. Information Sharing with other Funding Agencies When permitted under an MOU between NSF and another funding agency, NSF may share information from proposals for consideration of joint funding and may invite employees of such organizations to attend merit review panels as observers.

NIEHS - National Institute of Environmental Health Sciences

Identifier: 1908301 EcoWell: Smart Incubation Technology for Next-Generation Environmental Science Labs Project Summary Overview: The EcoWell™ platform addresses a critical gap in environmental science education by introducing a novel, affordable, and accessible classroom tool that models environmental conditions in real time. Built around a modular micro-incubation system, the platform empowers students to explore the biological effects of environmental pollutants and measure related biological endpoints. These environmental stressors are increasingly prevalent due to systemic pollution, habitat degradation, and industrial activity, yet remain underrepresented in K–12 science curricula. The Need: Systemic pollution has become a significant threat to public and environmental health. Despite the urgency of these issues, educational infrastructure has not kept pace with the tools needed to effectively engage students in hands-on learning about toxicological processes, bioremediation, and environmental monitoring. Traditional science classroom kits are often linear, rigid, and fail to replicate real-world complexity or generate meaningful data. Moreover, students frequently lack the tools to interpret experimental results, assess sources, or connect local phenomena to regional, national, and global systems. Innovation and Impact: EcoWell™ is a transformative tool that enables students to simulate, manipulate, and analyze complex environmental scenarios using compact, programmable six-well incubation chambers. Each chamber is capable of independently controlling and measuring variables such as temperature, ultraviolet light and CO₂ levels, and gas exchange—parameters critical to understanding pollution’s biological impact. This modularity supports a wide variety of experimental applications: students can assess bacterial growth under UV-induced DNA stress, explore algal blooms in nutrient-loaded water, or measure plant response to synthetic pollutants. The platform is paired with a suite of NGSS-aligned educational kits covering a range of NIEHS-relevant topics such as: Bioremediation using duckweed to extract nitrates and heavy metals, Water sterilization and pathogen load mitigation using UV radiation, Gas exchange and oxidative stress modeling, Growth response of model organisms under pollutant and light stress conditions. By offering customizable experimentation and quantifiable outputs, EcoWell™ bridges the gap between basic science education and environmental toxicology, preparing students for STEM careers while improving environmental literacy. Alignment with NIEHS Goals: EcoWell™ aligns with NIEHS's mission to understand how environmental exposures affect human health by educating future generations in exposure biology, toxicology, and environmental systems thinking. The system gives students the skills to explore real-world questions with real-time data, and to connect experimental results to ongoing public health and environmental challenges.

Edison International

Supports STEM education, workforce development, environment, and civic engagement through Southern California Edison's parent foundation.

U.S. National Science Foundation

The EDU Core Research (ECR) program offers this ECR:Core solicitation and invites proposals for fundamental research (curiosity-driven basic research and use-inspired basic research) that contributes to the general, explanatory knowledge that underlies STEM education in one or more of the three broadly conceived Research Areas: Research onSTEM Learning and Learning Environments, Research on Broadening Participation in STEM fields, andResearch on STEM Workforce Development. Within this framework, the ECR program supports a wide range of fundamental STEM education research activities, aimed at learners of all groups and ages in formal and informal settings. Fundamental researchgenerates knowledge and understanding with the potential for broad relevance. The potential implications of ECR fundamental research for improving STEM education practice may be indirect and long-term rather than direct and immediate. Moreover, whether they include basic or use-inspired basic research, all successful ECR:Core proposals focus on the advancement or refinement of foundational knowledge for STEM education. The amount of funding and duration requested in proposals submitted to the ECR:Core solicitation should align with the maturity of the proposed work and the size and scope of the empirical effort. The solicitation has three levels of funding with a range of budget sizes, and proposals may request a duration of 3 to 5 years for any level: (1)Level I proposals may request up to $500,000; (2)Level II proposals may request up to $1,500,000; (3)Level III proposalsmay request up to $2,500,000. All proposals should justify the level of funding and duration in the project description.

U.S. National Science Foundation

The EDU Core Research (ECR) program offers this ECR:Core solicitation and invites proposals for fundamental research (curiosity-driven basic research and use-inspired basic research) that contributes to the general, explanatory knowledge that underlies STEM education in one or more of the three broadly conceived Research Areas: Research onSTEM Learning and Learning Environments, Research on Broadening Participation in STEM fields, andResearch on STEM Workforce Development. Within this framework, the ECR program supports a wide range of fundamental STEM education research activities, aimed at learners of all groups and ages in formal and informal settings. Fundamental researchgenerates knowledge and understanding with the potential for broad relevance. The potential implications of ECR fundamental research for improving STEM education practice may be indirect and long-term rather than direct and immediate. Moreover, whether they include basic or use-inspired basic research, all successful ECR:Core proposals focus on the advancement or refinement of foundational knowledge for STEM education. The amount of funding and duration requested in proposals submitted to the ECR:Core solicitation should align with the maturity of the proposed work and the size and scope of the empirical effort. The solicitation has three levels of funding with a range of budget sizes, and proposals may request a duration of 3 to 5 years for any level: (1)Level I proposals may request up to $500,000; (2)Level II proposals may request up to $1,500,000; (3)Level III proposalsmay request up to $2,500,000. All proposals should justify the level of funding and duration in the project description.

U.S. National Science Foundation

ECR s Building Capacity in STEM Education Research (ECR: BCSER) supports projects that build investigators capacity to carry out high-quality STEM education research that will enhance the nation s STEM education enterprise. In addition, ECR: BCSER seeks to broaden the pool of researchers who can advance knowledge regarding STEM learning and learning environments, broadening participation in STEM fields, and STEM workforce development. Researchers institution types are particularly encouraged to submit proposals. Specifically, ECR: BCSER supports activities that enable researchers to expand their areas of expertise and acquire the requisite knowledge and skills to conduct rigorous research in STEM education. Career development may be accomplished through investigator-initiated professional development and research projects or through institutes that enable researchers to integrate methodological strategies with theoretical and practical issues in STEM education.

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

Project Summary Building a healthy adult brain requires the precise coordination of multiple developmental processes, including neural stem cell proliferation and differentiation, neuropil extension, synaptogenesis, and synaptic pruning. These processes are sensitive to genetic, environmental, and physiological conditions, and disruptions can have lasting consequences on brain structure, function, and behavior. Early-life immune activation, such as that triggered by infection, has been associated with impaired growth, cognitive deficits, and increased risk of metabolic syndrome later in life. However, the mechanisms linking immune activity during development to long- term neural outcomes remain poorly understood. This project investigates how systemic infection and innate immune signaling influence brain development and adult physiology. Neural stem cells depend on nutrient- responsive growth signaling pathways to support their proliferation and the production of neurons and glia. Preliminary data show that activation of a conserved innate immune pathway—whether through bacterial exposure or genetic manipulation—leads to reduced body and brain size and delays the reactivation of neural stem cells from quiescence. The central hypothesis is that early-life infection activates immune signaling that disrupts neurodevelopmental programs, leading to persistent changes in brain structure and function. This research will define how immune activation alters neural stem cell behavior, impacts brain growth, and shapes adult behavioral outcomes. The findings will provide insight into how developmental immune stressors influence long-term brain health and may inform our understanding of neurodevelopmental disorders associated with early-life inflammation.

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

PROJECT SUMMARY Over 1 million women living with HIV (WLWH) give birth annually. With widespread use of combination antiretroviral therapy (cART), vertical transmission has been significantly reduced, resulting in ~16 million HIV- exposed uninfected (HEU) children as of 2023. Despite being HIV negative, these children face increased risks of poor growth, infection-related mortality, and respiratory disease. These outcomes are believed to result from maternal HIV-induced inflammation and/or cART toxicity, as many antiretrovirals cross the placenta and may disrupt fetal immune development. However, distinguishing the effects of HIV versus ART is difficult in clinical studies due to challenges of studying non-HIV infected women receiving ART. Limited access to fetal tissues further hampers mechanistic insight, creating a need for translational animal models. To address this critical knowledge gap, we propose to use a rhesus macaque model of simian immunodeficiency virus (SIV) infection to investigate how maternal HIV and long-acting ART (LA-ART) affect fetal immune development. We hypothesize that despite the absence of vertical transmission, maternal SIV and LA-ART exposure dysregulates immune ontogeny in the offspring via altered hematopoiesis. A novel LA-ART regimen of FDA-approved drugs Lenacapavir (LEN) and Cabotegravir (CAB), shown to provide effective viral suppression in preliminary macaque studies, will be given bimonthly by injection to female macaques that will then undergo time-mated breeding following viral suppression. Three experimental groups will be studied: [1] SIV-infected, LA- ART treated; [2] uninfected, LA-ART treated; and [3] uninfected, untreated controls. Offspring will be delivered naturally and monitored through six months of age. Specific Aim 1 will assess how maternal SIV/LA-ART versus LA-ART alone affects infant immune maturation and function in the periphery and in tissues using flow cytometry, single-cell RNA/ATAC-sequencing, and in vitro stimulation. We will evaluate vaccine responsiveness using Varivax™ and examine B/T cell responses and receptor repertoires. Specific Aim 2 will study the impact of maternal SIV/LA-ART versus LA-ART alone on hematopoiesis in the offspring. We hypothesize that SIV/LA-ART exposure impairs differentiation and maturation of hematopoietic stem and progenitor cells (HSPCs). Bone marrow will be analyzed via flow cytometry, differentiation assays, and single-cell RNA/ATAC-sequencing. Functional HSPC capacity will be tested via transplantation into immunodeficient mice. This study uses a clinically highly relevant primate model for HIV cure research and neonatal immunity, and advanced immunological tools to uncover how maternal HIV and LA-ART exposure alter infant immune development. Findings will guide future strategies to improve immune outcomes in HEU children.

NIDCR - National Institute of Dental and Craniofacial Research

ABSTRACT Periodontitis is a common oral inflammatory condition that is epidemiologically linked to systemic disorders such as cardiovascular disease, rheumatoid arthritis, and type-2 diabetes. The relationship between periodontitis and systemic comorbidities is bidirectional, as proinflammatory diseases can also predispose to and accelerate the progression of periodontitis. Nevertheless, the factors leading to the association between periodontitis and comorbidities remains unclear. The low-grade systemic inflammation caused by periodontitis may contribute to its connection with systemic diseases. Recent studies have shown periodontitis to rewire hematopoietic stem cell (HSC) transcriptional and epigenetic profile, which is the base for trained innate immunity. Further, our own pilot data suggest that periodontitis activates HSC, inducing cell cycle entry and loss of repopulating potential in a sex-dependent way. However, the long-term effects of recurrent periodontitis on HSC function and clonal complexity remain unknown. Importantly, HSCs have limited replicative potential, and repeated acute inflammatory episodes that drive HSC proliferation may contribute to their decline. This decline is believed to be a major factor in the development of age-related hematologic diseases resulting from dysfunctional HSCs, such as clonal hematopoiesis, myeloid leukemias, and anemia. Understanding how inflammation regulates HSC fate and influences the blood system during development, aging, chronic inflammatory diseases, and hematological malignancies is crucial for uncovering the mechanistic foundations of these processes and their potential connections. In this study, we will: 1) establish a model for chronic periodontitis that mimics its long-term effects on HSCs, and 2) define the functional consequences of chronic periodontitis on HSCs, considering sexual dimorphism and local versus systemic effects. The results from this proposal will enhance our understanding of chronic inflammation's impact on HSC function. Moreover, the research outlined here will identify periodontitis as a risk factor for the development of hematopoietic pathologies. This will enable us to expand our studies to interrogate the consequences of this pathology in other tissues, both in isolation and alongside comorbidities, highlighting the importance of oral health in preventing inflammatory diseases.

U.S. National Science Foundation

The EHR Core Research (ECR) program establishes a mechanism in the Directorate for Education and Human Resources to provide funding in foundational research areas that are broad, essential and enduring. EHR seeks proposals that will help synthesize, build and/or expand research foundations in the following core areas: STEM learning, STEM learning environments, workforce development, and broadening participation in STEM. We invite researchers to identify and conduct research on questions or issues in order to advance the improvement of STEM learning in general, or to address specific challenges of great importance. Two types of proposals are invited: Core Research Proposals (maximum 5 years, $1.5 million) that propose to study a foundational research question/issue designed to inform the transformation of STEM learning and education and Capacity Building Proposals (maximum 3 years, $300,000) intended to support groundwork necessary for advancing research within the four core areas.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary / Abstract This is a R01 application from Dr. Daniel Lingwood (PI) an Associate Professor of Medicine at the Ragon Institute of MGH, MIT and Harvard and Dr. Batista (co-PI), a Professor of Medicine at the same institution. These investigators define immunological decision making by B cells to inform vaccine design and have built humanized mouse systems that recapitulate human antibody responses. Dr. Andrew Ward (co-I) is Professor in the Department of Structural and Computational Biology at Scripps and specializes in high resolution cryoEM of antibody:antigen complexes. The application goal is universal influenza vaccine development, centered on their discovery of a human broadly neutralizing antibody (bnAb) pathway that the investigators can vaccine-elicit to protect against all influenza A viruses (IAV), the major source influenza disease and all pandemic events. Differences in N-glycosylation generally prevents antibodies from engaging the otherwise conserved hemagglutinin (HA) stem of group 1 versus group 2 IAV. To solve this issue, the investigators engineered nanoparticle immunogens that elicit cross-group IAV immunity by selectively triggering and maturing germline B cell receptors (BCRs) encoding VH1-18 QxxV class bnAbs, a rare but genetically reproducible or ‘public’ category of human pan-IAV bnAbs that accommodates N-glycan diversity on the HA stem. The investigators successfully elicit this cross-group bnAb response using a single shot within a humanized vaccine model containing the VH1-18 QxxV bnAb precursors at physiologically relevant human frequency within the naïve B cell pool. The immunogens select for key affinity enhancing mutations, including N55T in the CDRH2, a hallmark of VH1-18 QxxV bnAbs. The investigators show that N55T alone provides cross-group IAV protection by a novel antibody tilting mechanism that accommodates N-glycan diversity on the HA stem. The investigators will now test the central hypothesis that this ‘molecular switch’ endows humans with an exceptionally simple vaccine- expandable pathway for eliciting broad spectrum IAV immunity. In Aim 1, the investigators will apply their modular human vaccine model to define the number of naive VH1-18 QxxV B cells needed for pan-IAV vaccine protection; if these bnAb precursors are absent, the germline stimulating nanoparticles no longer elicit pan-IAV bnAbs, revealing a human B cell repertoire effect encoding for unprecedently broad IAV immunity. In Aim 2, the investigators will define whether their nanoparticle immunogens can co-expand multiple classes of cross-group IAV bnAbs within their human vaccine model. Critically, their engineered nanoparticle immunogens also bear germline stimulating affinity for the naïve BCRs encoding the other known classes of genetically reproducible pan-IAV bnAbs produced by humans, potentiating multiclass bnAb elicitation via pan-germline stimulation. In the Aim 3, the investigators will define how prior exposure to IAV modulates (and enhances) germline stimulation and vaccine elicitation of pan-IAV bnAbs via imprinting effects. Collectively, this proposal will exploit novel genetically hardcoded templates for eliciting cross-group IAV immunity in humans.

NHLBI - National Heart Lung and Blood Institute

Project Summary Respiratory viruses can acutely lead to high mortality from respiratory failure. However, respiratory viral infections also cause permanent morbidity long after recovery from the acute infection. Such chronic debilitation was best exemplified during the COVID-19 pandemic that left many patients with post-acute sequelae of SARS-CoV-2 (PASC; aka long COVID). One unfortunate consequence after a severe COVID-19 infection is the development of persistent pulmonary fibrosis (PASC-PF). However, this fibrotic remodeling of the lungs is not unique to infections by SARS-CoV-2 and has also been found with other viral infections such as influenza, MERS-CoV, SARS-CoV-1. Investigations into PASC-PF have revealed common features when compared to idiopathic pulmonary fibrosis (IPF), the archetype of progressive lung fibrosis. A fundamental feature in PASC-PF, IPF, and other types of lung fibrosis is the maladaptive repair of the lung epithelium that is an upstream driver of fibroproliferation. In particular, the type 2 alveolar epithelial cell (AT2) cells, which are the facultative epithelial stem cells of the alveoli, are exhausted and fail to properly repair the lungs after injury. Accordingly, damaged alveoli have a repair deficiency with a failure of AT2 differentiation into alveolar type 1 (AT1) cells that are necessary for lining the alveoli to facilitate gas exchange in the lungs. To that end, recent studies have found IFN-γ to be a key signaling node that is enriched in PASC-PF and IPF. Moreover, studies by our group and others have demonstrated IFN-γ blockade to reduce fibrosis and augment epithelial repair in a viral-induced lung fibrosis model. Accordingly, we have developed a central hypothesis that anti-viral immunity by CD8+ T cells directly (via IFN-γ) and indirectly (via MDM secretion of IL-1β) stalls alveolar regeneration thereby shifting the injury response toward maladaptive repair thereby activating fibroproliferative pathways. We will test the hypothesis in three aims: Aim 1. Evaluate viral-mediated maladaptive reprogramming of AT2 cell. Aim 2. Uncover the cellular and molecular mechanisms that mediate the abnormal immune-epithelial interactions contributing to chronic lung fibrosis following viral infection. Aim 3. Identify abnormal immune-epithelial interactions in human post-viral lung fibrosis . The successful completion of this study promises to elucidate the cellular and molecular etiology of lung fibrosis and have a broad impact on understanding fibroproliferative mechanisms in PASC-PF, IPF, and other forms of lung fibrosis.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY Progressive familial intrahepatic cholestasis (PFIC) is a group of rare, inherited liver diseases that impair bile formation and excretion, leading to severe cholestasis, progressive liver damage, and, often, the need for liver transplantation in childhood. ATP8B1 deficiency, previously known as PFIC1, caused by mutations in the ATP8B1 gene, remains poorly understood due to the lack of suitable animal models and the rarity of the disorder. Current treatment strategies focus on reducing enterohepatic bile acid circulation but fail to prevent ongoing hepatocellular injury. The ATP8B1 protein (FIC1) maintains canalicular membrane asymmetry and modulates bile acid signaling through the farnesoid X receptor (FXR), but how its loss-of-function causes cholestasis is incompletely understood. Using patient-derived induced pluripotent stem cells (iPSCs) carrying the common ATP8B1 G308V mutation, our group has established clinically relevant hepatocyte and cholangiocyte models that recapitulate disease phenotypes. Preliminary studies reveal alterations in plasma membrane organization, FXR activation, glutamine metabolism, and cholangiocyte protective mechanisms. This proposal will test the central hypothesis that ATP8B1 G308V disrupts bile acid homeostasis and cellular resilience through impaired FXR activity, altered glutamine metabolism, and reduced cholangiocyte protection, leading to cholestasis and progressive liver pathology. Specifically, we will i) define how FIC1 deficiency and FXR suppression contribute to bile acid accumulation and hepatocyte vulnerability, ii) interrogate the role of glutamine metabolism in bile acid dysregulation and determine whether supplementation restores hepatocyte function, and iii) evaluate how restoring MUC1 expression improves cholangiocyte function and hepatobiliary homeostasis. The proposed studies will generate new mechanistic insights into ATP8B1 deficiency, provide a unique patient- derived model for studying rare cholestatic diseases, and identify molecular pathways that can be targeted for therapeutic intervention. Ultimately, this work will inform strategies not only for PFIC1 but also for other cholestatic and metabolic liver diseases of genetic origin.

NIGMS - National Institute of General Medical Sciences

Project Summary The broad, long-term objectives of this application are to characterize mechanisms that allow a competitive germline stem cell (GSC) and its descendants to dominate the GSC population and cause super-Mendelian inheritance. The proposal will determine how a GSC in the Drosophila testis remodels its niche and causes the selective loss of WT neighbor GSCs. To accomplish this, the proposal will utilize immunofluorescence, genetics, RNA interference, extended ex vivo live-cell imaging, transcriptomics, chromatin labelling, and innovative assays of GSC competition and allele inheritance in F1 offspring. We will capitalize upon the powerful genetics available in Drosophila, as well as the ability to unequivocally identify the niche, GSCs, differentiating germline cells, and somatic stem cells (CySCs) and their lineage in the Drosophila testes. This proposal is supported by our published results demonstrating that (1) loss of the transcription factor Chinmo in a GSC causes the ectopic secretion of the extracellular matrix (ECM) protein Perlecan (Pcan), (2) this Pcan accumulates around the endogenous niche resulting in an ectopic ECM termed the moat within the testis lumen; (3) the moat causes the selective loss of WT neighbor GSCs, which no longer have strong adhesion with niche cells; (4) chinmo-/- GSCs remain in the resculpted niche because they upregulate ECM-binding proteins. This proposal is also supported by our unpublished results showing that Chinmo protein expression is promoted by an RNA-binding protein (RBP) in GSCs and that a ZAD-ZNF protein likely acts as a Chinmo co-factor in GSCs. In the first goal, we will determine whether clonal loss of the RBP that promotes Chinmo expression imparts that GSC with a competitive advantage. We will also determine what regulates that RBP in GSCs and test whether loss of any regulators of the RBP imparts a competitive advantage to a mutant GSC. In the second goal, we will determine whether Chinmo and the ZAD-ZNF protein work together to repress Pcan by recruiting histone methyltransferases. We will also determine how niche cells promote the ectopic Pcan produced by chinmo-/- GSCs. In the third goal, we will test the role of somatic stem cells (CySCs) in GSC competition and assess whether they push out WT neighbors GSCs. We will also use live-cell imaging to determine the types of GSC division that occur in chinmo- /- GSCs. The studies in this proposal will increase the knowledge base about GSC competition and will foster new avenues of research into mechanisms and possible treatments for human paternal age effect disorders caused by competitive spermatogonial stem cells and for tumor cells which remodel their microenvironment to benefit themselves and disadvantage WT neighboring cells.

NHLBI - National Heart Lung and Blood Institute

Project Summary: Mammalian infants exhibit immature circadian regulation: the establishment and maturation of cellular and systemic clocks occur postnatally, driven by maternal cues, feeding cycles, and light entrainment. In parallel, the neonatal heart undergoes profound structural and functional remodeling, characterized by decreased cardiomyocyte proliferation, metabolic shifts, altered expression of ion channels, enhanced electrical coupling, and changes in alternative splicing mediated by RNA-binding proteins (e.g., Rbfox1). Despite these parallel developmental processes, no molecular pathway has been determined to link the development of the circadian clock with cardiomyocyte maturation. Importantly, induced pluripotent stem cell-derived cardiomyocytes (iPSC- CMs) share a common deficiency in maturity, which is a significant limitation for their application in disease modeling, drug screening, or as cell therapy agents. Therefore, uncovering the intrinsic regulatory mechanisms of mammalian cardiomyocyte maturation has significant implications for both basic developmental biology and pre-clinical applications. We propose that a circadian clock checkpoint, comprising activators (ATF3/MEF2s) and a suppressor (NFIL3), serves as a temporal regulator of cardiac maturation during early life. The aims of this proposal are as follows: Aim 1. Determine the enhancer (Rb1en)-transcription factors circuitry (ATF3/MEF2/NFIL3) that initiates the temporal and tissue-specific expression of Rbfox1; and Aim 2. Determine the critical role for circadian clock regulatory mechanisms on cardiomyocyte maturation in vivo and hiPSC-CM maturation in vitro. These studies will establish a molecular bridge between developmental chronobiology and cardiac maturation, reveal new mechanisms of temporal regulation in postnatal heart growth, and may inform novel strategies for conditions associated with impaired cardiac maturation and enhance maturity and disease relevance of hiPSCs. Collectively these insights will reduce the burden of cardiovascular risk and advance pre- clinical applications of stem-cell-based modeling and therapeutics.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

ABSTRACT Understanding the fundamental processes that underscore hematopoiesis is necessary to generate therapeutics that can correct hematopoiesis during disease or support hematopoietic regeneration during stress. The bone marrow microenvironment, or niche, supports hematopoiesis by providing cellular and acellular cues that influence hematopoietic differentiation, hematopoietic stem cell self-renewal, and the functional integrity of the bone marrow niche itself. Inadequate or inappropriate hematopoietic differentiation can lead to disease or death by depleting hematopoietic cell populations needed for organismal survival. Additionally, commonly used therapeutics like radiation and chemotherapy cause hematopoietic cell death and damage the bone marrow niche, leaving patients in a vulnerable state of hematopoietic insufficiency. The inability to restore hematopoietic homeostasis after radiation exposure puts patients at a heightened risk for developing deadly complications, such as infection or hemorrhage. Therefore, understanding how hematopoiesis is maintained and restored is of the utmost importance. Our previous studies showed that syndecan-2 (a specific heparan sulfate proteoglycan) expressed by hematopoietic stem cells promotes long-term hematopoietic stem cell self-renewal ability by supporting quiescence. The bone marrow niche is also a rich source of proteoglycans. Our preliminary data indicate that bone marrow mesenchymal stromal cells (MSCs) also highly express syndecan-2. Genetic depletion of syndecan-2 in MSCs using transgenic mouse models caused significant hematopoietic system imbalances in the peripheral blood at steady-state and after hematologic stress. In this application, we propose to elucidate how MSC-derived syndecan-2 regulates hematopoiesis in vivo. We will use a multi-scale approach to test the function of syndecan-2 at the molecular, cellular, and systemic scales by combining transgenic knockout mouse models and in vivo injury models with high-resolution bone marrow imaging and super- resolution imaging of MSCs. We will test the role of MSC syndecan-2 in hematopoietic differentiation, growth factor organization, and signaling. Because hematopoietic demands increase during states of hematopoietic stress, we will also test the function of syndecan-2 from MSCs in hematologic and niche regeneration from radiation injury. Successful completion of these aims will define the role of MSC-derived syndecan-2 in hematopoietic homeostasis and regeneration, providing foundational knowledge needed to leverage proteoglycans to correct or boost hematopoiesis during states of imbalance or stress.