Stem cell research — NIH Funding Overview

Why this matters now

iPSC-based disease modeling and CRISPR-edited iPSC platforms have become standard tools across many NIH portfolios, while clinical translation continues in cardiac, hepatic, and ocular regeneration. The NIH Regenerative Medicine Innovation Project supports late-stage translational work.

How NIH funds this area

Mechanisms span R01, U01, P01, R21, and U24 (data/resource cores). The Stem Cell Translation Laboratory at NCATS supports characterization. Data below covers all NIH awards mentioning stem cell in title, abstract, or terms.

Yearly NIH Awards for Stem cell research

Counts and total funding per fiscal year from NIH RePORTER. Recent fiscal years may understate final totals because of reporting lag.

Open the full interactive trends view for Stem cell research →

Top NIH Institutes (last 90 days)

Which NIH institutes funded the most Stem cells projects in the most recent 90-day window.

Common Activity Codes (last 90 days)

Which grant mechanisms (R01, R21, U01, P30, etc.) appeared most often for Stem cells in the recent period.

Most Active Institutions (last 90 days)

Universities and research organizations with the most Stem cells awards in the most recent 90-day window.

1. STANFORD UNIVERSITY — 20 awards
2. UNIVERSITY OF CALIFORNIA, SAN FRANCISCO — 15 awards
3. UNIVERSITY OF MICHIGAN AT ANN ARBOR — 14 awards
4. CINCINNATI CHILDRENS HOSP MED CTR — 13 awards
5. UNIVERSITY OF PENNSYLVANIA — 12 awards
6. MASSACHUSETTS GENERAL HOSPITAL — 12 awards
7. NORTHWESTERN UNIVERSITY AT CHICAGO — 12 awards
8. ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI — 11 awards

Recently Awarded Stem cell research Grants

Twelve most recent awards mentioning Stem cells, drawn from NIH RePORTER. Click through to Find PIs for the full investigator search.

• From genotype to phenotype in a GWAS locus: the role of REST in atherosclerosis

  7K08HL166690-04
  Marios Arvanitis · OHIO STATE UNIVERSITY, OH · $165,563 · awarded Apr 24, 2026 · K08

  Project Summary This K08 mentored clinical scientist research career development award is a five-year program designed to facilitate Dr. Marios Arvanitis’ (PI) development into an independent physician-investigator in vascular genetics. Atherosclerotic cardiovascular disease (ASCVD) is a major public health burden that accounts for over 600,000 deaths in the United States each year. ASCVD is highly heritable and genome-wide association studies have discovered many candidate genomic loci that increase the risk of the disease in the population, thereby providing a window to novel therapies. However, most genomic risk loci for ASCVD remain unexplored in terms of how they lead to disease risk. Previously published work by the PI has focused on the mechanistic interpretation of genomic risk loci for cardiovascular disease, including the development of a novel Bayesian method, called CAFEH, to prioritize the target tissue and genes in genomic loci. Our preliminary analyses of the genetic underpinnings of ASCVD reveal that endothelial cells are enriched for ASCVD heritability, and we have used those methods to prioritize a chromosome 4 locus that is predicted to affect ASCVD risk via altering the expression of the RE-1 silencing transcription factor (REST) gene in endothelial cells. This K08 project will explore the regulatory mechanisms via which the REST locus and gene influence the development of atherosclerosis. Aim 1 will employ CRISPR-Cas9 editing in human stem cells which will then be differentiated into endothelial cells to identify the causal variants and the upstream transcription factors that mediate the association in the 4q12 coronary disease GWAS locus. Aim 2 will define distal genes and pathways affected by REST in the endothelium and investigate their cellular consequences, starting with evaluating the role of REST in endothelial to mesenchymal transition. Aim 3 will use a tamoxifen inducible endothelial specific Rest knock-out mouse model to evaluate the in vivo effects of Rest in the endothelium and atherosclerosis. The success of this project is guaranteed by the support of a multidisciplinary mentoring team including a vascular biologist (Dr. Charles Lowenstein), a computational biologist (Dr. Alexis Battle), and a functional genetics expert (Dr. Andrew McCallion), along with an advisory committee of experts in vascular biology, stem cell differentiation and atherosclerosis (Dr. Harry Dietz, Dr. Chulan Kwon and Dr. Thomas Quertermous). This award period will help the PI boost their genomics skills, acquire new wet lab skills and generate preliminary data to successfully compete for R01 funding in order to translate the genetic insights into novel mechanisms for ASCVD.

• Development of chimeric antigen receptor T cells targeting cell surface U5 snRNP for the treatment of acute myeloid leukemia

  5R01CA291796-02
  Anthony Daniyan · SLOAN-KETTERING INST CAN RESEARCH, NY · $402,600 · awarded Apr 24, 2026 · R01

  Despite recent U.S. FDA approval of therapies for patients with acute myeloid leukemia (AML), clinical outcomes for AML patients continue to remain poor. Other than allogeneic stem cell transplant, there are no effective immunotherapies for AML, and this is, in part, due to a lack of known antigens which are unique to AML and not present on vital normal hematopoietic precursors. Hence, there is an urgent and critical need for novel therapies to improve outcomes in AML. To this end, we recently identified unique expression of the RNA helicase U5 snRNP200, on the surface of AML cells but not normal hematopoietic precursors. Anti-U5 snRNP200 therapeutic antibodies, originally isolated from AML patient in long term remission following allogeneic transplant, were efficacious across immunocompetent AML models. Genome-wide screens to identify regulators of AML cell surface U5 snRNP200 expression revealed that cell membrane localization of U5 snRNP200 required surface expression of the Fcγ receptor CD32A. Exhaustive evaluation of cell surface U5 snRNP200 expression on normal hematopoietic cells and non-hematopoietic tissues revealed that U5 snRNP200 expression was absent from the surface from normal cells except for robust expression on B-cells. The primary goals of this proposal are to develop novel cellular immunotherapies targeting U5 snRNP complex members and probe the mechanistic basis for their cell membrane localization in AML. Our preliminary data identify that the therapeutic anti-U5 snRNP200 antibodies which are most efficacious require engagement of activating Fcγ receptors and immune effector cells, factors often impaired in AML patients. We therefore have now developed novel chimeric antigen receptor (CAR) T cells targeting U5 snRNP200 and observed early evidence of their efficacy in preclinical models of AML. Importantly, CAR T cells which simultaneously target U5 snRNP200 and secrete IL-18, a cytokine known to upregulate CD32A (and consequently also cell surface U5 snRNP200) have augmented anti-tumor efficacy. We therefore hypothesize that IL-18 secreting CAR T cells targeting U5 snRNP200 will be a novel effective and safe cell therapy for AML. We further hypothesize that cell surface U5 snRNP200 expression may modulate CD32 signaling in a manner that provides mitogenic benefit to leukemia cells. Finally, we have found that additional U5 snRNP complex member EFTUD2, which physically interacts with U5 snRNP200 in the nucleus, is also translocated to the AML cell surface. This proposal will (1) test the efficacy and safety of CAR T cells directed against U5 snRNP200 in human and syngeneic mouse models of AML, (2) identify the mechanistic basis for cell surface U5 snRNP200 localization and potential requirement of this cell surface protein in AML, and (3) evaluate the cell surface distribution of additional U5 snRNP components and therapeutic potential of anti-EFTUD2 CAR T cells (either alone or in combination with anti-U5 snRNP200 CAR T cells).

• Epitranscriptomic regulation in the mammalian nervous system

  5R35NS137480-02
  Guo-li Ming · UNIVERSITY OF PENNSYLVANIA, PA · $985,026 · awarded Apr 24, 2026 · R35

  Epitranscriptomics, analogous to the epigenetic code formed by DNA and histone modifications, is the study of more than 170 chemically distinct types of RNA modifications, which modulate nearly all aspects of RNA metabolism, such as splicing, translocation, decay, stability, and translation. The recent profound success of COVID19 mRNA vaccines utilizing the pseudo-uridine modification highlights the translational potential of epitranscriptomics. Emerging evidence suggests diverse roles and mechanisms of dynamic RNA modifications in the mammalian nervous system and the association of epitranscriptomic dysregulations with developmental, neurological, psychiatric, and degenerative brain disorders. The majority of recent epitranscriptomic studies used cultured immortalized cell lines and the physiological functions of various RNA modifications remain largely unexplored. Recent technical advances in human induced pluripotent stem cell (iPSC)-derived brain organoids and genome editing open doors to investigate epitranscriptomic regulation in human brain development processes and associated brain disorders. The overarching goal of this research program is to investigate roles and mechanisms of epitranscriptomic regulation in the development and function of the mammalian nervous system, and pathological consequences of disrupting these processes, using both mouse and human iPSC-derived 2D and 3D brain organoid models. There are three interrelated projects designed to test innovative hypotheses and generate foundational data for the field. In Project 1, we will focus on the development of the hypothalamus, an understudied brain region that regulates many key physiological functions, such as sleep, reproduction, and feeding, through its distinct nuclei. Based on our preliminary finding of adult-onset obesity of mice with defective m6A signaling, we will test the hypothesis that m6A signaling regulates the fate specification of neural stem cells in the arcuate nucleus for generating feeding-related neurons both in mice and human arcuate organoids. In Project 2, we will use novel sequencing technology to reveal the landscape of locally translated transcripts at synapses and investigate the role of m6A signaling in regulating activity-dependent local translation of these transcripts at synapses in the mouse hippocampus and human hippocampal organoids. In Project 3, we will focus on several risk genes associated with microcephaly that encode writer proteins for diverse epitranscriptomic modifications beyond m6A. We will generate isogenic iPSC lines and genetically modified animal models to test the functional roles and mechanisms of these RNA modifications in cortical neurogenesis. Together, we will use several orthogonal approaches to investigate functional roles and mechanisms of neuroepitranscriptomics in regulating the mammalian nervous system and its causal roles in mediating some forms of developmental pathology. The research program will also provide a platform to train the next generation of scientists at all career stages. FACILITIES & OTHER RESOURCES The University of Pennsylvania Penn is home to a diverse body of over 20,000 students and over 4,000 faculties in its 12 leading graduate and professional schools. Penn’s schools are located on a compact campus, the geographical unity of which supports and fosters its multidisciplinary approach to education, scholarship, and research. Research and research training are substantial and esteemed enterprises, bolstered by an annual University budget of $6 billion. Penn’s 165 research centers and institutes bring together researchers from multiple departments, schools, and disciplines, and interdisciplinary collaboration is a key theme for Penn’s academic enterprises. The Perelman School of Medicine (PSOM) The Perelman School of Medicine at the University of Pennsylvania has been ranked among the top five medical schools in the United States for the 18th year in a row. The PSOM prides itself on the vision that education should be oriented toward combining theory and practice for the betterment of humanity. The PSOM has an internationally renowned research faculty and programs in all fundamental areas of basic and clinical biomedical science. The PSOM boasts a long record of innovation in both clinical and basic science, resulting in numerous landmark achievements, and is supported by state-of-the-art research core facilities and major clinical research facilities. Research and clinical training programs at Penn Medicine span the full range of participants – from high school and undergraduate students, through MD, PhD and master’s-level trainees, to postdoctoral and clinical residents and fellows. The PSOM has the nation’s largest combined degree training program, which is supported by one of the nation’s oldest and largest NIH- MSTP grants. My lab is fortunate to have talented young individuals from all these programs. Institute for Regenerative Medicine (IRM) I am the Associate Director of IRM, an Institute at Penn and a community of scientists working to explore ways to use cells and tissues to repair, rebuild, and replace organs and body systems afflicted by disease. IRM encourages collaborations across different fields of biology, engineering, and medicine. IRM provides an enriched environment for over 100 core labs with monthly stem cell clubs (organized by Dr. Ming) and faculty lunches, Annual Ralph Brinster Symposium and themed IRM symposiums and retreats. Our initial collaboration with neurosurgeon Dr. Issac Chen was established through IRM sponsored activities. IRM also provides a platform for trainees to interact and present their data in poster and short talk sessions at annual and themed symposiums. The Epigenetic Institute I am a member of the Epigenetics Institute, which was established in 2017 to bring together the epigenetics community at Penn, providing a space where scientific endeavors could flourish. With over 38 core labs, the Institute has created an unparalleled environment for collaboration and cutting-edge research, which is often published in top-tier journals. Faculty regularly collaborate with clinical investigators to conduct translational research that advances medical breakthroughs. I have been collaborating with several members, including Drs. Hongjun Song and Kathy Liu, of the Institute, and will continue our productive collaboration on the work proposed here. The Epigenetics also provides a platform for trainees into interact and present their data in poster and short talk sessions at annual and themed symposiums. The Institute for Diabetes, Obesity & Metabolism (IDOM) The IDOM was established in 2005 to address the ever-increasing prevalence of diabetes and obesity. The mission of the IDOM is to enhance and support research aimed at understanding the genetic, biochemical, molecular, environmental, and behavioral mechanisms underlying diabetes and obesity. IDOM initiatives include critical and unique scientific core facilities, and pilot grants that support new investigators as well as interdisciplinary science involving investigators from Penn Medicine and throughout the University of Pennsylvania that are relevant to the IDOM mission. We are collaborating with Dr. Lazar, the founding director of IDOM on the proposed project. We are also using the IDOM Rodent Metabolic Phenotyping Core to characterize the obesity phenotype of our genetically modified mice. The Penn Institute for RNA Innovation I am a member of the Penn Institute for RNA Innovation, which was recently established by Dr. Drew Weissman and dedicated to the understanding and development of all things RNA and will help form collaborations that will unify and link all elements from RNA-based basic science through therapeutic activities. There is a specific interest in RNA modifications in the institute with many investigators working on topics from basic science to therapeutic. It provides an enriching environment for the proposed studies in the current proposal and excellent training environment for trainees. Additional Neuroscience-related Core Research Support Facilities There are many biomedical research core facilities at Penn that are managed in a centralized manner. As a faculty member of PSOM, I have full access to the following Cores (relevant to the work proposed): The Cell & Developmental Biology (CDB) Microscopy Core is a full-service facility serving the entire Penn community. The Core provides personalized assistance on all aspects of imaging from consultation on experiment design to assisted imaging or hands-on training. The CDB also provides resources to help with image data analysis. The facility currently houses three laser scanning confocals, two spinning disk confocals, a widefield deconvolution microscope, and two widefield microscopes for routine work. In addition, the facility also houses a scanning electron microscope (SEM) and offers SEM sample preparation services. The Flow Cytometry and Cell Sorting Resource Laboratory is currently recognized as one of the largest and most comprehensive flow cytometry laboratories in the US. In 2010 it was designated a laboratory of exceptional merit by the National Cancer Institute. Using state-of-the-art technology, the resource provides a broad array of instrumentation, support, education and consultation to the research community at the University of Pennsylvania. A wide variety of cell sorting applications are supported, from high-speed multicolor (up to 14 colors) cell sorting to low-speed, large nozzle, improved viability sorting. Additionally, a wide variety of cell analysis services (up to 20 parameters) are offered, from traditional analog, easier to use tabletop analyzers to many-laser, many-color, high-speed, fully-digital modern instrumentation. Currently the facility offers 6 cell sorters and 19 analytical instruments. The Vector Core facility is an important technological resource for investigators, both within the University of Pennsylvania investigators and those external to Penn, interested in the use of vectors for gene transfer. The main objective of this Core is to provide investigators with access to state-of-the-art vector technology for preclinical studies and other basic research applications. Such studies provide tools critical to the understanding of gene function and development of therapeutic vectors. The Next Generation Sequencing Core offers ultra-high throughput sequencing services for the PSOM research community. We offer library quality assessments, sequencing, and optional preliminary data analysis for a wide variety of experimental protocols including ChIP-seq, RNA-Seq, HITS-CLIP, miR-Seq, exome capture, and BIS-seq. The Penn Genomic Analysis Core is comprised of the DNA Sequencing Facility (DSF) and the Molecular Profiling Facility (MPF). The Molecular Profiling Facility provides an integrated set of services for DNA and RNA profiling. These services are delivered by experienced genomics professionals, including a focused bioinformatics support staff. PSOM faculty benefit from consultations and training available throughout their projects, including during experimental design and budget development, sample accrual, Facility quality control assays and lab work, data management and analyses, and manuscript preparation. The core supports quantitative RNA profiling by Affymetrix GeneChips, Illumina BeadChips, real-time PCR, Sequenom custom multiplex assays, Fluidigm, Luminex and deep sequencing. DNA profiling of custom panels of sequence polymorphisms are conducted by quantitative PCR, Sequenom assays, and Illumina GoldenGate genotyping, while whole-genome assays are available on Affymetrix SNP GeneChip and Illumina Infinium platforms. Whole-exome and targeted genomic regions can be resequenced on an Illumina Genome Analyzer deep sequencer. Several other services including microRNA profiling, epigenetic DNA assays, and translational molecular diagnostics for clinical research are offered using these platforms. The Transgenic and Chimeric Mouse Facility provides a centralized service to efficiently produce infection-free transgenic, chimeric, and genome-edited strains of mice. These mice carry randomly inserted transgenes and/or site-specific alterations in the mouse genome of specific interest to Penn researchers. The Facility offers services including DNA pronuclear injection into fertilized oocytes (along with genotyping of transgenic founders), ES cell injection into blastocysts, cytoplasmic/pronuclear injections into fertilized oocytes of CRISPR-Cas9 mix (gRNA, Cas9RNA, ssDNA/dsDNA templates), embryo and sperm cryopreservation, in vitro fertilization, and re-derivation of live and cryopreserved lines. The Core also oversees a cyropreservation facility for long-term storage of mouse embryos and sperm samples. We have used the core to generate several genetically modified mice and will continue to use it for the current projects.  The Neurobehavior Testing Core provides core facilities and services to test mice in state of the art assays of simple and complex behaviors, including the assessment of circadian rhythms and sleep, learning and memory, motor and sensory function, as well as behavioral assays relevant to translational studies of neurological, neurodevelopmental and psychiatric disorders. The core offers comprehensive behavior phenotyping of your mice or can train your lab personnel to perform the tests in the facility. In addition, we provide consultation on study design including appropriate tests, mouse line/strain, numbers of animals, control groups and breeding strategies. The core will also provide consultation regarding ULAR, IACUC and other regulatory issues. Assistance with data analysis is also available. We have used the core for characterizing of our genetically modified mice and will continue to use it for the current project. The Small Animal Imaging Facility (SAIF) provides multi-modality radiological imaging and image analysis for cells, tissues, and small animals, primarily mice and rats. The assets of the SAIF include state-of-the-art instrumentation and a nationally recognized staff. SAIF currently provides a comprehensive suite of imaging modalities including: magnetic resonance imaging (MRI) and spectroscopy (MRS), optical imaging (including near IR and bioluminescence imaging), computed tomography (CT), positron emission tomography (PET), single photon emission computed tomography (SPECT), and ultrasound (US). In addition, dedicate housing is available for mice and rats undergoing longitudinal imaging studies. Ancillary facilities and resources of the SAIF are devoted to chemistry, radiochemistry, image analysis and animal tumor models. Other Relevant Research Resources The Biomedical Library, housed within PSOM, has a large collection of print and electronic journals, as well as many other services. As of July 2010, the Biomedical Library had close to 100,000 volumes, and access to over 6,000 current serials in the health sciences, primarily electronic, and 1,300 e-books. In addition, faculty, students and staff can access all the collections of the Penn Libraries, which number more than 5,000,000 printed volumes, more than 40,000 online and print journals and thousands of databases, e-books and other digitized resources. The Library's holdings are supplemented by membership in the National Network/Libraries of Medicine and many other resource-sharing consortia, and electronic delivery of documents is standard. The Biomedical Library houses 80 public workstations, several printers and a scanner, a poster printing service, a 10-station training lab, a wireless network throughout the library, and sixteen lending-laptops. Group study rooms are outfitted with computers and large flat screen monitors. Biomedical Library staff can provide in- library and off-site training and individual research consults in searching life science databases (Medline, PubMed, Scopus, CINAHL, ISI Web of Science, etc.), use of bibliographic management software (RefWorks), and research and productivity skills (mobile resources, systematic reviews, retrieving full text articles, PowerPoint, Excel, molecular biology tools). The Research Instrumentation Shop is non-profit, shared resource machine shop of the University of Pennsylvania, Perelman School of Medicine. Its mission is to assist University faculty in the design and construction of both laboratory and clinical instrumentation. The staff is comprised of mechanical and optical specialists and is experienced with working with scientists to design and construct custom instrumentation and apparatus. Career development and support for trainees The Perelman School of Medicine and University of Pennsylvania have established offices, programs, and research opportunities for trainees. These resources provide additional support for all trainees and are accessible to undergraduates, graduate students and postdoctoral associates. Undergraduates may apply for internship funding through the Center for Undergraduate Research & Fellowships. Current trainees have access to the Trainee Advocacy Alliance, which provides broad support for trainees at all levels. Postdoctoral associates have access to institutional support offices, such as the Biomedical Postdoctoral Programs Office, the Faculty Professional Development Office, and the Office of Research Support Services, which support career development. The Biomedical Postdoctoral Programs Office provides responsible conduct in research training, lab management workshops, career services, and grant writing seminars. The Faculty Professional Development Office offers workshops focused on career topics, such as mentoring, tenure track tips and science communication, as well as online courses and resources. The Office of Research Support Services provides help with grant proposal preparation and post-award grant management, as well as online access to internal and external funding opportunities. Laboratory The Ming laboratory is assigned approximately 2500 sq. ft. space in the Clinical Research Building (CRB) with seven bays of bench space. The laboratory has six individual rooms that are fully equipped to support cell culture, molecular biology, bioinformatics, cell biology, biochemistry, immunohistology, stereology, electrophysiology, optogenetics, confocal imaging, and CNS histology. Office and administrative space: Dr. Ming has 230 sq. ft. of personal office space in CRB and ~300 sq. ft. of space for administrative support and meeting rooms.

• Development and function of skin-resident innate-like T cells at early postnatal stages

  3R01AI174181-03S1
  Na Xiong · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER, TX · $54,277 · awarded Apr 24, 2026 · R01

  Summary Unlike conventional T/B lymphocytes, a group of innate-like T cells, such as γδT cells and invariant NK T (iNKT) cells, preferentially reside in epithelial tissues such as the skin where they play important roles in the first line of defense to maintain the tissue integrity and, when dysregulated, also contribute to the tissue inflammatory diseases. Understanding how skin-specific localization and maintenance of innate- like T cells are regulated is critical in helping to design strategies targeting these cells for therapeutic purposes. Our preliminary studies found that iNKT cells generated in the thymus of early postnatal stages preferentially acquire a skin-homing property for their specific distribution into the skin. Considering the skin is the outmost barrier tissue exposed to foreign environments immediately after the birth of a body, we propose that the preferential generation of the skin-homing iNKT cells in the thymus are important for protection of the “border” in the infant and young and the establishment of the local immune homeostasis. In this grant application, we will dissect mechanisms regulating thymic generation of skin-homing iNKT cells and their roles in helping skin tissue development and homeostasis.

• Functional Role of Tetraspanin CD82 in Hematopoietic Stem Cell Interactions

  5R01HL122483-11
  Jennifer Gillette · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR, NM · $376,845 · awarded Apr 23, 2026 · R01

  PROJECT SUMMARY The significant cellular demand of the hematopoietic system is maintained by a rare pool of tissue-specific, hematopoietic stem and progenitor cells (HSPCs) that are primarily found in a quiescent state. Upon hematopoietic stresses, such as significant bleeding, overwhelming infection, radiation exposure and myelosuppressive therapy, HSPCs are rapidly recruited into cell cycle, but ultimately must return to quiescence. The ability to transiently modulate HSPC return to quiescence has the potential to extend the activation of HSPCs and significantly improve overall patient outcomes from hematopoietic stresses and for transplantation therapies. However, in order to leverage a transient extension of HSPC activation to improve the regenerative response to stress, we must first understand the mechanisms by which the complex network of cell-intrinsic and -extrinsic signaling within the bone marrow are coupled to regulate HSPC quiescence. The objective of our current proposal is to evaluate the tetraspanin membrane-scaffold protein, CD82, as a tractable target to modulate HSPC quiescence signaling within the bone marrow. Tetraspanins are a family of membrane-scaffold proteins with the unique ability to regulate cell-cell/cell-matrix interactions and modulate intracellular signaling, thus linking cell-microenvironment interactions to downstream signaling consequences. Our new preliminary data indicate that the CD82 scaffold promotes a quiescent HSPC phenotype when cells are niche engaged and implicate a role for Transforming Growth Factor  (TGF) signaling. Thus, in this proposal, we will test the hypothesis that the CD82 membrane scaffold promotes HSPC quiescence by organizing and enhancing the signaling activity of a TGF receptor complex within the bone marrow niche. In Specific Aim 1, we will determine the molecular mechanisms by which CD82 modulates the TGFβ signaling response of HSPCs. For Specific Aim 2, we will identify the mechanism by which CD82 promotes the spatial activation of TGF signaling locally within the bone marrow niche during hematopoietic stress. In Specific Aim 3, we will evaluate CD82 as a therapeutic target to improve the hematopoietic regeneration response to hematologic injury. In pursuit of these aims, we will apply an innovative combinatorial approach that includes mutational analysis, biochemistry and sophisticated imaging techniques, which will enable us to obtain a multi- scale understanding of the mechanisms by which CD82 regulates TGF signal transduction in the context of hematopoietic stress. Moreover, the successful completion of the proposed aims will be significant because we expect to integrate mechanistic insights across multiple scales to identify the multifaceted contribution of CD82 to the regulation of TGF signaling in the context of hematopoietic stress and quiescence, which will build a foundation for the development of improved therapeutics that locally target the complex TGF signaling cascade within the bone marrow.

• FMRP regulation of mitochondria and metabolism in human brain development

  3R01NS138268-02S1
  Xinyu Zhao · UNIVERSITY OF WISCONSIN-MADISON, WI · $74,640 · awarded Apr 23, 2026 · R01

  Same as parent

• Enteric Glia is New Biological Target to Block Drug Resistance in Colon Cancer

  5R01CA270462-04
  Laurianne Van Landeghem · NORTH CAROLINA STATE UNIVERSITY RALEIGH, NC · $329,600 · awarded Apr 21, 2026 · R01

  PROJECT SUMMARY/ABSTRACT Resistance to anti-cancer therapies largely explains the abysmal 5-year survival rate of patients with advanced colon cancer. Traditional chemotherapy regimens have been designed to efficiently stop proliferation and initiate apoptosis in cancer cells, but have failed to appreciate the pro-chemoresistance signals emanating from cells surrounding the tumor. We have identified a novel cellular component of the tumor microenvironment: the enteric glial cells (EGC). We and others have shown over the last 15 years that EGC are potent inducers of barrier function and healing in a healthy colon. Recently we have demonstrated that the EGC network substantially infiltrates human colon adenocarcinomas and promotes cancer stem cell tumor-forming abilities via a paracrine PGE2-EP4 pathway. Nevertheless, whether EGC impact colon cancer resistance to chemotherapy remains unknown. Our preliminary studies indicate that EGC protect cancer stem cells against apoptosis induced by chemotherapeutic drugs, allowing for enhanced tumor formation and growth despite the chemotherapy treatment. We also have evidence that this is (1) dependent on activation of the MRN-ATM pathway - a central player in DNA repair- in cancer cells and (2) exacerbated by EGC activation with chemotherapy. Using mass spectrometry analyses, we have identified FSTL3 as a novel EGC-derived factor and generated preliminary results implicating FSTL3 in EGC chemoprotective effects. Therefore, we propose to test the hypothesis that “in response to chemotherapeutic drugs, EGC release larger amounts of FSTL3 in the tumor microenvironment, which enhances cancer stem cell chemoresistance and allows for tumor formation and growth by promoting DNA repair driven by the MRN-ATM pathway”. Specific Aim 1 will determine whether EGC promote cancer stem cell resistance to chemotherapies via the release of FSTL3. Specific Aim 2 will test whether EGC protective effects are mediated by increased DNA repair as a result of activation of the MRN-ATM pathway. Specific Aim 3 will determine whether blocking FSTL3 production in EGC sensitizes colon tumors to chemotherapies in vivo. Studies will use translationally relevant primary cultures of human EGC and cancer cells, 3D co-culture platforms, orthotopic co-engraftment in immunodeficient mice, murine models of colon carcinogenesis, transgenic mice allowing for chemogenetic activation of EGC (GFAP-hM3Dq) and inducible gene targeting in EGC (GFAP- CreERT2), in addition to cutting-edge molecular profiling using single cell RNA seq and mass spectrometry studies to identify the pro-chemoresistance factor(s) (and in particular FSTL3) and pathway(s) involved. These studies will not only improve our understanding of the cellular and molecular mechanisms driving colon cancer chemoresistance but will also demonstrate the therapeutic potential of developing strategies combining targeted therapies against EGC-derived FSTL3 and traditional chemotherapy regimens.

• Developmental and Genetic Basis of Neural Circuit Formation and Behavior

  5R01NS122903-05
  Haluk Lacin · UNIVERSITY OF MISSOURI KANSAS CITY, MO · $391,250 · awarded Apr 21, 2026 · R01

  Project Summary/Abstract The precise and largely stereotyped connectivity patterns of neurons underlie simple knee-jerk like reflexes and complex behavior, like playing the violin. While we have a good understanding of the conserved genetic and molecular mechanisms that drive the initial steps of nervous system formation, we possess a far more rudimentary knowledge of those that drive neural circuit formation and animal behavior. By focusing on the development and function of the Drosophila adult ventral nerve cord (VNC), which controls behaviors, such as walking, flying, and grooming, our research leverages the power of the fly model system to dissect the genetic and cellular basis of neural circuit formation and behavior. Like the vertebrate spinal cord, the Drosophila adult VNC is composed of segmentally repeated pools of lineally related neurons. In Drosophila, these pools of neurons are termed hemilineages and are the basic developmental and functional unit of the VNC. We have previously mapped the embryonic stem cell origin, axonal projection pattern, transcription factor expression, and neurotransmitter usage of all 34 hemilineages that comprise the adult VNC. In general, however, we lack a clear understanding of the behaviors each hemilineage regulates, the neural circuits within which each hemilineage resides, and most of all the genes that act within each hemilineage to regulate its connectivity and associated behaviors. The goals of this proposal are to elucidate the functions of two conserved transcription factors – the homeodomain-containing protein Hb9 and the Pou-domain containing protein Acj6 – in regulating neuronal connectivity and behavior in each of the six hemilineages in which they are expressed (aim 1), to map each Acj6- or Hb9-positive hemilineage to its associated neural circuit and behavior(s) (aim 2), and to construct a split-GAL4 library that will allow one to uniquely target gene and cell function in every hemilineage in the adult VNC (aim 3). Successful completion of these aims will initiate a systematic dissection of the transcriptional regulatory networks that act within the adult VNC to govern neuronal connectivity and behavior and help build a comprehensive map that links all VNC hemilineages to their associated neural circuits and behaviors. It will also create a genetic toolkit that will allow any lab to dissect gene and cell function in essentially any hemilineage of the adult VNC, facilitating the elucidation of the genetic and cellular basis of behavior. Given the strong parallels between the molecular pathways that govern CNS development in flies and vertebrates, our research holds great potential to uncover conserved genetic principles that underlie neural circuit formation and behavior from flies to humans.

• Mechanisms of Mammalian Genetic Hearing Loss

  5R01DC020574-04
  Rick Nelson · INDIANA UNIVERSITY INDIANAPOLIS, IN · $590,802 · awarded Apr 21, 2026 · R01

  PROJECT SUMMARY This work is designed to understand the mechanism of how the protein encoded by the human deafness gene, TMPRSS3, leads to hair cell death and hearing loss. Hair cells are surrounded by apical tight junction protein complexes, which form a barrier between the endolymph which covers the apical side of the hair cell and perilymph, which covers the basolateral side of the hair cell. The endolymph contains a high potassium concentration and high electrical charge, while the perilymph has low potassium concentration and low electrical potential. Disruption of the apical tight junctions leads to permeability of endolymph K+ and death of sensory hair cells. Variants in the multiple genes encoding tight junction proteins cause human deafness and result in rapid hair cell degeneration during the rapid rise in endocochlear potential. This unique temporal pattern of hair cell death mimics what is seen with variants in the gene encoding the serine protease, TMPRSS3. Our preliminary data shows that loss of TMPRSS3 disrupts apical tight junction formation. We hypothesize that TMPRSS3 functions to prevent hair cell degeneration by maintaining the tight junction barrier between hair cells through proteolysis of tight junction related protein substrates. The goal of this application is to define the biological mechanism of how loss of TMPRSS3 leads to disruption of tight junction function. In Aim1, we will test if TMPRSS3-mediated hair cell death is dependent on the endocochlear potential in vivo and we will determine if the location and/or proteolytic cleavage of tight junction proteins are altered in TMPRSS3- deficient hair cells. Using immunohistochemical, biochemical and ultrastructure techniques, we will determine how loss of TMPRSS3 physically alters tight junctions. Aim 2 we will use AAV-mediated gene delivery in vivo to determine if TMPRSS3 function is protease dependent and if hearing loss variants TMPRSS3 are functional. In Aim 3, we will use multiomic approaches in human stem cell-derived inner ear organoids to determine transcriptomic and proteomic pathways regulated by TMPRSS3. By accomplishing these aims we will not only advance our understanding of the molecular mechanism and protease substrates of TMPRSS3 in the inner ear, but also gain insights into the dynamic regulation of tight junctions. This has the potential to impact multiple forms for genetic deafness.

• Pathogenic hotspots illuminate mechanism and therapeutic potential in arrhythmogenic cardiomyopathy

  5R01HL168059-04
  Victoria Parikh · STANFORD UNIVERSITY, CA · $722,530 · awarded Apr 21, 2026 · R01

  PROJECT SUMMARY Recent exponential advancement of genome engineering technology has revived enthusiasm for its implementation in genetic cardiomyopathies. This is especially promising for arrhythmogenic cardiomyopathy (ACM), a cause of sudden cardiac death and end stage heart failure. Most early genome engineering therapies have focused on gene replacement; however, a significant minority of ACM variants likely act via dominant negative disease mechanisms that will not respond to gene replacement therapy. RNA Binding Motif 20 (RBM20) and plakophilin 2 (PKP2) are genes associated with deadly forms of ACM in which there are both dominant negative and haploinsufficient pathogenic variants. Variants in these genes cause cardiomyopathy and arrhythmia by disrupting global cardiomyocyte transcriptional splicing and desmosomal structure, respectively. hat these variants are clustered in pathogenic hotspots that align to known and novel functional protein domains, indicating that focused study of these hotspots can illuminate differential disease mechanisms and potentially reduce the burden of therapeutic design. Our central hypothesis is that variants in pathogenic hotspots of RBM20 and PKP2 have differential downstream mechanisms that converge on ACM disease phenotypes, and that these pathogenic hotspots allow the design of a genome engineering strategy to edit many pathogenic variants with a single reagent. In Aim 1, we will identify haploinsufficient vs. dominant negative variants in RBM20. We then use high throughput genome engineering techniques to create a library of these variants in induced pluripotent stem cell cardiomyocytes. We will apply a combination of single cell library preparation and long read RNAseq to define the downstream consequences of each disease mechanism on splicing of known and novel RBM20 targets. In Aim 2, we focus on a novel dominant negative mechanism for C-terminal PKP2 truncating variants in which they lose their plasma membrane localization, sequestering critical desmosome components in the cytoplasm. We will use variant effect mapping to define downstream mechanisms of a library of pathogenic PKP2 truncating variants, and will define the role of a novel PKP2 interactor on PKP2 membrane localization. In Aim 3, we will extend our work showing the feasibility of single prime editing (PE) reagents for correction of multiple variants in a pathogenic hotspot in vitro: We will design engineered prime editing (epe)gRNAs with the newest high efficiency PEmax construct for the PKP2 C- terminus hotspot and dominant negative RBM20 RS domain hotspot in vitro. We will then use innovative methods to package PEmax in AAVMYO to correct two pathogenic murine Rbm20 RS domain variants in vivo using the same epegRNA. We will go on to measure the effect of this editing on deep ACM phenotypes. In summary, this project will capitalize on our identification of pathogenic hotspots in RBM20 and PKP2 to provide a comprehensive evaluation of variant-level disease mechanism in these genes, and demonstrate the potential of hotspot directed prime editing as a tractable genome engineering therapeutic.

• Investigating the Heterogeneous Intercellular Signaling of Hematopoietic Stem and Progenitor Cells and its Changes around the Circadian Clock

  5F31HL178286-02
  Zachary Thomas · UNIVERSITY OF SOUTHERN CALIFORNIA, CA · $50,114 · awarded Apr 21, 2026 · F31

  PROJECT SUMMARY Blood regeneration must constantly adapt to bleeding, infection, injury, and disease. These processes rely on cell-cell communication to hematopoietic stem cells, HSCs, that are responsible for maintaining the homeostasis of the blood and immune systems. To fulfill this role, HSCs must engage in cell-cell communication with the surrounding cells in the bone marrow. Previous studies have demonstrated that some of these cells, including mesenchymal cells, vascular cells, and osteoblasts, referred to as their niche, play significant roles in regulating and maintaining HSCs via signaling pathways like KIT, CXCL, and VCAM. In these pathways, HSCs play the role of receiver by expressing the receptors for the ligands the niche cells produce. Several studies have suggested that HSCs play active roles in signaling within the bone marrow as well. Not only do they express the receptors for the ligands their niche produces, but they also secrete ligands to their microenvironment. However, individual HSCs do not have even access to these ligands in the dense, semi-fluid, heterogeneous bone marrow environment. This observation, coupled with the fact that gene expression within HSPC populations is heterogeneous, suggest significant signaling heterogeneity in the bone marrow. From my preliminary studies, HSCs exhibit heterogeneous signaling patterns with their niche, immune cells, and other hematopoietic progenitor cells (HPCs), some of which significantly correlate across individual cells. Further, it has been shown that HSPC homing to the bone marrow niche significantly alters with the circadian clock and preliminary data suggests circadian rhythms modulate gene expression and signaling in a lineage-specific manner. Given these preliminary findings, I hypothesize that individual HSPCs are engaged in diverse intercellular signaling pathways in the bone marrow that coordinate with each other and alternate around the circadian clock. The goal of this project is to better understand cell-cell signaling in the bone marrow between HSPCs and their microenvironment and how these signals influence their cell fate decisions and change around the circadian clock in the following three Specific Aims. Aim 1. To use single-cell RNA-sequencing data from HSPCs, their niche, and mature immune cells paired with single-cell spatial data from bone marrow to predict cell-cell signaling pathways. Aim 2. Determine intercellular signaling correlations to construct cell-cell signaling networks. Aim 3. Determine the impact of the circadian clock on HSPC’s intercellular signaling and production of blood and immune cells. In doing so, I will establish a compendium of potential pathways that influence HSPC fate decisions and elucidate the impact of circadian rhythms on HSPC signaling and blood and immune production.

• Hydrogen sulfide functions as a tumor suppressor in glioblastoma

  5R01NS127374-04
  CHRISTOPHER HINE · CLEVELAND CLINIC LERNER COM-CWRU, OH · $515,147 · awarded Apr 21, 2026 · R01

  ABSTRACT: Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. GBM growth and therapeutic resistance are driven by a combination of self-renewing cancer stem cells (CSCs) and an aging- induced tumor-supportive microenvironment. CSCs are regulated by cell intrinsic genetic and epigenetic networks, extrinsic cellular interactions with the surrounding microenvironment, and the interaction between those intrinsic and extrinsic regulatory programs. While multiple molecular mechanisms that drive self-renewal have been identified, the effects of advanced age on CSC maintenance has yet to be explored. Specifically, it is unclear how advanced age alters CSC maintenance and GBM growth. A recently recognized hallmark of advanced age is the shift in sulfur amino acid metabolism that suppresses enzyme-dependent hydrogen sulfide (H2S) generation, signaling, and bioavailability. H2S is a redox-active metabolite that signals through protein S- sulfhydration (R-SSnH) and impacts metabolism, immune activation, and longevity. Its enzymatic production by cystathionine γ-lyase (CGL) is repressed by thyroid hormone (TH). H2S has both pro- and anti-tumorigenic functions that are tumor-type dependent. However, there is limited information on cell intrinsic and tumor microenvironment functions of H2S in GBM. Recently, we modulated H2S levels through dietary and pharmacological interventions and found that H2S functions as a tumor suppressor in GBM and attenuates CSC self-renewal and tumor growth in pre-clinical models. H2S generation and sulfhydration were decreased in human GBM specimens as compared to non-tumor controls. While the data support the hypothesis that H2S functions as a tumor suppressor in GBM, the effects of aging-induced H2S declines on GBM progression and CSCs, and how to reverse this for clinical use, are unexplored. Based on our published findings and new preliminary data, we hypothesize that decreased H2S production during aging promotes CSC initiation, immune suppression, and drives GBM growth but can ultimately be reversed by anti-TH based H2S boosting approaches. We will test this hypothesis through the following aims by integrating our newly developed H2S and sulfhydration detection assays in combination with in vitro and in vivo GBM models that manipulate H2S production via genetic and pharmacological interventions with human samples to provide clinical relevance. Aim 1 tests the hypothesis that aging-induced suppression of CGL-derived H2S accelerates GBM progression. Aim 2 tests the hypothesis that chemically-induced hypothyroidism stimulates CGL to increase systemic and neural H2S production resulting in reduced GBM progression, CSC enrichment, and improved survival in preclinical GBM models. The long-term goal of this project is to interrogate the function of H2S as a GBM tumor suppressor that is lost during aging, while also studying the therapeutic effects of hypothyroid-induced H2S production and signaling to reduce CSC maintenance and immune suppression. Leveraging this axis represents a new strategy for the management of GBM that may synergize with standard of care chemo-, radio-, and immunotherapies.

Related topics

• Gene therapy