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NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY The persistence of Human Immunodeficiency Virus (HIV) in long-lived latent reservoirs remains one of the major barriers to a functional cure. The latent reservoir consists of cells harboring replication-competent, but transcriptionally inhibited proviruses that evade immune clearance even in patients on long-term antiretroviral therapy (ART). Spontaneous reactivation of these proviruses results in viral rebound upon treatment cessation, thus mandating life-long treatment. Furthermore, the production of viral transcripts and antigens from these cells, even in the absence of productive infection, is thought to contribute to persistent inflammation and increased rates of co-morbidities among people with HIV (PWH). Therefore, the development of small molecule regulators of viral transcription as ART adjuvants to reign in chronic inflammation and/or to manage the reservoir en route to a functional cure remains an NIH HIV/AIDS high priority research topic. The licensing of transcriptional elongation by the cyclin-dependent kinase complex known as P-TEFb is one of the most heavily regulated steps in mammalian gene expression. P-TEFb is normally recruited to sites of nascent transcription by a series of context-dependent complexes, including transcription factors, epigenetic regulators, and super elongation complexes (SECs). HIV-1 circumvents this regulatory step through its viral Tat protein, which directly recruits P- TEFb to sites of nascent proviral transcription through recognition of the TAR RNA stem loop produced at the 5’ end of viral RNA transcripts. Biochemical purifications of Tat have found that it also binds a specific cellular SEC, which has been shown to facilitate viral transcription in some cell line models. However, we recently found that this SEC is dispensable for viral replication in primary CD4+ T cells. To validate this finding, we characterized a series of small molecule SEC inhibitors (iSECs) that block the interaction of P-TEFb with these SEC complexes. Treatment of primary CD4+ T cells with iSECs increased viral replication and viral transcript production, suggesting that the SEC is not only dispensable for viral replication, but that it may serve as a reservoir for P- TEFb release. Several small molecules that enhance the availability of P-TEFb (e.g., BRD4 inhibitors) have been shown to stimulate viral transcription and reactivation from latency. Indeed, we found that iSECs synergize with latency reversing agents to enhance viral transcription in peripheral blood mononuclear cells from PWH on suppressive ART. Based on our preliminary data showing that the SEC is not required for viral transcription in primary CD4+ T cells and that it can be targeted as a reservoir of P-TEFb by iSECs for latency reversal, here we seek to address three critical questions: 1) What P-TEFb-containing complex is required for HIV transcription in primary CD4+ T cells?; 2) Does HIV use the SEC in other cellular contexts?; and 3) What is the potential of iSECs as latency reversing agents compared to other P-TEFb release strategies? Ultimately, these studies will clarify the transcriptional elongation complexes that regulate HIV replication and latency towards the development of next-generation ART adjuvants designed to manage the reservoir.

NHLBI - National Heart Lung and Blood Institute

Project Summary Dilated cardiomyopathy (DCM) is a common cause of heart failure with a severe lack of therapeutics, creating a significant clinical burden. The gene TRAPPC11 emerged from a whole transcriptome, functional screen for therapeutic targets for DCM using patient-derived human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), demonstrating reversion of contractile dysfunction upon knockdown in DCM hiPSC-CMs. TRAPPC11 is a modulator of endoplasmic reticulum (ER) stress. Since ER stress is recognized as a pathophysiological driver in DCM, my overarching hypothesis is that inhibition of TRAPPC11 would be therapeutic for DCM caused by TNNT2 mutations and possibly more broadly for other forms of DCM. This hypothesis will be tested through knockdown of TRAPPC11 in a mouse model of TNNT2 DCM and in myofilament and nonmyofilament induced DCM in hiPSC-CMs. Interestingly, single nucleotide polymorphisms (SNPs) in TRAPPC11 are associated with left ventricular hypertrophy (LVH) in response to pressure overload in African Americans. Therefore, my secondary hypothesis is that common mechanisms underlie TRAPPC11’s effect on hypertrophy induction and its therapeutic potential for DCM. Using CRISPR/Cas9 genome editing, I will test the effects of TRAPPC11 SNPs associated with LVH on ER/SR function in healthy hiPSC-CMs and introduce key SNPs into DCM hiPSC-CMs to assess their protective potential. Completion of this study will establish a translational and mechanistic rationale for targeting TRAPPC11 in DCM, and might warrant monitoring clinical outcomes of people carrying these SNPs for evidence supporting translatability of targeting TRAPPC11 to treat DCM. The training program proposed in this fellowship application was created to support my potential to become an independent investigator in the future. It will take place in the highly supportive, rich academic environment of Stanford University, where I will have access to state-of-the-art facilities and the opportunity to interact with leading cardiovascular researchers. The plan encompasses scientific technical skills, professional development skills, and both written and oral communication skills and will prepare me for writing my career development award.

NCATS - National Center for Advancing Translational Sciences

SUMMARY Adaptor proteins that function exclusively through protein–protein interactions (PPIs) comprise one of the largest classes of undruggable targets. SMAD4, the central adaptor in the canonical TGF-β signaling pathway, exemplifies this challenge. Germline mutations in SMAD4 cause Myhre Syndrome (MS), a rare autosomal dominant multisystem disorder characterized by severe fibrosis, vascular stenosis, restrictive cardiomyopathy, and respiratory complications. Our recent studies identified SMAD4-I500V as a gain-of-function mutation that drives a hypermorphic SMAD4–SMAD3 interaction (hyperPPI), leading to excessive TGF-β signaling output. This discovery establishes a new paradigm in Myhre biology, in which hyperPPIs can function as pathogenic drivers and potential therapeutic targets. However, no physiologically relevant platforms currently exist to interrogate SMAD4-I500V hyperPPI in the patient context or to discover small-molecule modulators that could normalize this signaling axis. This proposal will establish two complementary, patient-derived experimental systems that together address this critical gap. In Aim 1, we will develop the Myhre iPSC hyperPPI Biosensor System (MiBS) by CRISPR-engineering Myhre patient–derived and sibling control induced pluripotent stem cells (iPSCs) with live-cell biosensors for allele-specific monitoring of SMAD4-I500V/SMAD3 hyperPPI. MiBS will enable multiplexed, quantitative, and high-throughput detection of pathogenic SMAD4 interactions in their native genomic and cellular context, providing an unprecedented platform for chemical screening and mechanistic dissection. In Aim 2, we will establish the Cardiac Organoid Phenotyping System (CoPS) by differentiating Myhre and control iPSCs into multicellular 3D cardiac organoids that recapitulate cardiomyocyte, fibroblast, and endothelial interplay. CoPS will be used to define functional disease phenotypes—including contractility, calcium handling, and electrophysiology—as well as molecular signatures of fibrosis, vascular integrity, and cardiomyocyte maturation. Single-cell transcriptomic profiling will further resolve lineage-specific alterations and disrupted intercellular communication networks. By integrating MiBS and CoPS, this project will generate the first physiologically and mechanistically relevant platforms to model SMAD4-I500V hyperPPI in Myhre Syndrome. These tools will illuminate how undruggable adaptor proteins drive rare disease, while establishing scalable, HTS-compatible systems for future therapeutic discovery. More broadly, the approaches developed here are generalizable to other adaptor proteins and PPI-driven pathologies, offering a conceptual and experimental framework for expanding the target landscape to previously intractable biology.

NINDS - National Institute of Neurological Disorders and Stroke

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with no effective treatment. Among the identified ALS-causing genes, several encode RNA binding proteins including FUsed in Sarcoma (FUS). Mutant FUS protein is mis-localized to the cytoplasm where it forms inclusions, a pathological hallmark of ALS. We and others have studied the FUS protein under physiological and pathological conditions in various models. Notably, we recently identified six individuals in an extended ALS kindred who carry the ALS-linked FUS R521G mutation but remain free of ALS well into their 60s and beyond (Unaffected Mutation Carriers, UMCs). We generated induced pluripotent stem cell (iPSC) lines from four UMCs, six FUS ALS patients, and four healthy controls, differentiated them to motor neurons (iMNs), and measured their electrophysiological properties. FUS ALS iMNs demonstrated disease-related hyperexcitability, whereas UMC and control iMNs displayed normal electrophysiological properties. Using an integrated analysis of whole genome sequencing and RNA-Seq data, we identified a cluster of variants in the 3’ untranslated region (3’-UTR) of the microtubule- associated protein tau (MAPT) gene. This set of linked variants was highly expressed in all UMCs but was absent in all ALS patients. More excitingly, an isogenic line with these variants incorporated into MAPT 3’-UTR of an ALS iPSC showed normal electrophysiological properties, supporting that these variants are critical to mitigating the hyperexcitability phenotype. iMNs from FUS ALS patients had increased Tau protein levels as compared to those from UMCs with the MAPT variants. In addition, overexpression of Tau induced neuronal hyperexcitability whereas Tau knockdown restored neuronal excitability to normal. We thus hypothesize that the MAPT variants reduce Tau protein expression, mitigate iMN hyperexcitability, and ultimately protect UMCs from developing ALS. Three specific aims are designed to test the hypothesis. Aim 1 is to establish the causative role of the MAPT 3’-UTR variants in reducing the hyperexcitability phenotype. We will generate additional isogenic lines by introducing the wild-type MAPT allele to UMC iPSCs to solidify the causative role of the MAPT variants in determining ALS or UMC phenotypes. We will generate and characterize two isogenic lines carrying 4 rare variants or 10 common variants to delineate their contributions. Aim 2 is to determine how the FUS mutation increases Tau expression and alters other properties, and how the MAPT variants prevent these abnormalities. Aim 3 is to determine which ion channel or receptor is responsible for the ALS-related hyperexcitability phenotype, and to examine whether up- and down-regulation of Tau expression changes the specific ion channel or receptor activity. The proposed studies are highly innovative conceptually and technically. The results will provide insights into the mechanisms underlying the protective effects of the MAPT variants and identify potential novel therapeutic targets. This project has a broader impact beyond ALS since Tau plays a critical role in other neurodegenerative diseases.

NASA Johnson Space Center

The National Aeronautics and Space Administration (NASA), Johnson Space Center (JSC), Office of Education (OE), is releasing a Cooperative Agreement Notice (NNJ08237878C) for submission of proposals to support the administration and activities of Teaching From Space (TFS). TFS is a NASA Education office co-located with the Astronaut Office at Johnson Space Center (JSC). As part of the FY2006 realignment of NASA Education projects from NASA Headquarters to NASA Field Centers, management of the Educator Astronaut Project (EAP) and Education Flight Projects (EFP) and their associated activities transitioned to the JSC Education Office and were integrated with TFS. JSC is the Lead Center for the projects and other NASA Field Centers and JPL are involved in the implementation of project activities. The JSC Education Office has a single project manager for TFS activities. EAP/EFP and other TFS activities offer NASA Education unique capabilities and opportunities to involve educators and students through astronaut training, spaceflight missions, on-orbit education activities, future flight platforms and space missions, and a variety of education flight projects. All TFS activities are designed to support an integrated vision and objectives. The vision for TFS is: Facilitate education opportunities that use the unique environment of spaceflight and other flight platforms. TFS will focus its efforts to meet three objectives: 1. Develop and provide NASA-unique experiences, opportunities, content, and resources to educators and students to increase K-12 student interest in STEM disciplines. 2. Develop and facilitate a NEAT-like (Network of Educator Astronaut Teachers) group of highly motivated educators. 3. Build internal and external partnerships with formal and informal education communities to create unique learning opportunities and professional development experiences. Institutions eligible to respond to this CAN are limited to higher education institutions, nonprofit organizations, or consortia of organizations and institutions serving higher education. Upon it's release date, this CAN will be available electronically through http://www.grants.gov/. Electronically submitted Notices of Intent to propose are requested. Proposal due date is April 28, 2008. The electronic submission of each proposal's Cover Page/Proposal Summary/Budget Summary is required by the due date for proposal submission. This solicitation leading to the award of a Cooperative Agreement is issued pursuant to title 14 CFR Part 1260 for educational and nonprofit institutions and 14 CFR part 1274 for commercial organizations. Notwithstanding the posting of this opportunity at FedBizOpps.gov, Grants.gov, or at both sites, NASA reserves the right to determine the appropriate award instrument for each proposal selected pursuant to this announcement. Direct questions specifically regarding this solicitation to: Edward J. Pritchard, Project Manager, edward.j.pritchard@nasa.gov or Cynthia McArthur, Project Lead, Cynthia.1.mcarthur@nasa.gov.

NIGMS - National Institute of General Medical Sciences

How do cells in mammalian organisms integrate various inputs to generate elaborate spatial arrangement of differentiated cell types as seen in tissues and organs? Naturally evolved genetic networks based on ligands and receptors are essential for embryonic development and maintaining adult tissues. Alterations in genes, effector proteins, and cellular environments can disrupt normal development, leading to congenital disorders and adult diseases such as cancer and degeneration. Recently, synthetic genetic networks based on synthetic receptors have been developed and used in research settings to perturb and reconstruct complex multicellular networks (e.g., synNotch receptors that we developed). In our lab, we have two main goals: to develop new technologies to manipulate cell differentiation in space and time with synthetic signaling systems, and to apply these technologies to reconstruct specific examples of complex arrangement of cells, for example here a multilayered arterial vessel. In the Research Strategy section of this proposal, we outline two research Tracks, and their respective goals: 1. Development of New Technologies for 3D Differentiation Control: We will develop and integrate two technologies: (i) control of differentiation in three dimensions (3D) layers of defined thickness around spherical or thread-like scaffolds to model organs with radial symmetry around a nucleus like liver, branched epithelia, skin, and blood vessels among others; (ii) autonomously patterning genetic circuits of the reaction-diffusion family to obtain 2D and 3D gene expression domains like spots, stripes and labyrinth, known as Turing-like patterns. 2. Study and control of cell-cell communication among differentiating endothelial and vascular support cells: we will utilize patterned Syn-Notch signaling to build a perfusable vasculature comprised of an endothelial intima and a smooth muscle media layer of controlled thickness. We will generate and perturb these constructs where human induced pluripotent stem cells are differentiating to endothelial cells and vascular smooth muscle cells in geometrically controlled fashion in 2D and in 3D. We will identify and use the signals and communication network that support construction of perfusable functional tissues. These studies aim to enhance synthetic and developmental biology by deepening our understanding of cell signaling mechanisms in multicellular communities. Ultimately, these insights could advance cell-based therapies and improve disease treatment strategies.

OD - NIH Office of the Director

Abstract Musculoskeletal (MSK) disorders affect approximately 126.6 million adults in the United States, accounting for more than half of the adult population. The development of disease-modifying drugs (DMDs) for these conditions remains particularly challenging due to subjective clinical assessments, the absence of reliable animal models that closely mimic human pathology, and the high costs associated with large-animal studies. MSK disorders are influenced by various factors, including environmental exposures, aging, hormonal changes, degenerative diseases, and injuries, impacting individuals across all demographics. While surgical interventions are sometimes an option, they often have high failure rates, leading to disability and progressive tissue deterioration. The financial burden is immense, with U.S. healthcare costs related to MSK conditions exceeding $400 billion annually. To overcome these challenges, innovative preclinical platforms incorporating human cells and tissues are crucial for generating reliable data to support DMD development. Our team consists of experts with a strong track record in bioengineered systems that accurately replicate human MSK structures and functions. Leveraging our extensive experience with stem cells, organoids, and advanced in vitro culture platforms, we propose the establishment of an MSK New Approach Methodologies (NAMs)Technical Development Center (TDC) to drive the innovation of combinatory physiological models for muscle, cartilage, tendon, and intervertebral disc research. Through this initiative, we will investigate MSK pathologies—including mechanical overloading, inflammation, and injury—while considering key influences such as environmental exposures, aging, and hormonal effects. Additionally, by collaborating closely with the Consortium Steering Committee, the Validation and Qualification Network (VQN), and the NAMs Data Hub and Coordinating Center (NDHCC), the MSK NAMs developed through this effort will be widely accessible to a broad range of downstream users.

NIA - National Institute on Aging

Abstract Telomere entanglements: formation, disentanglement, and impact of failed disentanglement on genome stability To preserve genome stability, replicated sister chromatids must be disentangled and cleanly separated at mitosis. Telomeres safeguard this process by protecting chromosome ends from degradation and end-joining reactions that generate dicentric chromosomes and rampant chromosome instability. In most human somatic cells, however, telomerase is inactive, leading to progressive telomere erosion over time. This raises a fundamental question: what protective functions are lost as telomeres shorten and become dysfunctional? Telomeres are well known for preventing end fusions, but we have uncovered an additional threat: telomere entanglements. These arise when stalled replication forks at dysfunctional telomeres fail to restart and engage in aberrant interactions, leading to persistent DNA bridges during mitosis. The fission yeast telomere-binding protein Taz1, and its mammalian ortholog TRF1, promote replication fork progression through telomeres and prevent such entanglements. Loss of Taz1 causes stalled telomeric forks that generate anaphase-spanning DNA bridges. We find that resolution of these structures depends on the timing of anaphase midregion nuclear envelope breakdown, which exposes the entanglements to the cytoplasm, an unexpected but essential step for entanglement resolution. This proposal dissects the mechanisms governing telomere entanglement formation and resolution. We hypothesize that the most problematic entanglements stem from strand invasions between stalled forks on different chromosomes, forming non-sister telomere entanglements. We will define their molecular structure and investigate how long noncoding telomeric RNAs and RecQ helicases contribute to their formation. We further show that resolution involves a noncanonical function of Topoisomerase II, likely modulated by the condensation state of Top2- DNA complexes, a novel concept with broad implications. While these discoveries emerged from studies in S. pombe, our preliminary findings reveal similar entanglement phenotypes in mammalian cells, particularly in response to telomeric replication stress. We will extend these studies to human cells undergoing telomere-driven replicative aging, to assess whether telomere entanglements contribute to the genomic instability associated with aging. Together, this work defines a previously unrecognized consequence of telomere dysfunction and illuminates the molecular handoff between stalled replication and chromosome segregation at the critical final act of mitosis, the moment of truth when euploidy is either preserved or lost.

NINDS - National Institute of Neurological Disorders and Stroke

Abstract. Why can’t adult mammalian brains fully regenerate after damage or degeneration? The primary reason lies in their limited capacity for neurogenesis. In adult mice, neurogenesis occurs slowly and only in the olfactory bulb and the hippocampus. This is a stark difference from embryonic stages, where rapid neurogenesis occurs throughout all brain regions. The source behind this rapid embryonic neurogenesis is the embryonic neural stem cells (NSCs), also known as radial glia. Shortly after birth, however, these cells “disappear” by retracting their long radial processes and transforming into other cell types. Consequently, neurogenesis is terminated throughout the majority of the central nervous system (CNS). Similar to mice, radial glia in humans rapidly generate neurons during embryonic development and disappear postnatally, leading to the termination of neurogenesis. How do NSCs keep time and shut down neurogenesis on a predictable schedule? What is the molecular logic underlying the disappearance of radial glia? These questions remain unanswered. Temporal control of postnatal termination of neurogenesis is one of the major knowledge gaps in brain development and this lack of understanding presents a significant bottleneck in stem cell therapy development. Currently, experimental NSC transplantation therapies fail to generate sufficient numbers of neurons to significantly improve disease outcome and, consequently, there is no Food and Drug Administration-approved NSC therapy yet. Investigating the regulation of the termination of neurogenesis in the developing brain will reveal novel molecular targets for maintaining or expanding the duration of neurogenesis of transplanted NSCs, which can be targeted for the development of next generation NSC therapies. NSC therapies with enhanced neurogenesis capacity could transform the treatment landscape of a broad range of neurological disorders including stroke and neurodegeneration. Here, we propose to investigate the temporal control of the postnatal termination of neurogenesis and the disappearance of embryonic radial glia. A serendipitous discovery led us to study the role of PR-domain containing 16 (Prdm16), a histone methyltransferase, in postnatal NSCs. Our preliminary studies show that genetic deletion of Prdm16 from NSCs leads to the persistence of radial glia in the adult NSC niche and prolonged postnatal neurogenesis in the cerebral cortex. Based on these findings, we hypothesize that Prdm16 promotes the postnatal disappearance of embryonic radial glia and the termination of cortical neurogenesis. In Aim 1, we will determine the role of Prdm16 in regulating the fate and function of quiescent and activated NSCs. In Aim 2, we will identify the downstream mechanisms through which Prdm16 regulates the postnatal disappearance of embryonic radial glia and neurogenesis termination. In Aim 3, we will target the Prdm16-Vcam1 pathway to promote post-stroke neurogenesis.

Tennessee Department of Education

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

NINDS - National Institute of Neurological Disorders and Stroke

SUMMARY/ABSTRACT Hereditary Spastic Paraplegia 4 (SPG4-HSP) is an underdiagnosed neurodegenerative disorder characterized by progressive weakness and spasticity in both legs that escalate into wheelchair dependence. Symptoms result mainly from dying-back degeneration of corticospinal tracts. The disease is caused by mutations in the SPAST gene, which encodes spastin, a microtubule-severing protein with membrane-related properties. Recent studies indicate that that disease pathology is primarily driven by the M1 isoform of spastin, which, when mutated, becomes toxic. A logical therapeutic strategy would be to reduce mutant M1 levels and restore axonal integrity, with the goal of halting and potentially reversing disease progression. Mutant M1 becomes not only toxic but also resistant to degradation, causing it to accumulate. A multi-PI team at Drexel University has developed three recombinant monoclonal antibodies with high specificity for M1. These antibodies were then engineered into intrabody vectors encoding their variable regions for intracellular expression in affected neurons. These intrabodies include a lysosome-targeting sequence to direct the antibody–antigen complex for degradation. This strategy, previously validated for other mutant proteins, is well-suited for SPG4-HSP and could represent a breakthrough therapy. Key questions remain: Can mutant M1 be effectively and sustainably depleted without off-target toxicity? If wildtype M1 is also affected, can any ill effects of this be mitigated? The multi-PI team has developed human induced pluripotent stem cell (hiPSC)-based platforms for studying SPG4-HSP. To test the intrabody approach, the multi-PI team has developed two isogenic hiPSC lines, each with a distinct SPAST mutations, and five SPG4-HSP patient-derived hiPSC lines with their mutation-negative familial controls. These cells are differentiated into motor cortical organoids (MCOs), which are forebrain organoids enriched for corticospinal motor neurons, the neuronal population most affected in SPG4-HSP. Across diverse mutations, MCOs consistently recapitulate disease-relevant phenotypes, including elevated HDAC6 activity, reduced microtubule acetylation, and enhanced neurodegenerative phenotypes. By introducing intrabody vectors into MCOs, it will be determined whether degrading mutant M1 restores cellular homeostasis and reverses neurodegeneration. By integrating precision intrabody engineering with patient-specific hiPSC-derived MCOs, this proposal seeks to mechanistically validate and therapeutically correct the pathogenic accumulation of mutant M1, establishing a novel, targeted approach with strong potential for clinical translation in SPG4-HSP treatment.

NHLBI - National Heart Lung and Blood Institute

Project Summary Sickle cell disease (SCD) is an inherited hemolytic anemia that afflicts 100,000 patients in the United States and millions worldwide. Those with SCD suffer from recurrent pain, ischemia-perfusion injury, chronic inflammation, progressive organ damage and a shortened life and healthspan. SCD epitomizes chronic hematologic stress in the form of bone marrow (BM) inflammation, increased hematopoietic demand, and BM niche damage, which can damage and deplete BM hematopoietic stem and progenitor cells (HSPCs). Evidence is building that the pathologic stress of SCD selects for mutant HSPCs that put patients at risk for additional hematologic disease, especially when subject to stressors such as exposure to cytotoxic chemotherapy prior to hematopoietic cell transplant (HCT) or during gene therapy. As these are the only potentially curative therapies for SCD, it is important to better understand and prevent SCD-induced insults to HSPCs. We found that BM HSPCs from mice and SCD individuals contain DNA damage, oxidative stress, and precocious senescence. These phenotypes correlated with a severe loss of blood repopulating and hematopoietic colony activity from the BM of mice and individuals with SCD, respectively, that inversely correlated with high expression of molecular enforcers of senescence. We demonstrated that treatment of SCD mice with the senescence targeting therapy (STT), navitoclax (ABT-263), reduced numbers of HSPCs with DNA damage and restored hematopoietic repopulating activity to the BM. Thus, STTs have the potential to rejuvenate damaged BM HSPCs for downstream applications in hematopoietic cell transplant and gene therapy in SCD. Here, we propose to build on these promising ‘proof of principle’ studies and establish the pre-clinical rationale for STTs to improve HSPC function and numbers during SCD. As navitoclax causes dose-limiting cytopenias and is not FDA approved, in Aim 1 we will employ a pre-clinical SCD mouse model and BM HSPCs from individuals with SCD to interrogate the ability of FDA-approved STTs to restore function to BM HSPCs during SCD. We will also define the therapeutic window of STTs in our pre-clinical SCD model. In Aim 2, we will test our hypothesis that STTs can improve the mobilization of high-quality HSPCs during SCD following treatment with the CXCR4 antagonist, plerixafor, using a pre-clinical model of SCD. We will also test mobilized cells for gene editing efficiency in furtherance of translating this work to our ongoing clinical trial for gene editing-based autologous therapy for SCD (SAGES1, NCT06506461). In Aim 3, we will interrogate the cellular mechanisms behind improved function following STT during SCD and test the hypothesis that non-cell autonomous effects on BM HSPCs contribute to their restored function. Via this work, we will establish the pre-clinical rationale for STTs as a tool to improve the function of HSPCs in individuals with SCD, which has major implications for the emerging field of potentially curative therapies for SCD.

Texas Education Agency

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

Textron Foundation

Supports workforce development, STEM education, and community programs in Textron brand communities.

NCI - National Cancer Institute

Abstract The FASEB SRC TGF-β family in Development and Disease in 2026 (hereafter "TGF-β 2026") will convene investigators who are advancing TGF-β research, from fundamental discovery through clinical application. This gathering unites researchers across the full spectrum of the TGF-β family, which encompasses over 30 ligands including TGF-βs, BMPs, GDFs, activins, and inhibins, who are driving innovations in cancer immunotherapy, regenerative medicine, vascular therapeutics, and age-related interventions. The conference program emphasizes mechanistic insights that inform therapeutic development, featuring sessions on cancer signaling mechanisms, development-disease intersections, vascular physiology and angiogenesis, tissue homeostasis, stem cell biology and regeneration, structure-function, and strategic therapeutic avenues. These presentations will showcase how advances in understanding TGF-β pathway regulation are being translated into clinical solutions for cancer, cardiovascular disease, immune disorders, musculoskeletal conditions, and aging-related pathologies. TGF-β 2026 represents the 14th iteration of this premier conference series, now spanning nearly 25 years of scientific evolution that has paralleled the field's maturation from basic signaling studies to therapeutic targeting. The sustained research momentum, with continued high publication and funding rates across TGF-β research domains, reflects the field's transition toward clinical impact and commercial development. This conference also bridges academic discovery with industry innovation, featuring speakers from leading pharmaceutical companies alongside academic researchers, creating opportunities for translational partnerships and therapeutic advancement discussions. The 2026 meeting will also foster cross- continental partnerships that have become essential for modern therapeutic development. Drawing from 13 previous conferences, TGF-β 2026 provides an intensive forum for sharing evaluating therapeutic targets, discussing regulatory pathways in model systems, and addressing translational challenges. The conference particularly emphasizes developing the next generation of TGF-β researchers equipped for the increasingly interdisciplinary and translational nature of the field, ensuring continued progress toward therapeutic breakthroughs that benefit human health.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary Immune responses to cancer and chronic infection often collapse, corresponding to progression of disease. This collapse is not inevitable, however, and both natural and therapeutic exceptions have been shown occur through re-invigoration of a stem-like progenitor population of T cells. It remains unknown how aberrant type 2 responses are maintained in the face of chronic antigen exposure, rather than succumbing to immune exhaustion or tolerance. In a large scale informatic survey of human type 2 inflammation, we recently identified a stinkingly abundant progenitor-like Th2 population in human disease tissue, the Th2 multipotent progenitor (Th2-MPP). We propose that this aberrant tissue progenitor acts as the mirror image of the exhausted T cells seen in cancer and chronic infection, in this case causing pathology through overactivity of the T cell progenitor system. This project sets out to define the factors that sustain the Th2 progenitor population using human disease tissue and a novel mouse model. The experiments in this proposal are designed to reveal the core features of tissue human and mouse Th2 progenitors and to identify the factors that promote their maintenance. In Aim 1, we will deconstruct the Th2 compartment by comparing aspirin-exacerbated respiratory disease (AERD) and chronic rhinosinusitis with nasal polyposis (CRSwNP), two diseases that are clinically similar, yet thought to be driven by different factors. Using single-cell RNA-seq with T cell receptor-seq, multiomics, spatial in situ transcriptomics, single-cell metabolism assessment, and high-dimensional flow cytometry, we will identify the core and distinct features of the human Th2 compartment including the Th2-MPP population. In Aim 2, we will utilize a newly-developed chronic, multi-allergen mouse asthma model that recapitulates key features of human tissue type 2 inflammation, including a tissue Th2-MPP population that is sufficient to cause airways hyperactivity on adoptive transfer. We will utilize this new model to transcriptomically define the mouse Th2 progenitor in fine resolution and test the disease-causing capacity of this population in vivo. In Aim 3, we will use both a human in vitro system and our new mouse model to test the impact of ongoing T cell receptor signaling, TSLP, IL-33, and glucocorticoid on the Th2 progenitor population. Through these aims, our proposal will use human and mouse systems and cutting-edge approaches to define in detail a previously unrecognized human Th2 progenitor population present across type 2 disease tissues, with the potential to sustain multiple key Th2 lineages. These studies will lay the groundwork for targeting this progenitor system, with the goal of disease modification.

NCI - National Cancer Institute

PROJECT SUMMARY/ABSTRACT B-cell clones in blood are commonly detectable in individuals over the age of 40 years, categorized as high- count monoclonal B-cell lymphocytosis (HC-MBL) when present at a clone size of 500 to 5000 cells/μl. HC-MBL predisposes to chronic lymphocytic leukemia (CLL), other cancers, and infections, but the full spectrum of its phenotypic consequences is unknown due to the limited scale of studies thus far, which have relied on flow cytometric screening. CLL-initiating chromosomal alterations can arise in hematopoietic stem and progenitor cells (HSPCs) and penetrate into both the myeloid and lymphoid lineages. Immune dysfunction is a major source of morbidity in CLL and may underlie phenotypic consequences of HC-MBL. While miR-15/16 is a well- characterized CLL driver in del (13q) and its role in myeloid malignancies and T-cells has been studied, comprehensive, lineage-spanning studies of del (13q) and trisomy 12 in patient samples to uncover novel pathogenic mechanisms and potential therapeutic targets have been lacking. The applicant’s preliminary studies have identified a strong relationship of HC-MBL with mosaic chromosomal alterations (mCAs) – large somatic deletions and duplications of DNA segments – leading to a model for detecting HC-MBL using existing genetic and hematologic data in large biobanks. Preliminary studies have also revealed the presence of del (13q) and trisomy 12 beyond the B-cell lineage and the ability to detect these mCAs and their transcriptomic output in single-cell RNA-sequencing (scRNA-seq) of patient samples. Aim 1 will determine phenotypic consequences of HC-MBL in two large biobanks (n = 402,973) by performing a phenome-wide association study and test the hypothesis that immune-related diseases are more common in those with HC-MBL. Aim 2 will determine the impact of del (13q) and trisomy 12 on HSPC and mature blood cell biology through scRNA-seq analyses of bone marrow and blood samples from untreated CLL patients and test the hypothesis that these mutations exert cell- intrinsic effects on the biology of hematopoietic cells beyond their roles as drivers in the B-cell lineage. Successful completion of these aims will lay the foundation for developing risk mitigation strategies for HC-MBL, a common precancerous condition, and provide a deeper molecular understanding of initiating events and immune dysfunction in CLL, which could uncover novel therapeutic opportunities. The applicant, Dr. Aswin Sekar, is an oncologist at Dana-Farber Cancer Institute (DFCI), where he spends 80% of his time in research and 20% caring for patients with MBL, CLL and lymphomas. His five-year career development plan draws upon mentorship, collaborations, conferences, coursework, and seminars. Dr. Sekar’s primary mentor is Dr. Benjamin Ebert, a leader in hematologic malignancies and premalignant states with a long track record of mentoring trainees to independent positions. Dr. Sekar has assembled a committee of internationally recognized experts in MBL, CLL, hematopoiesis, and genetics to provide scientific and career mentorship. Dr. Sekar will leverage the exceptional environment at DFCI and Harvard to achieve his career goal of becoming an independent physician-scientist.

NIAID - National Institute of Allergy and Infectious Diseases

SUMMARY Picobirnaviruses (PBVs) are small double-stranded, bisegmented RNA viruses that are found in humans, other mammals and birds. PBVs are among the most commonly detected RNA viruses in the human enteric tract, and they have been linked to human diseases. For example, PBV is associated with type 1 diabetes and detection of PBVs is predictive of the development of severe graft-versus-host-disease in hematopoietic stem cell transplant recipients. These observations raise a key question as to whether PBVs play causal roles in these diseases. However, since no PBV culture or animal model exists, it is currently impossible to experimentally test disease causality. The lack of any PBV isolate is the rate-limiting step in further characterization of the basic biology of PBVs and their role in pathogenic outcomes. Key to overcoming this technical barrier is the understanding of the type of host organism(s) PBVs infect. Dogma asserts that PBVs are human and animal- infecting viruses, but definitive proof of this is lacking. Instead, recent studies support the hypothesis that PBVs are RNA phages that infect bacteria. For example, there is high prevalence of bacterial ribosome binding sites (Shine-Dalgarno) preceding PBV ORFs, a feature characteristic of most phages. In addition, many PBVs encode proteins that can lyse bacteria (lysins) a property necessary for phages to egress from their host bacteria. Critically, in preliminary data we demonstrate that PBV3 can be cultured anaerobically in a stool-derived bacterial community, establishing the first in vitro culture for any PBV. Furthermore, some antibiotic treatments completely block PBV3 growth, and PBV3 RNA and conserved bacterial 16S rRNA co-localize in the same bacteria from in vitro cultures. To identify the hosts of PBVs, we will optimize a bacterial single-cell RNA-sequencing (scRNAseq) approach for co-detection of phage and host RNA in individual bacteria from complex communities. In parallel, specific PBV-targeted FISH- and antibody-FACS approaches will be used to purify and identify PBV infected bacteria. As a key step towards obtaining pure PBV isolates, we will harness germ-free mice to propagate PBVs in vivo. As shown in our preliminary data, germ-free mice gavaged with PBV-containing human stool specimens serve as a vessel to propagate PBVs in vivo. This innovative approach will generate renewable quantities of infectious PBVs and their host for in vitro isolation efforts. Guided by this information and results from scRNAseq, antibody-, and FISH-based assays, we will isolate PBVs by infecting bacterial monocultures of the candidate hosts. Importantly, lytic RNA phage proteins have been coined “protein antibiotics”. PBV-encoded bacterial lysins provide a unique opportunity to characterize new lytic phage proteins and mechanisms that could provide an alternative to traditional antibiotics for treatment of bacterial infections. The overall goals are to: (1) Identify the bacterial hosts of PBVs; (2) establish PBV culture systems in vivo and isolate PBVs in vitro; (3) Define mechanisms of action of PBV-encoded bacterial lysins.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY Bicuspid aortic valve (BAV) is the most common congenital cardiovascular malformation, characterized by the fusion of two rather than three aortic valve leaflets, and predisposing affected individuals to severe complications including aortic regurgitation, infective endocarditis, and aortic dissection. Despite its prevalence, the molecular mechanisms that govern BAV formation remain poorly understood. Through exome sequencing of a family with inherited BAV, we identified a missense variant in the transcription factor GATA4 (GATA4S377G) that we hypothesize drives the disease. Introduction of this single nucleotide variant into mice produced BAV in 43 percent of animals, establishing the first genetically precise mouse model of BAV caused by a single point mutation. This discovery provides an unprecedented opportunity to mechanistically define how a specific human GATA4 variant alters valve morphogenesis. In Aim 1, we will comprehensively characterize the Gata4S379G mouse model, quantifying birth rates, mortality, and sex-specific penetrance, and assessing cardiac structure and function by echocardiography and magnetic resonance imaging. In Aim 2, we will apply single-cell RNA sequencing, spatial transcriptomics, and HiChIP to define the cell type-specific regulatory networks disrupted by mutant Gata4 during valve morphogenesis, revealing how altered AP- 1/NFAT/TNFα signaling reprograms transcriptional and chromatin architecture to drive abnormal cusp formation. In Aim 3, we will use patient-derived and isogenic human induced pluripotent stem cells (iPSCs) carrying the GATA4S377G mutation to define how this variant disrupts transcriptional regulation, chromatin architecture, and cellular function across key cardiac lineages: endocardial cells, fibroblasts, and cardiomyocytes. Using multi-omic integration and functional assays of endothelial-to-mesenchymal transition, extracellular matrix remodeling, and cell viability, we will determine how dysregulated AP-1/NFAT/TNFα signaling drives abnormal valve cell behavior. Pharmacologic rescue experiments will test whether correcting AP-1/NFAT activity restores normal phenotypes. Together, these studies will integrate in vivo and human iPSC systems to establish a mechanistic framework linking GATA4-driven transcriptional dysregulation to bicuspid aortic valve pathogenesis and identify actionable molecular targets for therapy.

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

Project Summary/Abstract This application is submitted in response to RFA-HD-18-011, Child Health Research Career Development Award (CHRCDA) Program to provide K12 awards through the CHRCDA mechanism to young pediatric investigators. This new application requests resources to support three pediatricians each year who hold MD or MD/PhD degrees and have completed scholarship training in a clinical subspecialty. The rationale for the program is based on the well-documented and urgent need to support mentored career development for pediatricians to enable them to become fully independent and productive basic science researchers, and the fact that the department of Pediatrics at UCSF has the vision, experience and infrastructure to train the next generation of leaders in pediatric science. Our aims are to (1) offer a structured program for training academic pediatricians, (2) foster career development and promote retention of junior faculty, (3) expose promising early career pediatricians to the intellectual richness of UCSF research and (4) promote diversity in academic pediatrics. The scholars trained by this program will bring state-of-the-art approaches to bear on diagnosis, treatment and prevention of health problems in children as well as childhood onset of adult illness. The design of this program involves harnessing the expertise of world- class basic laboratory scientists who will serve as mentors for interdisciplinary training. The basic science training program is focused around eight scientific cores: cancer, cardiopulmonary medicine, developmental biology, genetics, immunology, neurobiology, stem cell biology, and our new computational sciences core. Each core has a Director, designated faculty, and a specific didactic curriculum. The scholars, in conjunction with their mentor and Core Director, will also participate in a program of additional discipline-specific course work dependent on both the prior experience and training of the applicant and the scientific theme of the trainee’s research, which may often overlap amongst different cores. In this application, we provide evidence that the Department of Pediatrics together with the broader UCSF research community comprise an exceptional environment for preparing young pediatricians who will receive support through the CHRCDA mechanism for successful careers as basic science researchers. There are > 1,200 research laboratories and > 2,200 active research projects at UCSF, and the faculty includes 5 Nobel laureates, 64 members of the American Academy of Arts and Sciences, 76 members of the Institute of Medicine, and 18 Howard Hughes Medical Institute investigators. This program is an investment in the future of children's health, as the diverse group of researchers we will train will harness advanced research strategies to address urgent problems that will result in new treatments to improve child health.

Renaissance 21

Renaissance 21 will run a 10-week after school program at Garfield Teen Life Center located at 428 23rd Avenue. The program will train 10-12 youth to develop mobile and desktop websites. In addition to paid instructors, STEM professionals, college, and high school volunteers will serve as mentors to the program participants. This project will be completed by January 31, 2020.

Renaissance 21

Renaissance 21 will pilot a 10-week after school program that will train 10 youth to develop mobile/desktop game and website applications. STEM professional, college, and high school volunteers will also serve as mentors to the program participants.

NCI - National Cancer Institute

Abstract Acute myeloid leukemia (AML) is one of the most common acute leukemias stemming from genetic alterations in hematopoietic stem/progenitor cells (HSPCs). Currently, effective targeted therapies for AML are limited. A comprehensive understanding of the molecular mechanisms driving AML is crucial for developing innovative treatments. RNA modifications, including pseudouridine (Ψ), are crucial for the regulation of gene expression and cellular function. While aberrant Ψ levels have been linked to certain cancers, its role and underlying mechanisms in AML remain elusive. Pseudouridine modification is catalyzed by pseudouridine synthases (PUSs), including PUS1, a major regulator of Ψ modification across RNA species. Although Ψ has been extensively characterized in tRNA and rRNA, its distribution and function in mRNA remain incompletely understood because of limited sensitive genomic approaches. Using Bisulfite-lnduced Deletion sequencing (BlD-seq) to quantify mRNA Ψ at base resolution, we identified abundant Ψ sites in human leukemia cells and found that PUS1 regulates hundreds of transcripts through PUS1-mediated pseudouridylation. PUS1 is significantly upregulated in subsets of AML patients, and PUS1/Pus1 knockdown markedly inhibits growth and induces apoptosis in human leukemia cells and primary human and mouse leukemia cells, with minimal effects on normal human or mouse HSPCs. These data support a previously unrecognized and leukemia-selective role for PUS1 in AML. Our central hypothesis is that PUS1-mediated mRNA Ψ modification post-transcriptionally regulates genes required for leukemogenesis and AML maintenance. We will test this hypothesis by: 1) defining the oncogenic role of PUS1/Pus1 in AML pathogenesis; and 2) elucidating how PUS1-mediated mRNA Ψ promotes leukemogenesis through post-transcriptional regulation of gene expression. Using animal models and integrated multi-omics approaches, we will determine the in vivo function of PUS1 in normal hematopoiesis and leukemia and define how PUS1 regulates downstream targets from transcription to translation. Successful completion of these studies will establish the role and mechanisms of PUS1/Pus1 in AML development and maintenance, particularly in LSC/LICs, and advance understanding of RNA epitranscriptomic regulation in AML pathogenesis. Animal studies are essential to evaluate leukemogenesis and leukemia stem cell function in vivo within the physiologic bone marrow microenvironment, which cannot be adequately modeled in cell culture alone.

NIMH - National Institute of Mental Health

Human brain rhythms serve as representations of inner states of the brain for vigilance and behavior. Dysregulation of brain rhythms is implicated in most neuropsychiatric and neurodegenerative disorders. The molecular, cellular, and circuit mechanisms underlying mammal brain rhythms have been mainly elucidated in animal models. However, the lack of tractable model has challenged the investigation in human system. We have developed methods to produce the 3D structures representing the human cortical (hCO, human cortical organoids) and thalamic (hThO, human thalamic organoids) areas by applying stem cell technologies. These organoids reproduce the developing and functional human brain. Most recently, we generated ventralized thalamic organoids (vThOs) that contain interneurons that are specifically present in thalamic reticular nucleus (TRN). The fusion or assembly of two or more neural organoids have shown the possibilities to study the interaction of the brain domains. While many previous studies have successfully demonstrated the utility of human brain organoids in modeling diseases, no studies have developed human brain organoids that reproduce human brain rhythms. The neuronal connection between thalamus and cortex are crucial for the formation of human cortical oscillations commonly observed in scalp EEG. Thus, our established hCOs and ThOs are essential elements to produce the cortical oscillations. Here, we will assemble the organoids to test the hypothesis that assembloid of hThO and vThO together with hCO generate thalamocortical oscillations via a synaptic interaction among these functionally distinct organoids. In Aim 1, we will develop hThO-vThO assembloids to produce intrinsic thalamic network oscillations. We will examine the role of TRN GABAergic cells in intrinsic thalamic network oscillations. In Aim 2. we will develop methods to produce hCOs assembled with hThO-vThO thalamic assembloid to generate thalamocortical network oscillations. Here, we will develop a thalamocortical network oscillation that reproduces human cortical rhythms. In Aim 3, we will test effect of the noradrenaline and acetylcholine on thalamocortical oscillation formation by examining the neural gene regulation, cellular and synaptic properties of thalamic neurons, and development of thalamocortical network activity. The results will define molecular, cellular, and circuit mechanisms of how neuromodulators promote proper thalamocortical network oscillation development. Overall, our project will generate the assembloids of cortical and thalamic organoids to reproduce the human corticothalamic oscillation, and will offer a highly innovative platform to define the molecular and cellular underpinnings of human cortical oscillation and its associated diseases.