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NIAID - National Institute of Allergy and Infectious Diseases

Candida spp. are the leading causes of invasive fungal infections in hospitals globally. Invasive candidiasis (IC) includes bloodstream infections (BSIs) and intra-abdominal candidiasis (IAC), which are associated with mortality rates of 20%-40% despite treatment with echinocandins (ECHs), the frontline antifungal class. IAC pathogenesis is under-studied and poorly understood compared to that of Candida BSIs. Candida glabrata is the 2nd leading cause of IC overall and the leading cause of IAC in patients undergoing abdominal surgery. C. glabrata is notable for its haploid, rather than diploid genome, and its propensity to antifungal resistance. However, most ECH treatment failures of C. glabrata IC are not linked to an ECH-resistant strain. Antifungal heteroresistance (HR, a low-frequency subpopulation of resistant cells co-existing with susceptible cells) and tolerance (some cells grow better than controls in presence of drug without minimum inhibitory concentration changes) are reported among Candida spp., but their clinical relevance is not broadly validated. The long- standing paradigm is that almost all sterile site infections, including IAC, stem from a single, clonal organism that passes through a bottleneck to establish disease. Our preliminary data challenge the “single organism” paradigm by demonstrating that blood cultures from individual patients with C. glabrata BSIs are comprised of mixed populations of genetically and phenotypically diverse strains, including strains exhibiting virulence differences and antifungal-HR or tolerance that was not recognized by the clinical lab. We do not know if this diversity was generated in the blood or during gastrointestinal (GI) tract commensalism. In this study, we will investigate C. glabrata diversity during GI tract colonization and from sites of IAC. We hypothesize that C. glabrata strains at sites of IAC originate from GI tract flora, genetic and phenotypic diversity of C. glabrata strains is present at IAC sites but less than that encountered during GI colonization, certain within-host C. glabrata genetic variants enriched in IAC cultures impact pathogenesis of IAC, and other within-host genetic variants enriched during ECH exposure impact ECH-HR or tolerance. In aim 1, we will identify phenotypic and genetic diversity of C. glabrata colonizing the GI tract and from sites of IAC in individual patients. We will recover C. glabrata strains from stool and IAC cultures in each of 6 patients, including those receiving ECH prophylaxis, and assess virulence- associated phenotypes and ECH resistance, HR and tolerance in vitro. We will perform whole genome sequencing on strains from patients in whom phenotypic differences are identified and prioritize certain genetic variants for validation studies. In aim 2, we will validate that C. glabrata genetic variants contribute to pathogenesis of IAC and/or to ECH HR or tolerance. We will create isogenic mutant C. glabrata strains for prioritized genetic variants. Strains will be tested for impact of genetic variants on phenotypes in vitro and on pathogenesis and ECH responsiveness during C. glabrata IAC of mice. This project will afford original scientific insights and carry potentially important implications for clinical and microbiology lab practices.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY Female carriers of Duchenne muscular dystrophy (DMD) typically do not manifest symptoms; however, they are susceptible to dilated cardiomyopathy. DMD is caused by the lack of dystrophin expression. The gene encoding dystrophin is located on the X chromosome. Females have two X chromosomes, one of which is transcriptionally silenced during development. Mosaic expression of the wildtype copy prevents muscle degeneration, but in the heart, mosaic expression can result in premature cardiomyocyte loss and progression to dilated cardiomyopathy. Physical exertion or lifestyle risk factors, such as obesity and smoking, can lead to cardiac stress that exacerbates progression to heart failure. This proposed research will investigate how the lack of dystrophin affects cardiomyocytes differentiated from human induced pluripotent stem cells of female carriers. We will compare the functional characteristics of cardiomyocytes in dystrophin-expressing and dystrophin-deficient female cells. Specifically, we will test calcium handling and mechanical contraction in the context of chronic stress and acute stress. We will also measure cell viability in cells exposed to chronic stress as premature loss of cardiomyocytes is a hallmark of dilated cardiomyopathy. We will then examine the role of mosaic pattern of expression in 2D and 3D cardiac tissues. Collectively, the findings from this proposed research will elucidate how the mosaic pattern of dystrophin expression in the hearts of female carriers contributes to cardiomyocyte dysfunction and provide insight into therapeutic strategies to prevent heart failure.

NHLBI - National Heart Lung and Blood Institute

Recent studies have revealed the existence of distinct, non-membranous Ca2+ signaling compartments within the myocyte, which independently control gene expression involved in pathological cardiac remodeling. However, the precise mechanisms underlying such compartmentation remain poorly understood. Elucidation of the mechanisms conferring compartmentalized Ca2+ signaling in remodeling will inform the development of targeted therapies for heart failure, including non-ischemic Dilated Cardiomyopathy (DCM). We have defined a Ca2+ compartment organized by the scaffold protein A-Kinase Anchoring Protein 6β (AKAP6β, mAKAPβ) at the myocyte outer nuclear membrane (ONM), where AKAP6β is required for the induction of pathological gene transcription and myocyte hypertrophy by the Ca2+/calmodulin-dependent phosphatase calcineurin (CaN). In this application we present new preliminary data that phospholamban (PLN) interacts with AKAP6β and regulates Ca2+ efflux from the AKAP6β compartment into the lumen of the nuclear envelope. In addition, a pathogenic mutation in PLN (p.R14del) increases perinuclear CaN signaling in patient-specific induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs). These findings suggest a novel, non-canonical role for PLN in perinuclear Ca2+ homeostasis that regulates gene transcription. We propose the central hypothesis PLN is a critical regulator of perinuclear Ca2+ signaling responsible for pathological gene expression, such that targeting of PLN within this compartment comprises a new therapeutic strategy for DCM. Specific Aim 1: Defining the role of PLN in regulating AKAP6β Ca2+ signaling and myocyte hypertrophy. Preliminary data suggest that AKAP6β-bound PLN at the ONM plays a critical role in regulating Ca2+ efflux from a nanometer-scale perinuclear Ca2+ compartment. Using live cell imaging and biochemical and cytochemical assays in primary rat ventricular myocytes and human iCMs, we will elucidate how ONM-localized PLN modulates AKAP6β-associated Ca2+ signaling. Specific Aim 2: Targeting of Perinuclear PLN in Dilated Cardiomyopathy. To test the hypothesis that dysregulation of local Ca2+ efflux from the AKAP6β compartment contributes to DCM pathogenesis, we will use adeno-associated virus (AAV) vectors to confer gain- and loss-of perinuclear PLN function in wildtype and DCM mice. Specific Aim 3: Therapeutic targeting of perinuclear Ca2+ signaling in PLN R14del Cardiomyopathy. We hypothesize that increased AKAP6β-associated Ca2+ signaling contributes to PLN R14del DCM. We will use patient-specific iCM monolayers and engineered heart tissues to study transcriptional and contractile defects associated with PLN R14del DCM and test whether altered AKAP6β signaling will be beneficial in this disease. Together, these aims will define the function of ONM PLN in controlling Ca2+ efflux from the AKAP6β perinuclear compartment. As AKAP6β signalosomes regulate gene expression promoting pathological remodeling, these studies will establish a new paradigm for treating heart failure, including PLN DCM, based upon the targeting of AKAP6β-PLN complexes.

NCI - National Cancer Institute

SUMMARY/ABSTRACT Although human genetic studies have indicated a significant hereditary predisposition to myeloproliferative neoplasms (MPNs) the underlying mechanisms driving the genetic risk remains unknown. Our large genome wide association study (GWAS) on MPNs identified several non-coding genetic risk loci associated with disease and implicated modulation of hematopoietic stem cell (HSC) self-renewal by the genetic variants. The long-term goal is to utilize our GWAS results to better understand MPN disease initiation and progression and draw out key unknown MPN predisposition genes. The overall objectives in this application are to elucidate the mechanisms by which MPN risk variants promote disease initiation and progression. The central hypothesis is that common genetic variants increase MPN risk by affecting regulatory elements that influence clonal expansion of HSCs carrying MPN driver mutations. The rationale for this project is that the HSC clones with most prevalent driver mutation found in MPN, JAK2V617F show individual specific growth rates and can develop into MPN or remain as clonal hematopoiesis without any consequences indicating that germline genetic factors influence this process. The central hypothesis will be tested by pursuing two specific aims: 1) To determine the mechanisms by which genetic variation at the GFI1B locus influences MPN predisposition in vivo. 2) To define upstream transcriptional mechanisms disrupted by common genetic variants that predispose to MPN. Under the first aim, a newly generated mouse model will be used to evaluate clonal expansion of JAK2V617F HSCs in the context of a germline Gfi1b enhancer deletion by in vivo competitive transplantation assays. The murine studies will be complemented by an assessment of Gfi1b allele specific clonal expansion in primary human hematopoietic stem and progenitor cells (HSPCs) engineered to carry JAK2V617F mutation. Mechanistically activated mitochondrial respiration will be examined in germline enhancer inactivated JAK2V617F HSPCs in murine models and human patient samples. For the second aim, perturbation of RUNX1 bound cis-regulatory elements by MPN risk variants will be evaluated as a mechanism of clonal expansion in MPN by using lentiviral reporter assays and endogenous CRISPR/Cas9 editing approaches in primary human HSPCs and degron tagged RUNX1 cell lines. A Runx1 haploinsufficiency mouse model will be used to assess global influences of RUNX1 transcriptional network on MPN initiation. Collectively, our proposed studies aim to bridge the gap between inherited genetic variations and the clonal expansion dynamics of MPN stem cells, shedding light on crucial factors influencing disease development. The mouse models proposed in this study provide the in vivo physiological context and functional readouts required to investigate HSC clonal expansion and MPN pathogenesis.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

OVERALL: PROJECT SUMMARY The Cedars-Sinai Digestive Diseases Research Center (CSDDRC) is designed to leverage the substantial and multidisciplinary research base and exceptional research facilities at Cedars-Sinai Medical Center (CSMC) to attract colleagues and junior scientists and to provide solutions to as-yet unsolved problems in digestive diseases research. The CSDDRC has 58 members and a total peer-reviewed direct cost of $26.1 million in the research base, of which $9.7 million (37.3%) is from the NIDDK. The central theme of the CSDDRC is mechanisms and measurements of the fibroinflammatory response in gastrointestinal tissues, which reflects Center members’ research in three subthemes: 1) Gut Microbiome, 2) Gastrointestinal and Liver Metabolism, and 3) Gastrointestinal and Liver Injury, each will be headed by a subtheme leader charged with defining the aspirational goals. The CSDDRC structure (three Biomedical Research Cores, a Pilot and Feasibility (P&F) Program, and an Enrichment Program) will provide an unparalleled platform for advancing the science and addressing unmet needs in digestive diseases research to improve patient outcomes. The CSDDRC Cores are: The Administrative Core (Core A) will provide administrative leadership for optimal management and operation of the Cores, P&F projects, and the Enrichment Program, by employing effective performance improvement activities via close communication with Center membership and the Internal and External Advisory Boards of the CSDDRC. The Advanced In Vitro Model Systems Core (Core B) will harness institutional expertise in induced pluripotent stem cell technology to create novel model systems for mechanistic studies and therapy development. The Gnotobiotics and Gut Microbiome Core (Core C) will bring an expanded gnotobiotic facility and advanced microbiome measurement and analysis tools to the institution. The Human Imaging and Biorepository Core (Core D) will enable collection of deeply annotated human biospecimens and quantitative feature analysis of radiologic imaging, as parameters for biologically-driven investigation of disease subtypes, and translation and validation of preclinical findings. Our P&F Program and Enrichment Program will host lectures, meetings, and symposia to facilitate new collaborative research efforts of Center investigators as they address the themes of the CSDDRC, enhance the career development of early-stage investigators and those new to digestive diseases research, and translate novel discoveries in the lab to the clinic. The large patient population at CSMC allows unique opportunities to examine how our discoveries impact clinical care. Leaders of the CSDDRC will use the tools, mechanisms, and resources of the Center to meet its aspirational goals of accelerating translational research and improving the care of patients with digestive disease and liver disorders. We envision that the CSDDRC will provide a sustainable and growing organization for advancing both careers and the science in the digestive diseases field.

NIA - National Institute on Aging

Summary Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is one of the leading causes of dementia. In addition to memory deficits, Alzheimer’s patients exhibit sleep impairments. Aberrant neuronal circuit activity contributes to the disease etiology and its progression. Anomalies in sleep-dependent brain rhythms, specifically slow oscillations important for consolidation of memories during NREM sleep, have been reported in Alzheimer’s patients. Multiple lines of evidence suggest that disruptions in slow oscillations facilitate Alzheimer’s progression and might contribute to dementia. Thus, aberrant slow wave activity is not simply symptomatic but can be targeted with therapies. Therefore, it is necessary to develop therapeutic strategies targeting restoration of circuit function, such as slow wave activity, to rescue cognitive impairments associated with sleep-dependent memory dysfunction. Stem cell-based therapies are being developed for a number of neurological disorders and could be applicable to Alzheimer’s disease. Alzheimer’s disease is characterized by circuit hyperexcitation at early prodromal stages due to deficits in inhibition, thus disrupting slow brain rhythms, including slow oscillations. Thus, restoration of inhibitory tone through transplantation of inhibitory interneuron progenitors might restore circuit function and slow Alzheimer’s progression. We show that isolation of embryonic mouse MGE-derived interneuron progenitors and their transplantation into an animal model of amyloidosis restores slow wave activity in young mice. We will test the degree to which cell therapy slows neuropathophysiology and rescues sleep as well as memory impairments. Furthermore, to increase translational impact of this work, we will transplant human iPSC-derived interneuron progenitors and determine their role on circuit function and Alzheimer’s progression in a mouse model of amyloidosis. We will implement leading-edge methodology including imaging with voltage-sensors and high-resolution multiphoton microscopy to monitor circuit function as well as optogenetics to control neuronal activity with high temporal precision. Thus, as a result of this work we will evaluate the efficacy of stem cell therapy using mouse and human progenitors for the treatment of Alzheimer’s disease in a mouse model of amyloidosis. This work will provide strong bases for translating cell therapy as a cure to slow AD progression in patients as part of a novel therapeutic approach.

NCI - National Cancer Institute

Project Summary Since 1990, the overall incidence of late onset colorectal cancer (LOCRC ≥50 yrs. old) has decreased. However, these rates have steadily increased in younger individuals (<50 yrs. old). The cellular and molecular mechanisms underlying early onset CRC (EOCRC), and its poorer survival outcomes in men are unclear. Approximately 80% of EOCRC tumors are sporadic, arising from acquired genetic mutations. Epidemiological studies have noted a higher incidence and advanced-stage cancers in males with EOCRC compared to females, with males exhibiting a larger Wnt/β-catenin signaling component, a major driver of cancer stem cell (CSC) population expansion. The enzyme asparagine synthetase (ASNS) links CSC function and sex differences to EOCRC development. Targeting ASNS-expressing ISCs could offer therapeutic potential as high tumoral asparagine (Asn) levels correlate with cancer aggressiveness in male EOCRC alone. The objective of this proposal is to investigate sex- dependent mechanisms in EOCRC progression. My central hypothesis is that ASNS drives CSC expansion and tumorigenesis in EOCRC, which is enhanced in males. I will test my hypothesis through the following Specific Aims. Aim 1 (K99 phase): Analyze untargeted metabolomics data of 372 paired CRC and normal mucosa tissues from EOCRC and LOCRC. I will perform whole exome sequencing and use machine learning to identify unique mutational signatures and metabolites associated with EOCRC. Aim 2 (K99 phase): Develop patient- derived organoids (PDOs) from EOCRC/LOCRC samples, supplement them with Asn at varying concentrations, and examine organoid number, growth, size, and crypt budding. I will assess CSC dynamics in PDOs using time- of-flight mass cytometry (CyTOF). I will delete ASNS in PDOs using CRISPR-Cas9 and test the sex-specific effects of ASNS loss on PDO growth and crypt budding. Aim 3 (R00 phase): Evaluate the effects of ASNS deletion on tumor growth and survival using a patient-derived xenograft model. Investigate tumor heterogeneity using single cell/nuclei RNA-Sequencing and spatial transcriptomics. This research will provide novel insights into the sex-dependent roles of ASNS and Asn in ISC niche expansion during EOCRC progression, improving our understanding of EOCRC development. The training will equip me with skills in machine learning, stem cell biology, and tumor heterogeneity, which will be foundational for developing pre-clinical models of EOCRC in my future independent laboratory.

NIGMS - National Institute of General Medical Sciences

Project Summary/Abstract: Tissue homeostasis requires the precise control of the development of differentiated cell types from multipotent stem and progenitor cells (SPCs). This balance is regulated by signals originating from multi-tissue niches or SPCs themselves, which affect SPC development. Increasing data supports that these normal developmental processes can be aided or disrupted by inflammatory signal transduction pathways. While prior studies using whole animal knockouts identified the role of inflammatory signaling pathways in HSPC differentiation, open questions remain about the relative contributions of specific cell types to the observed phenotypes and the downstream targets of these pathways. The proposed research program uses the Drosophila melanogaster blood system as a model to address unresolved questions about how multiple cell types found within SPC niches use inflammatory signaling pathways to control the balance between SPCs and differentiated cells during homeostatic development and after injury. As blood SPCs differentiate they make fate choices between alternate paths of development, specifically between distinct intermediate and differentiated cell types, which in turn produce signals to influence the balance between SPC maintenance and differentiation. One goal of the proposed research is to address open questions about how the inflammatory signals activated by injury are propagated through distant niches to control the balance between SPCs and differentiated cells, and how these injury-induced changes influence wound healing. Another goal is to address unresolved questions about how pro-inflammatory signaling pathways influence normal SPC development, specifically which cell types and downstream targets are involved. Tissue damage is a hallmark of many human diseases including atherosclerosis and type 2 diabetes. These inflammatory diseases are also associated with disruption of normal SPC biology in multiple organ systems and increased likelihood of developing diseases that result from SPC dysfunction. Thus, determining the molecular mechanisms required for homeostatic tissue development and understanding how differentiation and SPC biology are changed by tissue damage and inflammatory signaling will provide information that gives insight into disease-related SPC dysfunction.

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY/ABSTRACT: Sepsis results from a dysregulated host response to infection leading to life-threatening organ dysfunction. It is a complex and dynamic disease process, and a leading cause of morbidity and mortality in intensive care units (ICUs). Due to the therapeutic challenges of patients with sepsis, and the fact that management remains predominantly supportive, there is an undeniable need to develop new treatment strategies for sepsis. New advances being explored include cell-based therapies. For more than 25 years my laboratory has explored the pathobiology of sepsis, and related organ injuries, including the lung. Our approach is to investigate mechanisms of disease, starting at the cellular level in vitro and translating these findings into models of disease ex vivo and in vivo. To complement our work further in sepsis, with an interest in therapy, we became interested in stem/stromal cells. My laboratory has explored the use of mesenchymal stem/stromal cells (MSCs) for therapeutic intervention in pre-clinical models of sepsis and lung injury. We investigate mechanisms responsible for the biological activity of MSCs, including paracrine actions via their conditioned medium and the impact of MSC-derived extracellular vesicles (EVs) and their cargo (miRNAs). To advance our understanding of cellular therapy for sepsis, we recently began to explore a new source of cells – placenta-derived trophoblast stem cells (TSCs). Our laboratory was the first to isolate murine (m) TSCs, using CD117 as a cell surface marker of stem/progenitor cells. Beyond paracrine actions, these cells can engraft and differentiate into parenchymal cells. We now propose to advance our investigation of TSCs harvested from human(h) term placentas. hMSCs are immune evasive, and hTSCs are immune privileged, allowing the use of both cells for allogeneic therapy. We will investigate hMSCs and hTSCs to modify the pathobiology of sepsis and provide insight into the immune response to eradicate microbes, resolve inflammation, and decrease organ injury along with promoting repair. Sepsis and organ injury, such as acute respiratory distress syndrome (ARDS), are very heterogeneous clinical processes, thus targeting a specific biological pathway is challenging. We propose that viable therapeutic cells will sense the underlying septic environment, and respond accordingly with varied paracrine actions. Plasma and immune cells from patients with sepsis ± ARDS, compared with ICU control (non-infected) patients, will allow us to explore a personalized approach using hMSCs and hTSCs. Moreover, due to differences that exist between human and mouse lungs, we propose to evaluate the actions of hMSC and hTSCs using human lung organoids and precision-cut lung slices (PSLS) as human models of lung/alveolar injury, and transcriptomic approaches to identify pathways critical for disease modification. Thus, our vision is to advance the insight into therapies for sepsis using hMSCs and hTSC, and that using human models of disease in vitro, ex vivo, and with confirmation in a pre-clinical model of pneumosepsis will provide insight into critical sepsis pathways and advance our approach to the therapy of sepsis and ARDS.

NIAID - National Institute of Allergy and Infectious Diseases

Summary The transformative advancements in cell and gene therapy have significantly enhanced our understanding and treatment of congenital diseases and regenerative medicine. As we approach the 10th annual Center for Definitive and Curative Medicine (CDCM) symposium, scheduled for March 30-31, 2026, at Stanford University's Li Ka Shing Learning and Knowledge Center, we seek financial support to facilitate this pivotal event. This symposium will serve as a platform for scientific discourse on the latest discoveries and developments in the field, inviting participation from experts and trainees across academia, non-profits, government, and industry. The two-day event will focus on the theme “Past, Present, and Future of Cell and Gene Therapy,” addressing critical challenges in translating laboratory discoveries into clinical applications. Day 1 will feature a Clinical Trial Bootcamp, workshops on relevant topics, a poster session for early- stage investigators, and an evening networking event. Day 2 will showcase luminary speakers discussing breakthroughs in lentiviral and AAV gene therapy, CAR-T, gene editing, regenerative medicine, and hematopoietic stem cell transplantation. Specific aims of the symposium include: (1) elucidating the bench-to-bedside journey through real-world case studies presented by the Stanford CIRM-funded Alpha Clinic; (2) providing a platform for graduate students and early-career researchers to present their findings; (3) facilitating workshops that address community engagement in clinical trials, the role of Artificial Intelligence in healthcare, and career opportunities in health sciences; and (4) fostering collaboration through platform sessions that expose participants to emerging research areas. This symposium has been a cornerstone of the Cell and Gene Therapy Community for the past nine years, celebrating past achievements while catalyzing future innovations. The 2026 meeting promises to be a significant milestone, driving forward the dialogue and collaboration necessary to tackle the complexities of cell and gene therapy and improve patient outcomes.

U.S. National Science Foundation

CREST Center awards provide support to enhance the research capabilities of Minority-serving institutions (MSIs) through the establishment of centers that effectively integrate education and research. CREST Center awards promote the development of new knowledge, enhancements of the research productivity of individual faculty, and an expanded presence of students historically underrepresented in science, technology, engineering, and mathematics (STEM) disciplines. Successful CREST Center proposals will demonstrate a clear vision and integration of STEM research and education and will align with the mission of the Division of Equity for Excellence in STEM (EES) with respect to the development of a diverse STEM workforce. CREST Centers are also expected to provide leadership by meaningfully involving the efforts of those faculty, students, and postdoctoral researchers who are traditionally underrepresented in STEM at all levels. Centers are required to use evidence-based and innovative strategies to address salient broadening participation and workforce development issues, such as recruitment, retention, and mentorship of participants from underrepresented groups. Successful proposals are expected to achieve national research competitiveness, broaden participation in STEM, and generate sustained, non-CREST funding from federal, state, and/or private-sector sources. PhaseI and Phase II CREST Center Awards Preliminary proposals are required for Phase I and Phase II projects. Thus, an invitation from NSF must be received before submitting a full proposal. Both Phase I and Phase II CREST Center awards provide multi-year support for institutions that demonstrate a strong research base. Phase I CREST Center awards provide funding for five years of research on a specific NSF-supported topic. If invited, institutions may submit a Phase II CREST Center proposal requesting funding to continue research in the same disciplinary area as the Phase I Center or may submit a Phase I proposal focused on a disciplinary area that is significantly different from those of the previous award(s). CREST Partnership Supplements CREST Partnership Supplemental funding requests are invited from current CREST Center awardees. Supplements support the establishment or strengthening of partnerships and collaborations with active CREST Centers and other nationally or internationally recognized research centers (including NSF-supported research centers), private sector research laboratories, K-12 schools, and/or informal science entities, including museums and science centers, as appropriate. Such partnerships and collaborations should aid CREST Centers quest in advancing knowledge and education on a research theme of national significance.

U.S. National Science Foundation

The Centers of Research Excellence in Science and Technology (CREST) program provides support to enhance the research capabilities of minority-serving institutions (MSIs) as defined in this solicitation s Eligibility section, through effective integration of education and research. The CREST program, composed of the CREST Centers, the CREST Postdoctoral Research Program, and the projects supported by this CREST-RISE solicitation, promotes the development of new knowledge, enhancements of the research productivity of individual faculty and postdoctoral scholars, and an expanded presence of research doctoral students in science, technology, engineering, and mathematics (STEM) disciplines, especially those from underrepresented groups. CREST-RISE is the component of the CREST program that supports the expansion of institutional research capacity by increasing the strength of institutional graduate programs and the successful production of research doctoral students, especially those from groups underrepresented in STEM. The CREST-RISE component supports STEM research doctoral programs in all NSF supported areas and encourages proposals in areas of national interest, such as artificial intelligence, data science and analytics; advanced materials, manufacturing, robotics; cybersecurity; plant genetics/agricultural technologies; quantum information sciences; nanotechnology, semiconductors/microelectronics technologies; climate change and clean energy. CREST-RISE projects must have a direct connection to the long-term plans of the host department(s) and the institution s strategic plan and mission. Project plans should emphasize activities designed to increase the production of research doctoral students, especially those underrepresented in STEM as well as expand institutional research capacity. The goals of CREST-RISE are to increase: 1) the number of STEM research doctoral programs at MSIs (as defined in the Eligibility section), 2) the number of STEM research doctoral students graduating from MSIs, especially those from groups underrepresented in STEM, and 3) institutional research capacity to increase doctoral students graduation rates.To achieve these goals, the CREST-RISE program includes three tracks as follows: CREST-RISE STEM Doctoral Programs Support Initiative (CREST-RISE DPSI) CREST-RISE Research Advancement and Development (CREST-RISE RAD) CREST-RISE Equipment &amp; Instrumentation (CREST-RISE E&amp;I)

U.S. National Science Foundation

The Centers of Research Excellence in Science and Technology (CREST) program provides support to enhance the research capabilities of minority-serving institutions (MSIs) through the establishment of centers that effectively integrate education and research. CREST promotes the development of new knowledge, enhancements of the research productivity of individual faculty, and an expanded presence of students who are members of groups underrepresented in science, technology, engineering, and mathematics (STEM) disciplines. The CREST Postdoctoral Research Program (CREST-PRP) awards are part of the overarching CREST program and provide two years of support for research experience and training for early career scientists at active CREST Centers. The goal of the CREST-PRP awards isto increase the workforce presence of individuals from groups underrepresented in STEM fields. CREST-PRP awards recognize investigators with significant potential and provide them with research experiences that broaden perspectives, facilitate interdisciplinary interactions, and prepare CREST-PRP scholars for positions of leadership within the scientific community. Postdoctoral scholars conduct research on topics aligned with the research focus of the host CREST Center. The awards are also designed to provide active mentoring to the postdoctoral scholars by thescientific mentorwho, in turn, will benefit from the incorporation of these talented scientists into their research groups. Proposals must be submitted by individual postdoctoral candidates. However, if an award is recommended, the award will be transferred to the host institution where the postdoctoral scholar will be named as the PI. The award will be issued to the host institution as a regular research award, and the award will be administered by the host institution. Women, veterans, persons with disabilities, and members of groups underrepresented in STEM are especially encouraged to apply.

NIH

Background and Innovation: The proposed work is focused upon enhancing our understanding of CD34+ melanocyte stem cells (McSCs). These are cells previously described by us which localize to the bulge area of the hair follicle (HF) during its resting stage. Unlike their counterparts, CD34- McSCs which reside at the base of the resting HF and principally undergo melanocytic differentiation, CD34+ McSCs resemble a neural crest stem cell; and differentiate principally as neural crest derivatives other than melanocytes- including glia. The prospect of isolating and expanding a skin-derived stem cell type to treat demyelinating diseases and restore nerve function is enticing and may represent one of the most innovative solutions to these problems faced by Veterans. VA has an interest in treating Veterans with demyelinating diseases through its support of centers such as the Multiple Sclerosis Centers of Excellence. Rehabilitation and restoration of function following neurotrauma has consistently been a strong interest in VA healthcare. Seemingly unrelated, but nonetheless linked to the ability of melanocytes and McSCs to transition between discrete differentiation states, is the relevance of CD34+ McSCs to melanoma therapeutic resistance. The less differentiated CD34+ McSC subtype has been correlated with relative resistance to immunotherapy in murine melanoma models. Understanding the molecular and cellular basis of McSC dedifferentiation could inform strategies designed to block melanoma cell dedifferentiation as a novel strategy to maintain therapeutic responsiveness. Scientific efforts in this direction are synergistic with VA’s interest in Precision Oncology, both with the new Precision Oncology Actively-Managed Research Portfolio and with its clinical support of precision oncology programs. Significance and Impact to Veterans Healthcare: The proposed work is relevant to Veteran healthcare and disease as follows: (1) Developing stem cells easily accessible from autologous skin that have the potential to undergo glial differentiation represents a potential cellular therapy solution to diseases that affect Veterans. These include demyelinating diseases such as multiple sclerosis and recovery from neurotrauma, since stem cells with glial differentiation properties introduced into a neural injury environment facilitate recovery of nerve function. Both multiple sclerosis and recovery from neurotrauma are priorities for Veteran health care. (2) Dedifferentiation enables melanoma cells to escape as targets for immunotherapy. Understanding the mechanistic underpinnings of McSC dedifferentiation, which are likely to share a molecular basis with melanoma cells, may illuminate strategies designed to block dedifferentiation in cancer and enhance therapeutic responsiveness. Novel strategies to treat cancer are relevant to VA health priorities, given the recent emphasis on developing Precision Oncology clinical care pathways and research initiatives within the Veterans Health Administration. Path to translation/implementation: We need to refine the identification of the CD34+ McSC subtype in murine skin to maximize the opportunity to identify a similar cell in human skin. Optimizing techniques to expand CD34+ McSCs that have glial differentiation potential will be important for obtaining sufficient cells that maintain the glial differentiation phenotype to evaluate for cellular therapy. Identifying the master regulators of melanocyte dedifferentiation will be important. Those regulators, or critical effector genes of those regulators, could represent therapeutic targets to be tested in clinical trials of advanced melanoma refractory to standard therapy, as part of VA’s Precision Oncology initiative.

NCI - National Cancer Institute

PROJECT SUMMARY Acute leukemias are the most common pediatric cancers, exhibiting significant variability in treatment response and relapse rates among genomic subtypes. A major challenge in treatment is the presence of leukemic-initiating cells that are resistant to therapy. While these cells were first discovered in acute myeloid leukemia, their role in other types of acute leukemia remains poorly understood. Recent studies have uncovered a neoplastic population of hematopoietic stem and progenitor cell-like (HSPC-like) blast in high-risk subtypes of acute lymphoblastic leukemia. These HSPC-like blasts are molecularly heterogeneous and linked to treatment resistance and poor outcomes. This study aims to investigate the molecular characteristics and clinical implications of HSPC-like blasts across major high-risk leukemia subtypes, including myeloid, lymphoblastic, and mixed-lineage leukemias. Our goal is to uncover common, targetable mechanisms of treatment failure and to develop therapeutic strategies that specifically target these cells. Using single-cell multiomics and patient samples, we will identify the mutational and transcriptomic signatures and define gene regulatory networks using novel network biology algorithms. We will determine the prognostic significance of HSPC-like signatures and explore therapeutic strategies through ex vivo drug screening and in vivo validation in PDX models. Because primary human leukemic blasts are a scarce, patient-limited resource, expansion in immunodeficient mice yields the millions of cells needed for ex vivo drug testing, in vivo therapeutic studies, and mechanistic analyses.

NIDCD - National Institute on Deafness and Other Communication Disorders

Project Summary Olfactory sensory neurons (OSNs) facilitate our sense of smell but constantly need to be replaced, likely because they are in direct contact with the external environment. The olfactory epithelium (OE) houses OSNs, and maintains our ability to smell throughout adulthood through nearly life-long neurogenesis. This remarkable ability for adult neurogenesis is not limitless, however. With increasing lifespan and a hostile external environment, a near majority of people develop hyposmia or anosmia by the age of 80. This is correlated with reduced quality of life, a slew of mental disorders, and malnutrition. Pathologic examination of aged human patient tissue suggests that olfactory neurogenic stem cells exhaust with age, and previously neuronal olfactory epithelium gradually becomes a-neuronal potentially even becoming respiratory epithelium. Unfortunately, no facile preclinical model that closely mimics this human OE pathology exists, hampering research and therapeutic development. Previous models were slow and poorly penetrant. Here, we describe a new model using an engineered nitroreductase enzyme (OMP-NTR2.0) that is highly effective at accelerating OSN turnover, can strikingly mimic aged human olfactory epithelium in as little as 12 weeks time, and could be used as the first platform for testing therapeutic approaches. In this grant, we propose to (Aim 1) extensively characterize this new model of accelerated aging in the OE, stage and compare it to human biopsy and donor tissue, (Aim 2) test the hypothesis that respiratory metaplasia results from conversion of exhausted olfactory epithelium as well as invasion from the surrounding respiratory epithelium, and finally, (Aim 3) test targeted therapies developed on our knowledge of olfactory epithelial stem cell dynamics. The objective of this proposal is to establish the OMP-NTR2.0 model as the viable preclinical model of age-associated olfactory dysfunction and use it to test first-generation therapeutic approaches. Our approach is innovative because it leverages a novel mouse model that we generated de novo that incorporates an engineered enzyme, which effectively accelerates aging of the olfactory epithelium and creates a platform for drug testing. Our long-term goal of our research is to develop prophylactic or curative treatments for age-associated anosmia.

NIAID - National Institute of Allergy and Infectious Diseases

New treatments are desperately needed to control the ongoing tuberculosis (TB) pandemic. Newly emergent antibiotic-resistant strains of Mycobacterium tuberculosis (Mtb), the causative agent of TB, are hampering control efforts. Mtb is an unusual pathogen with the remarkable ability to cause both acute life-threatening disease and symptomless latent infections that can last a lifetime. It is estimated that 25% of the world has latent tuberculosis, and in 2023 alone, there were more than 8.2 million TB cases and 1.3 million deaths, making Mtb the leading cause of infectious disease world- wide. Mtb is such a successful pathogen partly due to its extraordinary metabolism; part of its virulence stems from the metabolic flexibility to utilize and scavenge a range of nutrients derived from its human host. A fundamental and currently unanswered question regards how the bacterium regulates its metabolism to cause infection. Answering this question is of therapeutic significance as targeted dysregulation would both starve the bacteria and prevent it from successfully colonizing the human host, effectively killing the bacteria and stalling pathogenesis. We have discovered a novel regulatory system that Mtb requires to consume essential energy sources for its survival in the host and to cause disease. Our hypothesis is that Virulence Associated Dikinase (VadK) coordinates metabolism and virulence by interacting with partner proteins. Importantly, VadK also represents a novel drug target. We will test this hypothesis using a combination of biochemistry, structural biology and microbiology. We will investigate how VadK physically and functionally interacts with its partner proteins to gain insights into how this novel histidine kinase system functions, while also unraveling the mechanism of action of VadK.

NIGMS - National Institute of General Medical Sciences

Glycosylation is a ubiquitous post-translational modification in mammalian systems that fine tune or fully control every aspect of cellular function. This process involves the biosynthesis of glycans by the concerted action of ~400 genes that are called ‘glycogenes’. Because of the importance of glycosylation in normal physiology and pathophysiology, understanding how glycans are regulated is of the utmost biomedical importance. The factors that regulate glycan biosynthesis in mammals remain incompletely known because systems-level characterization of glycosylation regulatory network is absent. This project brings together synergistic expertise in systems biology and bioinformatics (Gunawan), glycobiology and biomolecular engineering (Neelamegham), and machine and deep learning (Chen), to address this knowledge gap. We hypothesize that single-cell profiling coupled with mechanistic and deep learning-based modeling and analysis can reveal the key regulators and regulatory networks of glycosylation. The specific aims are: 1) Generate single-cell epigenomics, transcriptomics, and glycomics profiles in hematopoietic stem cell (HSC) differentiation. We choose blood cell system due to their broad biological importance and ease of access. This aim produces single-cell multi-omics data related to glycosylation that will be computationally analyzed in subsequent aims using mathematical and deep learning (DL) modeling. 2) Curate transcriptional regulators and reconstruct gene regulatory networks of glycosylation using data mining and integrative bioinformatics analysis of single-cell data. This aim focuses on transcriptional regulation of glycogenes. We will catalog transcriptional regulators (TRs) and reconstruct and experimentally validate gene regulatory networks of glycosylation in HSCs using single-cell epigenomics and transcriptomics data. 3) Bridge the expression of glycogenes and glycans using flux analysis and deep learning to elucidate regulatory factors of glycosylation. This aim employs first-principle and deep learning models of glycosylation reaction networks to learn the complex, non-linear mapping from glycogene expression to glycoenzyme activity to glycosylation fluxes and glycan abundances. A novel DL model using a combination of Representation Learning and Graph Attention Network will be developed. Systems analysis of the model using Metabolic Control Analysis will provide network-level insights on the regulators of glycosylation. Model-derived glycosylation regulators will be experimentally validated in HSCs, the data from which will be used to fine-tune the model. Overall, this project will generate systems-oriented methods for the Glycosciences that will enable linking cellular epigenetics, transcriptomics, glycoenzyme activity, glycosylation network, and glycan structures. By iterating modeling, systems analysis, and experiments, we will generate insights into gene-level and network-level regulation of glycosylation. Given the importance of glycosylation in human biology, such insights will have broad impact on basic science and disease studies, and in the development of related protein therapeutics.

NIMH - National Institute of Mental Health

Project Summary Autism spectrum disorder (ASD) is a neurodevelopmental disorder long associated with functional connectivity abnormalities that are widespread throughout the brain. Despite countless studies on the topic, no single unifying model of functional connectivity abnormalities in ASD has emerged to date. Enthusiasm for studying functional connectivity differences in ASD has subsided in light of evidence of alterations that are more heterogeneous than some of the earlier hypotheses suggested, and because the links of these alterations to neural mechanisms of ASD have been challenging to map. Yet, one related theme that has garnered support has been that functional connectivity in ASD is increased in the bottom-up (or "feedforward") direction and decreased in the top-down (or "feedback) direction. Here, we propose to test a hypothesis that the functional characteristics of ASD are rooted in a fundamental imbalance between feedforward and feedback influences. This hypothesis stems from our preliminary data and prior studies, and it is motivated by many aspects of the ASD phenotype: These include increased perceived salience of sensory stimuli and evidence of reduced top-down control in ASD, which manifest across a range of atypical behaviors characteristic of the disorder. Thus far, mapping feedforward and feedback inputs non-invasively in the human brain has been methodologically challenging. Here we propose a multimodal neuroimaging approach, which combines (a) effective connectivity measures using millisecond temporal resolution magnetoencephalography (MEG) with (b) highly novel submillimeter-resolution layer- specific 7T functional MRI. We will use these advanced techniques to characterize feedforward and feedback flow of information along the auditory cortical hierarchy, in 90 ASD and 60 neurotypical (NT) adults, ages 21- 35, with average or above average IQ. Using our multimodal research design, which is firmly rooted in laminar neurophysiological recordings in non- human primates, we will pursue the following Specific Aims: (1) Test the hypothesis that feedforward inputs are abnormally increased in ASD relative to NT individuals; (2) Test the hypothesis that feedback inputs are abnormally decreased in ASD relative to NT individuals; (3) Test the hypothesis that the extent to which feedforward and feedback inputs in the ASD group are indeed different, is predictive of ASD severity and the extent of auditory processing deficits, assessed behaviorally. We expect that the results of this study will lead to a substantially more detailed, comprehensive, and mechanistically motivated framework for the wide range of functional connectivity abnormalities observed in ASD.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

Abstract Mature cell types must be properly differentiated and distributed in tissues during development in all organisms, including humans. Some examples of cells that are broadly distributed include mucus cells (also called goblet cells) and ionocytes, which populate many human mucosal tissues, including the lung. Mucus cells produce mucus to lubricate and protect the epithelial surface; ionocytes regulate the ion balance on either side of the epithelial barrier. Dysregulation of either of these cell types causes severe human disease in many organ systems. Analogous cell types are also found in embryonic zebrafish skin, a highly tractable model system in which live imaging can be easily used to study development. This proposal will characterize the development of recently discovered intraepithelial migratory cells in embryonic zebrafish skin that are precursors to mucus cells and ionocytes, dissecting their mechanism of migration as well as the gene expression patterns responsible for their differentiation. The Sagasti lab has found that these cells derive from stem-like tp63+ basal cells in zebrafish skin during the first day of development, migrate between the basal and periderm layers of skin throughout the body for several hours, and eventually halt and intercalate into the periderm, where they become differentiated mucus cells or ionocytes. We propose that this process functions to spatially distribute mature ionocytes and mucus cells throughout the skin and may be conserved in human mucosal tissues. In this proposal, I will use live imaging and antibody staining to determine whether these migratory cells exhibit mechanisms of amoeboid or mesenchymal migration, as well as pharmacologic and genetic inhibitions to functionally characterize these pathways. Additionally, I will use single-cell RNA sequencing and pseudotime analysis to describe the process by which these cells differentiate into mature cell types and generate candidate genes that are involved in migration. Finally, I will use a CRISPR screen to find genes that are required for migratory cell motility and distribution, and create knockout lines for future study. Taken together, this project will investigate a method of simultaneous cell migration and differentiation within a developing epithelial tissue, resulting in the proper distribution of mature cells. My training goal is to be an independent investigator in the field of skin developmental biology. The proposed fellowship training is an important step towards this career. The research proposed here will give me an excellent background in zebrafish research and epithelial development, training me in impactful techniques, including live imaging, genetic manipulation, and bioinformatics. Further, my training plan includes the IRACDA program at UCLA, which will train me in teaching pedagogy and provide experience designing and delivering lectures at CSULA under the mentorship of experienced professors. This experience will prepare me for the multifaceted career of a principal investigator by gaining experience with zebrafish epithelial research, teaching, and mentorship.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY Tuft cells are rare chemosensory cells, which reside in the epithelial lining of the small intestine (SI) where they serve as key intestinal sentinels by detecting luminal cues and triggering type II immune responses to infections. Specifically, tuft cells signal to and activate type 2 innate lymphoid cells (ILC2s) to mount an immune response and enhance tuft cell production from undifferentiated epithelial cells through a feed forward mechanism. Recent work has demonstrated that fully differentiated tuft cells can dedifferentiation and regenerate all intestinal lineages under damage conditions, highlighting a new facet of epithelial regeneration; however, the molecular signals that balance tuft cell specification and epithelial plasticity remain incompletely understood. Previous work from the Roose lab has identified the Ras Guanine Nucleotide Exchange Factor, RasGRP1, as a suppressor of proliferative EGFR/Ras signals in colorectal cancer. My foundational studies, using a novel multi-antibody spectral flow panel capable, show that mice deficient for Rasgrp1 (Rasgrp1-/-) have significantly fewer tuft cells and clear helminth infections less efficiently than wild-type controls. Single-cell RNA sequencing of sorted tuft cells reveals a reduction in immature tuft cell populations in Rasgrp1-/- mice, which also show increased proliferative activity compared to wild-type controls. Strikingly, I recently discovered that intestinal stem cell (ISC) ablation in Rasgrp1-/- mice results in lethality, suggesting that RasGRP1 is required for the dedifferentiation process that normally restores the ISC pool after injury. These findings support my central hypothesis that RasGRP1 coordinates both forward differentiation and dedifferentiation programs in response to environmental cues. In Aim 1, I will test whether RasGRP1 promotes commitment to the tuft cell lineage by combining transgenic overexpression models, multiplexed spectral flow cytometry, and organoid-based pharmacological assays to mechanistically dissect how RasGRP1 modulates progenitor proliferation and tuft cell generation during homeostasis and infection. I will also determine whether RasGRP1-driven tuft cell hyperplasia spontaneously activates the tuft–ILC2 circuit and alters local immune composition. In Aim 2, I will define whether RasGRP1 enables progenitor-to-ISC dedifferentiation during epithelial injury. I will map RasGRP1 expression patterns in homeostasis and post-injury, use ISC ablation and conditional knockout models to test whether RasGRP1 loss impairs ISC recovery. I will apply innovative real-time lineage tracing and live imaging of organoids to directly visualize RasGRP1+ cells regenerating ISCs. Together, these integrated approaches will reveal how RasGRP1 governs epithelial plasticity and the balance between differentiation and regeneration. Insights gained from this proposal will have broad implications for understanding intestinal homeostasis, type II immunity, and epithelial repair. Furthermore, I anticipate these findings to have implications for future therapeutic strategies to modulate tuft cell proportions in diseases characterized by disrupted epithelial homeostasis or impaired immune responses, such as chronic infections, inflammatory disorders, obesity, or cancer.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary: Annually, millions of patients are diagnosed with autoimmune disorders. The majority of these are treated with global immune suppressants. These drugs often tip the balance from autoimmunity to immune suppression, triggering undesirable, systemic side effects. Previously, it had been established in literature that Exportin-1 (XPO1) is a novel target for the inhibition of T cell activation. XPO1 is canonically recognized as a nuclear cargo export protein where it shuttles cargo from the nucleus into the cytoplasm. Recently, it has been reported that XPO1 also plays a critical role as a chromatin factor. XPO1’s chromatin function can be inhibited with novel molecules coined “Selective Inhibitors of Transcriptional Activation” (SITAs). Mechanistically, it has been determined that these SITAs covalently bind to the C528 position of XPO1 in the same binding pocket as known nuclear export inhibitors called “Selective Inhibitors of Nuclear Export” (SINEs), as exemplified by the FDA approved inhibitor, Selinexor. While SITAs and SINEs covalently engage the same pocket, it is mechanistically unclear how and why these reported SITAs have the disparate phenotypic effect of inhibiting T cell activation compared to established SINEs which inhibit nuclear export. This proposal seeks to test the central hypothesis that the SITAs’ phenotypic deviation from SINEs stems from the rapid reversion of the covalent bond formed by SITAs in the C528 pocket.

NCI - National Cancer Institute

PROJECT SUMMARY/ABSTRACT Prostate cancer arises as an androgen driven disease, and androgen receptor (AR)-targeted therapies are the mainstay of treatment for men with advanced disease. One mechanism of resistance is ahistologic transformation from an AR-driven prostate adenocarcinoma to an AR-independent small cell neuroendocrine carcinoma, often referred to as neuroendocrine prostate cancer (NEPC). NEPC is clinically aggressive, frequently metastasizes to visceral organs, and carries a poor prognosis. A thorough molecular understanding of NEPC progression is needed for the development of strategies to treat, prevent, or reverse the development of this lethal disease. Although NEPC tumors arise clonally from prostate adenocarcinoma, there is significant epigenetic and transcriptomic dysregulation that occurs during the lineage plasticity process. Mechanistically, we still do not know how these alterations arise and how best to leverage these alterations as a therapeutic opportunity. Based on published reports and on our preliminary data, E2F1 is over-expressed in the majority of NEPC cases and in a subset of CRPC cases and is associated with a poorer prognosis compared to CRPC with low to no E2F1 expression. However, little is known about the role of E2F1 in the progression from CRPC to NEPC. Our preliminary and published data from patient tumors and in vivo, in vitro and ex vivo models (patient- derived organoids) suggest that E2F1 drives a reprogramming of chromatin accessibility which in turn, results in a NEPC-associated change in gene expression and that this is potentially mediated through a physically interaction with specific NEPC-associated co-factors and transcription factors. Our long-term goal is to develop new biomarker-driven therapeutic strategies for treating patients with advanced prostate cancer and untreatable NEPC. The objective here is to identify the key molecular events and mechanisms underlying lineage plasticity in prostate cancer. This would allow for early therapeutic intervention and improve patient outcome. Our over- arching hypothesis, which is based on our published and preliminary data, is that specific molecular alterations (e.g. RB1 loss and E2F1 induction) in prostate cancer cells drive the progression of CRPC tumors towards NEPC resulting in changes to chromatin accessibility and interactions with specific pro-stem cell- and neural lineage- associated transcription factors to drive a NEPC-associated change in gene expression. To address this hypothesis, we will define essential E2F1-transcriptional complex proteins that mediate the gene expression program driving and maintaining NEPC-progression (Aim 1) and determine if E2F1 is essential in mediating the gene expression program associated with the transition from CRPC towards NEPC (Aim 2). Successful completion of these Aims will provide unique insights into NEPC development, identify potential targetable mediators of lineage plasticity, and a timely and unique opportunity for the early detection of patients with E2F1- expressing CRPC that are evolving towards NEPC that may not respond to standard-of-care anti-AR therapy.

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