Yale University

NIH Research Projects · FY 2026 · 2023-07

Project summary/abstract The prevalence of type 2 diabetes mellitus continues to rise worldwide and despite different treatment options, many patients fail to achieve glycemic target, which leads to increased morbidity and mortality. Chronic exposure to hyperglycemia has been shown in both animal and human studies to decrease glucose transport into the brain, presumably through down-regulation of GLUT1 at the blood brain barrier, which has been postulated to be a protective adaptation of the central nervous system against the harmful consequences of hyperglycemia. However, GLUT1 down regulation may lead to reduced brain glucose metabolism leading to neuronal damage, neurodegeneration and cognitive decline. Whether these changes in cerebral glucose transport seen in patients with poorly controlled diabetes can be reversed is unknown. The main goal of this study is to determine whether improvement of glucose control in poorly controlled T2DM patient will restore brain glucose transport kinetics and rigorously assess which factors (i.e. duration DM and glycemic control) contribute to the observed improvements by using classic metabolic studies as well as state-of-the-art brain nuclear magnetic resonance spectroscopy (MRS) techniques. The findings obtained from this study will help elucidate if intensive diabetes therapy may be associated with reduced brain dysfunction from hyperglycemia.

NIH Research Projects · FY 2026 · 2023-07

PROJECT SUMMARY Fluid shear stress-dependent vessel remodeling is an essential regulatory mechanism in embryonic development and in adult vascular homeostasis where it optimizes blood flow to target tissues. Conversely, un- or mis-regulated remodeling results in vascular malformations, while poor remodeling is a key aspect of blood flow restriction in coronary and periphery artery disease. Our preliminary data reveal the existence of a regulatory network with two mutually inhibitory states, one associated with vessel stability and one with physiological outward remodeling or pathological AVM formation. These results allow us to propose a unifying hypothesis that links physiological and pathological remodeling, and suggest the existence of control points that can be manipulated to either increase or decrease vascular lumen diameter. The project aims to elucidate these regulatory mechanisms and then harness these new insights to investigate their relevance to vascular development, to identify therapeutic targets for HHT patients who suffer from excessive pathological remodeling, and identify therapeutic targets for coronary and peripheral artery disease patients where physiological remodeling is impaired. We will define the molecular basis of this novel EC shear stress mechanism, determine its biological role and develop and test therapeutic applications based on this knowledge.

NIH Research Projects · FY 2026 · 2023-07

Project Summary Neurons communicate with each other by the quantal release of neurotransmitters stored in synaptic vesicles (SVs), and the strength and efficacy of neurotransmitter release are dynamically altered during physiological activity. This process is essential for learning and memory and is disrupted in many neurological disorders. The neurotransmitter release occurs from a pool of SVs docked at the presynaptic active zone and is tightly controlled by activity-dependent changes in the presynaptic calcium ions concentration ([Ca2+]). At nerve terminals, Ca2+- sensing proteins (Synaptotagmins) couple vesicular release machinery (SNAREs) to Ca2+ signals, thus orchestrating neuronal communication. Despite years of research, there remains a substantial gap between a qualitative description of how the vesicle fusion machinery operates and the millisecond-precision and Ca2+- dependent kinetics of neurotransmitter release observed at the neuronal synapses. In this proposal, we describe the first systematic and comprehensive effort to reconcile the `molecular biochemistry' of vesicle fusion with the `physiology' of Ca2+-evoked neurotransmitter release in the neuronal synapses using a combination of complementary in vitro and in vivo experimental systems. Specifically, we aim to resolve whether Synaptotagmin isoforms with distinct biochemical properties (Syt1 and Syt7), along with the synaptic SNAREs represent the minimal protein machinery for different modes of neurotransmitter release and short-term plasticity. We also propose to quantitatively test the hypothesis that the `dual-binding' of Syt1 and Syt7 to SNAREs allows for synergistic regulation of vesicular release kinetics. For in vitro analysis, we will deploy a biochemically-defined, high-throughput fusion system capable of tracking individual vesicle docking and Ca2+ triggered fusion on a millisecond timescale, which is integrated with fast Ca2+-uncaging protocols to generate [Ca2+] transients mimicking presynaptic calcium dynamics. This will be complemented by physiological analysis in cultured neurons utilizing fast, fluorescent glutamate sensor (iGluSnFR) and Ca2+ dyes to image quantal glutamate release and presynaptic Ca2+ dynamics in individual presynaptic boutons with 2-4 millisecond temporal resolution. We anticipate that this project will provide important insights into the molecular mechanisms underlying neurotransmitter release and build toward a detailed mechanistic model of Ca2+-evoked synaptic vesicle fusion. Overall, this will greatly enhance our understanding of neurotransmission and of how it is tuned across different nerve cells allowing specific yet diverse communication in neuronal networks.

NIH Research Projects · FY 2025 · 2023-07

HIV transmission continues in low- and middle-income countries (LMIC), especially among key affected populations (KAP) and in settings of high stigma and discrimination. In Malaysia, a LMIC in SE Asia, HIV incidence and mortality is increasing. HIV is concentrated among KAPs, especially people who inject drugs (PWID), a group that has substantially lower ART prescription and viral suppression (VS) levels relative to other KAPs, undermining HIV treatment as prevention (TasP) goals. PWID are especially vulnerable to overlapping and intersectional stigmas due to criminalization drug use and sex work, experiences with incarceration, social class and the presence of HIV itself. Our preliminary studies confirm high levels of negative stereotypes, prejudice and stigma toward PWID among medical students and HIV experts, with clear evidence of intention to discriminate against PWID by withholding ART prescription. Stigma-reducing interventions have mostly centered on educational and contact-based strategies. Such strategies, however, appear less effective where stereotypes and stigma are deeply entrenched, as in Malaysia, thus requiring the introduction and testing of alternative strategies. Behavioral design interventions are potentially effective ways to address stigma in such settings. Behavioral design interventions use tools like framing, nudges, and choice architecture, which can be used to re-design how physicians behave – or make non-discriminatory healthcare decisions. Rapid start antiretroviral (RS-ART) is an evidence-based strategy to initiate ART immediately, thereby supporting TasP goals by reducing time to VS, achieving VS and improving individual health. It has not been tested among PWID. It fits the criteria for behavioral design interventions by re-arranging clinician decision-making by first focusing on eligibility criteria (i.e., presence of opportunistic infections) rather than inaccurate perceptions of ART adherence or deservedness. Behavioral design interventions have not been tested in HIV stigma research, nor has they been assessed longitudinally or infusing clinically relevant dyads analyses of patients and clinicians. To guide the behavioral design of RS-ART among PWID, we will use the Delphi method to develop guidelines. Then we will use nominal group technique, a rank-ordering mixed method strategy to assess the multi-level barriers and facilitators to RS-ART for PWID, in order to adapt existing RS-ART protocols for PWID. Once the new guideline concordant RS-ART protocol is developed, we will pilot test it in 125 PWID over six months and conduct a longitudinal dyadic analysis of patients and clinicians of stigma, physician trust and social support. The RS-ART protocol will be refined further during pilot-testing to determine its utility as a stigma-reducing intervention that can be tested in a future implementation trial. This proposal brings over 17 years of productive collaboration between Yale and University of Malaya, with expertise in clinical HIV and addiction treatment, participation in clinical guidelines development, mixed methods research, intervention development and refinement, multi-level stigma assessment and intervention and dyadic analyses.

NIH Research Projects · FY 2026 · 2023-07

Socio-structural and environmental stressors such as persistent poverty are well-documented predictors of poor mental health among American adults. Social connectedness is directly associated with improved mental health and buffers the negative impact of several health risk factors, such as social isolation. Yet, research on social connectedness and mental health among many groups of adults from low-income groups remains limited. This paucity of work reflects a critical gap in knowledge regarding a psychosocial protective factor that may be salient to reducing poor mental health outcomes among adults. To address this gap, we will use quantitative data from adults in Milwaukee, WI, who participated in the Midlife in the United States (MIDUS) study (n=1489 combined across waves) and collect qualitative data from adults to contextualize the quantitative findings and develop potential intervention strategies. Specifically, we will develop and assess the measurement properties of a multidimensional social connectedness indicator constructed from existing items assessed in MIDUS (e.g., social integration, religious/church-based social support, and social cohesion) (AIM 1a). Then we will test the associations between neighborhood- and individual-level social connectedness with three mental health outcomes (e.g., Kessler-6 psychological distress, MASQ general distress-depressive symptoms, and DSM-III-R major depression) (AIM 1b). To better understand how social connectedness influences mental health, we will estimate the degree to which social isolation and loneliness mediate the association between social connectedness and mental health (AIM 2). Lastly, in partnership with community stakeholders, we will conduct focus groups to contextualize the quantitative findings and use the first two steps of 6SQuID model to develop potential intervention strategies and targets to address persistent mental health challenges among midlife adults (AIM 3). Impact: Investigating the mechanisms undergirding the associations between multidimensional social connectedness and mental health is an important step toward advancing the overall health of Americans. These study findings will provide strong evidence to inform community-based interventions to modify and leverage social connectedness as part of a larger strategy to improve health among Americans and catapult interventions to build and strengthen social connectedness in America.

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY Immune checkpoint inhibitors (ICIs) targeting the PD-1 pathway have transformed the management of many advanced cancers, including renal cell carcinoma (RCC), but most patients do not receive durable benefit from these treatments. Whereas many efforts to understand ICI response and resistance in other tumor types have often focused on investigating the role of total mutation burden (and consequent neoantigen load) or total T cell infiltration in the tumor microenvironment (i.e. “hot” vs. “cold” tumors), RCC is biologically distinct from other immunogenic solid tumors. In contrast to other solid tumors, the total mutation burden does not correlate with response to ICI in RCC. Further, despite its relatively modest tumor mutational load, RCC stands out as one of the most highly CD8+ T cell-infiltrated solid tumors at baseline, but the degree of CD8+ T cell infiltration into the tumor-immune microenvironment (TME) does not associate with ICI response. These observations highlight the gaps in our knowledge of the somatic alterations and infiltrating immune cell composition, phenotypic states, and cellular interactions that mediate an effective immune response against RCC in the context of ICI. Thus, there is a critical need to better understand the disease-specific mechanisms of response and resistance to current ICI- based therapies in RCC, which may also uncover the general principles of how a modest mutation burden tumor like RCC can be immunogenic. Prior smaller-scale analyses in RCC identified tumor-intrinsic somatic alterations that impact ICI response in RCC, and co-occurring and interacting immune populations (terminally exhausted CD8+ T cells and immunosuppressive macrophages) that are enriched in advanced disease. We therefore hypothesize that somatic alterations and the TME interact to explain the unique immune landscape of RCC and modulate response to ICI. By leveraging our expertise in immunogenomic analysis and our close collaborations with academic and industry partners, we are now uniquely poised to address this hypothesis. In Aim 1, we seek to systematically define the recurrent somatic alterations that impact immune infiltration and therapeutic response through the interrogation of large-scale genomic data (whole exome sequencing and bulk RNA- sequencing) from over 2,800 RCC tumors (including over 1,500 RCC tumors treated with ICI). In Aim 2, we strive to uncover the cell composition and cellular interactions within the TME that mediate response to ICI through large-scale single-cell transcriptomic analysis of 96 pre-treatment RCC tumor specimens (including 75 tumors subsequently treated with ICI). We aim to validate inferred interactions using advanced spatial phenotyping methods and through functional interrogation using an ex vivo patient-derived tumor fragment model. Overall, this work will identify genetic and immune determinants of effective ICI-mediated anti-tumor immunity in RCC, and will nominate specific therapeutically targetable immune inhibitory interactions in the TME for clinical translation for patients with RCC (and potentially other low and intermediate mutation burden tumors).

NIH Research Projects · FY 2025 · 2023-07

CSF1 is the principal colony stimulating activity released by osteoblasts in response to PTH treatment. Its receptor, c-fms, is more highly expressed on mature osteoclasts than any other cell in bone. We found that deleting c-fms in osteoclasts attenuates the anabolic response to PTH. This indicates that part of PTH's anabolic actions could be via a paracrine loop in which PTH stimulates expression of CSF1 in osteoblasts, which then acts on osteoclasts to induce anabolic clastokines that augment bone formation. There are two major isoforms of CSF1: soluble (sCSF1) and membrane-associated (mCSF1). We found that the anabolic response to PTH is augmented in animals only expressing the sCSF1 isoform due to a greater increase in osteoblast number in these mice compared to PTH-treated controls. In striking contrast, animals only expressing mCSF1 had no increase in bone mass in response to an anabolic PTH regimen. Importantly, sCSF1 and mCSF1 differ in the kinetics and extent to which they activate the CSF1 receptor, c-fms, suggesting that their divergent in vivo actions may be due in part, to intrinsic differences in cell-signaling. Based on these data, we hypothesize that mCSF1 inhibits PTH anabolism by opposing the actions of sCSF1 on osteoclasts. When unopposed, sCSF1 contributes to PTH anabolism by inducing production of anabolic clastokines. Specifically, single daily doses of PTH induce transient increases in sCSF1 in osteoblasts that cause bursts of anabolic clastokine production. Consistent with this, we found that sCSF1 stimulates production of the anabolic clastokine, sphingosine-1-phosphate (S-1-P) in osteoclasts. To test these hypotheses, we will, in SA1, determine if adding intermittent dosing of sCSF1 to an anabolic PTH treatment regimen augments the skeletal response to PTH in wild type animals, while adding mCSF1 to that regimen attenuates the response. We will then try to restore the anabolic response to PTH in the sCSF1-/- mice by treating with PTH plus sCSF1. These experiments will provide pharmacologic evidence that the very different response to PTH in sCSF1-/- and mCSF1-/- mice is directly due to differing actions of the two CSF1 isoforms in bone. In SA 2, we will treat wild type mice that were ovariectomized 5 months earlier, with PTH plus sCSF1 to determine if it restores bone mass to pre-OVX levels as a model of therapy for established post-menopausal osteoporosis. In SA 3, we will determine if sCSF1 and mCSF1 induce production of different clastokine profiles in mature osteoclasts. We will use osteoblast/osteoclast cocultures as a model of in vivo paracrine signaling in bone and profile the transcriptome of osteoclasts exposed to PTH-treated osteoblasts expressing only sCSF1 or only mCSF1 to identify differences in the types of clastokines produced. We will also determine differences in the transcriptomes of osteoblasts in the cocultures stimulated by these different clastokine profiles. Finally, we will examine binding kinetics of sCSF1 and mCSF1 to c-fms, and differences in downstream signaling, to gain molecular insight into the divergent in vivo and in vitro actions of these two isoforms.

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY/ABSTRACT Despite significant advances in cancer care, pancreatic ductal adenocarcinoma (PDAC) remains the third leading cause of cancer death in the United States with a 5-year survival rate of ~10%. Obesity and high fat diet (HFD) consumption increase PDAC risk in human cohorts and accelerate PDAC progression in mice, but the mechanistic basis for these relationships is not well understood. Given the rapid rise in both the worldwide prevalence of obesity and consumption of dietary fat, deciphering mechanisms of obesity-driven PDAC could broadly impact human health. The translational relevance of prior diet research, however, has been limited by uncontrolled variations in fat source and intake across human populations and mouse experiments. Therefore, whether and how specific dietary fats promote pancreatic tumorigenesis remain critical unanswered questions of great societal importance. Leveraging a unique isocaloric panel of HFDs differing only in fat source, we identified a correlation between consumption of diets high in oleic acid – a monounsaturated fatty acid typically associated with good health – and enhanced tumor development in a genetic model of PDAC that faithfully mimics the genetic and histologic progression of the human disease. We further observed that tumorigenesis correlated with increased incorporation of oleic acid into specific phospholipids in tissues, including the pancreas. In this proposal, we aim to test the hypothesis that excess dietary oleic acid directly incorporates into cellular lipids in the pancreas to drive PDAC development. The studies in Aim 1 utilize sophisticated genetic, pharmacologic, and dietary approaches to modulate systemic oleic acid levels and establish whether excess oleic acid is necessary and sufficient to promote pancreatic tumorigenesis. The proposed work in Aim 2 uses lipidomic analyses to clarify the relationship between dietary fatty acids and pancreatic lipid composition during PDAC progression and tests whether specific resultant unsaturated lysophospholipids drive tumorigenesis. Finally, the experiments in Aim 3 combine metabolic and radioactive isotope tracer analyses with conditional knockout models to decipher the mechanisms by which dietary oleic acid is directly taken up by the pancreas and whether inhibition of fatty acid uptake pathways in pancreatic cells blocks the pro-tumorigenic effects of oleic acid. Together, these studies will link fatty acid consumption to specific changes in pancreatic lipid composition as driving forces in PDAC progression. Results from this work have transformative potential to identify novel targeted dietary and pharmacologic strategies for the prevention of a largely incurable cancer.

NIH Research Projects · FY 2025 · 2023-07

Despite successes in diagnosing and initiating antiretroviral therapy (ART) in people with HIV (PWH) in Peru, a LMIC with an HIV epidemic concentrated in key at-risk populations, the implementation gap is highest for retention in care (RIC), resulting in low levels of viral suppression (43%) and increasing HIV incidence. HIV care in Peru is currently concentrated in large secondary health centers (SHCs). Based on WHO recommendations to decentralize healthcare, an evidence-based practice that increases RIC, the Peruvian Ministry of Health recommended in 2019 to decentralize HIV services to primary health centers (PHCs). We propose to work in the 4 largest regions in urban Lima that manages 37% of all PWH in care. Currently, <15% of PWH in Lima receive care in PHCs, supporting the need for more effective implementation of decentralized services. Using the RE- AIM implementation framework, we propose to accelerate decentralization by combining NIATx, an evidence- informed implementation strategy with a bundle of implementation tools to scale up evidence-based practices, with Project ECHO, an evidence-informed tele-educational strategy to increase clinical skills in primary care providers to competently provide specialty (i.e., HIV) services. We will first use the Delphi method to establish guidelines to safely decentralize PWH using a hub (SHC) and spoke (PHC) model and to establish the minimal number of quality health indicators that are needed to safely keep patients in PHCs. These guidelines can be used to create clinical checklists that can be used to support guideline concordance in clinical practice. We will then conduct a rapid, multi-level (patients, clinicians, healthcare system) assessment of barriers and facilitators to decentralizing HIV care, which will be assessed just before each of the four hub and spoke regions will be randomized to 24 months of implementation using NIATx and ECHO in a stepped wedge design. The primary effectiveness outcome will be proportionate change of PWH receiving HIV care in PHCs. Secondary outcomes include RIC and VS with exploratory analyses for mortality. The primary implementation outcomes are confidence in managing PWH at PHCs. Collaboration, workplace climate and adoption of HIV care at new PHC sites will be measured within each hub and spoke. Adoption of HIV care at new PHCs in each region will be assessed. Importance is high due to the MoH’s goal to decentralize HIV care in an urban, low/middle income setting where HIV is concentrated in key populations with low levels of RIC and VS levels. Innovation is high due to combining NIATx and ECHO in an urban South American context and using them beyond addiction treatment. Feasibility is high due to the longstanding relationships between team members alongside the strong commitment by the Ministry of Health. The team brings expertise in HIV care (Sanchez, Altice), Public Health (Konda, Altice), implementation science (Altice, Madden, Konda) and service integration (Altice, Madden). Public Health benefit is high not only in terms of systems-, clinician- and patient-level benefits through implementing decentralized care in Peru, but also serves as a template for other urban, low/middle income settings.

NIH Research Projects · FY 2025 · 2023-07

Project Summary Treatment resistant depression (TRD) is a major cause of distress and disability. The discovery of the antidepressant effects of ketamine, an N -Methyl- D -aspartate glutamate receptor (NMDAR) antagonist, has brought new hope to TRD patients. The search for the biological bases underlying the antidepressant effects of ketamine is a key priority. Preclinical studies suggest that, in the subcallosal cortex (SCC), ketamine activates cortical circuits, increasing glutamate release, stimulating α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid glutamate receptors (AMPAR), and engaging downstream neuroplasticity mechanisms. In animal models of depression, AMPAR blockade prevents the antidepressant effects of ketamine. However, it is unclear whether this applies to humans with TRD. With the availability of the first FDA-approved AMPAR antagonist, perampanel, we can now test this hypothesis. Aim 1 evaluates whether perampanel pretreatment prevents the reduction in depression symptoms produced by ketamine in TRD patients. Aim 2 tests whether perampanel pretreatment augments ketamine-related increases in SCC resting state functional connectivity. Aim 3 assesses whether perampanel blocks ketamine-associated increases in SCC cerebral metabolic rate of oxygen relative to the pre-ketamine baseline. These metabolic increases may subserve restoring synaptic connectivity in TRD patients. Together these aims would provide an important test of a central hypothesis related to the mechanism underlying the therapeutic effects of ketamine and could inform efforts to develop alternatives to ketamine as a treatment for TRD.

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY/ABSTRACT Obesity is a well-established risk factor for developing cardiometabolic diseases such as diabetes and hypertension. While the impact of obesity on reproductive health is less understood, studies conducted in high- income countries have associated obesity with menstrual and ovulatory dysfunction and subsequent infertility. These findings have significant public health implications for low- and middle-income countries (LMICs) where access to assisted reproduction treatment remains practically nonexistent despite rapidly increasing obesity prevalence. Obesity-related morbidity and mortality are particularly high among Pacific LMICs. However, few studies have assessed the relationship between cardiometabolic and reproductive health in this region. Previous attempts to characterize menstrual irregularity among Pacific Islander women have relied on retrospective self-report of cycle length and variability, which is notoriously subject to recall bias and interlocuter variation. No studies to date have characterized anovulatory cycles among Pacific Islander women. This is likely because the gold-standard for determining ovulation involves daily transvaginal ultrasonography, an invasive and resource-intensive procedure that is impractical for epidemiological studies. My proposal addresses these gaps through two scientific aims and five training aims that leverage an existing cohort of approximately n=150 Samoan women aged 25-39, whose families Dr. Nicola Hawley (sponsor) and colleagues have followed since 2015. These women have participated in health and wellbeing assessments in 2015, 2017/2018, and 2019/2020. During the fourth data collection wave planned for 2022, I will measure adiposity and prospectively assess ovulatory function. In Aim 1, I will examine associations between menstrual irregularity and current adiposity and longitudinal trajectories of change in adiposity among Samoan women. In Aim 2, I will biochemically evaluate the presence or absence of ovulation among regularly menstruating women and explore the association between anovulation and BMI. Findings will provide critical insight on secondary infertility among women with obesity and inform the development of protocols for evaluating female reproductive potential in low-resource settings. Moreover, this project will shed light on the dual burden of cardiometabolic and reproductive risk among Pacific Islander women, who despite having among the highest obesity prevalence globally, are underrepresented in epidemiologic research. My training plan will enable me to develop research, clinical, and professional skills necessary to become a physician-scientist who conducts longitudinal epidemiologic studies to investigate the impact of obesity on maternal and child health outcomes in low-resource settings. My training plan outlines coursework, mentored research, and clinical experiences to enhance my skills in biostatistics, epidemiological study design and implementation, and reproductive endocrinology.

NIH Research Projects · FY 2025 · 2023-07

No Abstract

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY Despite the remarkable successes of targeted cancer therapies, certain cancers, including lung, breast, and prostate cancer and melanoma, invariably become resistant to therapy. One mechanism of secondary resistance—lineage plasticity—arises when cells transition into aggressive states, and, in the case of prostate cancer, acquire a neuroendocrine histology. This results in a rapid downhill course for a subset of the so–termed castrate–resistant prostate cancer (CRPC) patients. This, in essence, not only poses a clinical challenge, but also confronts us with a wide–open biological question—what are the molecular underpinnings of lineage plasticity, and importantly, can the process be reversed? We have very recently documented that the activation of JAK/STAT and FGFR signaling pathways promote lineage plasticity and result in complete insensitivity to androgen receptor signaling inhibitors (ARSIs) [*Chan, *Zaidi, et al., Science, 2022, PMID: 35981096, *co– first authors]. Importantly, we found that FDA–approved inhibitors of JAK/STAT (ruxolitinib) and FGFR (erdafitinib) synergize to reverse lineage plasticity and restore ARSI sensitivity. We therefore hypothesize that signals downstream of JAK/STAT and FGFR, including novel transcription factors, interact to promote lineage plasticity, and their timed perturbation can reverse plasticity and ARSI insensitivity. Thus, in Specific Aim 1, to study how FGFR signals synergize with JAK/STAT to impart plasticity, we will use chemical inhibitors and CRISPR–Cas9 to delete specific molecules in TP53/RB1–null mouse and human tumor organoids. Specific Aim 2 will focus on further deconvoluting the molecular complexity of lineage plasticity through unbiased single cell paired RNA and ATAC (multiome) sequencing in murine organoids. We expect to identify novel transcription factors and study their DNA accessibility post–TP53/RB1 deletion across the evolution of lineage plasticity, with and without ruxolitinib and/or erdafitinib. In Specific Aim 3, in proof–of–concept in vivo studies, we will examine the efficacy of combined treatment with ruxolitinib plus erdafitinib in reversing lineage plasticity and restoring ARSI sensitivity. For this, the ruxolitinib+erdafitinib combination will be studied in NOD SCID mice grafted either with TP53/RB1–null murine organoids, orthotopically, or with the human tumoroid MSK–PCA3, subcutaneously. These studies will not only inform future therapeutic strategies to subvert drug resistance in CRPC patients but should also provide a unique platform for my Training Aims. Under the tutelage of my primary mentor, Dr. Charles Sawyers, and my Advisory Committee, I expect to enhance my competencies in advanced computation, cancer modeling and genetic editing, and bedside translation. Together with the rich scientific environment and vast array of resources at MSKCC, my research and training should position me to achieve my goal of becoming an independently funded physician–investigator in genitourinary oncology by the end of this grant period.

NIH Research Projects · FY 2025 · 2023-07

Project Summary/Abstract This proposal describes a rigorous training program leading to the career development of Dr. Anna Eisenstein as an independent scientist. The principal investigator is a physician scientist who recently completed Dermatology residency. Her career goal is to become an independent investigator studying the interplay between the skin barrier and immune function, with a particular interest in allergic disease. She proposes to expand her training in immunology and allergy through an intensive research experience under the co-mentorship of Dr. Andrew Wang and Dr. Joseph Craft as well as a preeminent advisory committee with leading scientists and physician scientists in immunology and dermatology. In addition to excellent mentoring, the proposal includes rigorous coursework, seminars and external meetings. These planned activities will equip her with the necessary skills to become a successful independent investigator. The research objective of this proposal is to understand why individuals with atopic dermatitis (eczema) are more prone to food allergies, both conditions whose prevalence are exponentially rising. Preliminary data reveals that environmental xenobiotics, like common over-the-counter medications and food preservatives, act as allergic adjuvants both when given orally or applied topically. These products were all found to activate the xenobiotic receptor, Nuclear factor erythroid 2-related factor (Nrf2). Cutaneous disruption or topical application of Nrf2 activators was sufficient to induce sensitization to orally introduced food antigens, suggesting a novel mechanism of sensitization, distinct from the current epicutaneous paradigm wherein food allergens are thought to physically contact a damaged skin barrier to program the allergic immune response. The proposal will test the hypothesis that disruption of the skin barrier and/or topical chemical adjuvants that activate Nrf2 in keratinocytes promote epidermal production of alarmins, which signal on the intestinal epithelium and gut resident dendritic cells to initiate allergic sensitization to coincident non-tolerized oral allergens in a skin-gut-immune axis using a unique collection of full body and conditional knock out mice. This proposal serves as a training vehicle for Dr. Eisenstein to become an expert in immunobiology, mechanisms of allergic sensitization, and cutaneous barrier function so that she can apply this expertise to the field of dermatology and harmonize her clinical and research programs for maximal impact in translating her basic science investigations to the clinical management of atopic diseases. This project has the potential to explain the modern rise in incidence of food allergies as well as the clinical association between eczema and food allergies, which could lead to significant influence on public health and lead to novel therapeutic approaches to food allergy. Furthermore, these results may yield important novel insights into our fundamental understanding of the mechanisms of allergic sensitization.

NIH Research Projects · FY 2025 · 2023-07

Project Summary Uncontrolled inflammation is a key driver of acute and chronic cardiovascular pathology. However, the accompanying edema, one of the four cardinal signs of inflammation defined by Celsus and Galen two millennia ago, is poorly understood and often ignored at the mechanistic level. Yet ample evidence shows its causal roles in ischemia reperfusion injury (IRI) and resultant sequelae in the heart, brain, and other organs. While a number of molecules can induce edema formation, vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF) has been viewed as the key component of IRI-associated edema development. There are a number of drugs capable of blocking VEGF signaling, including vascular permeability that are widely used as anti- angiogenic cancer and ophthalmologic drugs such as bevacizumab, sorafenib, sunitinib and pazopanib among others. However, none of them can be used in acute/chronic ischemia settings due to the induced loss of blood vasculature. Exciting new data from our lab have demonstrated that it is possible to selectively block VEGF- induced permeability defects without affecting other aspects of its signaling, thereby eliminating anti-angiogenic effects of non-selective anti-VEGF therapies. In preliminary studies, blocking VEGF-blocking edema formation leads to a ~50% reduction in the size of myocardial infarction and preservation of LV systolic and diastolic function and suppression of VT inducibility. With these preliminary results in hand, we propose to examine the functional effects myocardial edema and evaluate the effect of anti-edema therapies in this setting.

NIH Research Projects · FY 2025 · 2023-07

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. The predoctoral Cellular, Molecular and Quantitative Biology Training Program (CMQBTP) will be a comprehensive, rigorous and forward-thinking program designed to graduate the leaders of the 21st century biomedical workforce. It will bring together a group of talented students interested in developing the technical, operational, and professional skills essential for their future careers both in and outside of academia. These students will apply to the CMQBTP through two graduate admission tracks that feed four degree granting departments: Cell Biology, Genetics, Molecular, Cellular and Developmental Biology, and Molecular Biophysics and Biochemistry. Thus, the students will be immersed in an interdisciplinary training environment that prioritizes collaborative team science based on rigorous and quantitative experimental design and analysis. Our 60 training faculty represent all ranks of the academic ladder. They have all been National Research Mentoring Network-trained and thus prioritize mentoring graduate students within a supportive environment. The mission of the CMQBTP is to develop rigorously trained early-career scientists prepared to operate ethically as future scientific leaders. It will advance 6 Training Objectives so that trainees master a well-defined set of transferable technical, operational and professional skills. This will be facilitated by a set of CMQBTP- specific courses and activities designed to not only teach the specific skills but also to build a cohesive cross- cohort community of scholars. Activities for CMQBTP trainees throughout their graduate career are designed to enrich their education while providing experiences to effectively inform their future career choices. We will offer a “Beyond the Bench” seminar series (to develop transferable skills beyond academia), Informational Interview workshops (to help identify viable career options), a course on “Statistical Inference and Models in Molecular and Cellular Biology” (to enhance reproducibility and rigor), an annual student-run Symposium Retreat (to develop leadership skills) and regular research in progress talks (to learn about their exciting discoveries). These activities are paired with peer mentoring and community building initiatives designed to forge a sustainable CMQBTP community that will persist beyond graduate school. To ensure the continued growth and improvement of our program, we have instituted a modern set of evaluation tools designed by PhD- level educators well-trained in program assessment and are independent of the CMQBTP leadership. These assessments will provide quantitative metrics to evaluate whether students are meeting competency benchmarks and whether our faculty are succeeding as trainers. These assessment and outcome datasets will be made fully available to CMQBTP trainers and prospective students to better inform their mentorship practices and future career goals, respectively. Particular attention will be paid to ensure that faculty will be rigorously trained in and evaluated on best mentoring practices to ensure our mission of creating a CMQBTP that provides an educational community for trainees to flourish.

NIH Research Projects · FY 2025 · 2023-07

The broad mission of the predoctoral Chemistry/Biology Interface Training Program (CBITP) is to educate, train, and develop early-career scientists to be thought leaders, role models and innovators at the Chemistry/Biology Interface for the greater benefit of humanity. The overall objective of the program is to train scientists who will make strong contributions to the chemical biological sciences leading to a sustained impact, ultimately benefitting society. During their supported training period in years 2 (5 students) and 3 (5 students) of the overall CBITP, students will: 1) Develop broad background knowledge of modern chemical biology research; 2) Develop strong background knowledge of detailed methods used in the chemical biology field; 3) Demonstrate advanced knowledge in specialized areas of chemical biology, including critical evaluation of molecular structure, function, (bio)synthesis, reactivity, and application in basic cellular/ organismal physiology; 4) Design, perform and communicate original, high-quality, rigorous (robust controls and statistical analysis), and ethically-conducted research upon critically examining previous scientific knowledge in chemical biology; 5) Express self-efficacy and professionalism to navigate the biomedical science career landscape; and 6) Develop professional oral and written communication skills. As large pharma internal Research & Development (R&D) efforts have decreased, job opportunities within the growing biotech/biopharma sector have increased. The founding of new biopharma ventures, by definition, involves a combination of chemistry and biology. The rationale for the training of students at this interface will not only help supply the workforce in the biotech/biopharma sector but will also produce the next generation of faculty and entrepreneurs to promote science and technology innovations and maintain U.S. leadership in these areas on the world stage. The program takes advantage of the very deep chemical, biological, and biomedical sciences applicant pool at Yale University as well as the extraordinary research strengths of the associated faculty. We have established a rigorous CBITP core curriculum with new and intensive half credit modules, which allows the students more flexibility in matching instruction and coursework with their educational and research needs. We have also established an assortment of CBITP-specific hands-on research (e.g., high-throughput screening, genomics, proteomics, etc) and career (e.g., internships with biopharma, alternative careers in bioscience, etc) workshops in addition to chemical biology symposia and conferences to promote overall student and program successes. To evaluate the efficacy, training outcomes, and career outcomes emerging from our existing and new programmatic activities, in addition to exploring the experiences of our trainees, we will employ a data-driven mixed-methods approach for continuous refinement. Collectively, we propose to modernize our successful 20-year CBITP for this new, next generation CBITP.

NIH Research Projects · FY 2025 · 2023-07

The introduction of recombinant tissue plasminogenactivators (r-tPA, alteplase) 25 years ago, and the recent development of endovascular therapy (EVT), significantly reduced neurologic disability in patients with ischemic stroke. Still, only 20% of stroke patients in the US are eligible for these therapies and 70% of those treated are left disabled. Unfortunately, these therapies are also associated with toxic effects such as brain hemorrhage. For many patients, such as those who would be treated at 4.5-24 hours after stroke without large vessel occlusion, no established therapy exists. We urgently need to develop safer and more effective treatments that can lessen the suffering and enormous costs of disability after ischemic stroke. NINDS-funded research shows that a2-antiplasmin (a2AP) is a molecule that plays a crucial, deleterious role in acute ischemic stroke. High a2AP levels are linked to an increased risk of r-tPA failure clinically, and a2AP increases brain injury in a dose-dependent fashion in preclinical models. a2AP blocks thrombus dissolution ini- tiated by r-tPA and increases microvascular thrombosis. a2AP promotes neutrophil recruitment and matrix met- alloproteinase-9 (MMP-9) expression, which enhances blood brain barrier breakdown to cause intracranial hem- orrhage. Conversely, a2AP deficiency, or a monoclonal antibody that inactivates a2AP (a2AP-I), profoundly reduces apoptosis, MMP-9 expression, microvascular thrombosis, hemorrhage and swelling by comparison to r-tPA or no treatment. Importantly, an a2AP-I has a several-fold longer therapeutic window than r-tPA. Compared to r-tPA, an a2AP-I significantly decreases brain infarction, brain hemorrhage, disability and mortality in preclinical stroke. Robust studies from multiple labs, using different models and tools, show consistent effects. Taken together, these data suggest that an a2AP-I alone has extraordinary potential for safe treatment of human ischemic stroke, particularly in an extended ischemic time window. The monoclonal antibody a2AP-I, TS23, was developed with NIH/NINDS research support. In a Phase I trial of healthy volunteers TS23 induced dose-related a2AP inactivation, amplified endogenous thrombus disso- lution, and was well-tolerated. A randomized, placebo-controlled, blinded, Bayesian, dose-finding, Phase II SISTER trial within the NIH StrokeNet will test the central hypothesis that, when compared to standard medical care, TS23 will safely improve neurological outcomes in patients with extended ischemia, without completed infarction. TS23 will be compared to placebo in 300 acute ischemic stroke patients presenting 4.5-24 h after symptom onset with favorable perfusion imaging. If TS23 proves be safe and potentially efficacious, based on reduction of neurological impairment, a future, pivotal clinical trial will be planned.

NIH Research Projects · FY 2024 · 2023-07

PROJECT SUMMARY Although T cell mediated immune responses are critical for the success of immunotherapy, those T cells associated with malignant lesions are typically dysfunctional and fail to control tumor growth. Treatment with tumor infiltrating lymphocytes (TIL) that are isolated, activated, and expanded ex vivo has proven very effective in some patient populations of melanoma. However, a substantial number of patients do not respond, presumably due to one of a number of host immune factors. Current understanding of TIL mechanism of action suggests that both an early robust expansion of tumor-specific effector T cells and transfer of less differentiated cells with long-term survival capacity are key to a successful therapy. Evidence for the former includes the need for high dose exogenous IL-2 at the time of TIL infusion, the correlation of response with a high frequency of effector T cells, and the majority of tumor killing occurring very early after the initiation of therapy. Evidence for the latter is found in many pre-clinical experiments as well as clinical observations where the presence of TILs from the central memory subset in the infusion product correlates with tumor regression. Our overall goal is to improve TIL therapeutic efficacy through the generation of TIL products with both the transient ability to effectively immediately kill tumor cells as well as the long-term ability to persist and maintain durable anti-tumor responses. To address these challenges we have developed robust methods to reprogram TILs with mRNA-mediated gene therapy. The use of our mRNA approach has the advantages of increased safety, high efficiency, rapid production, tightly controlled expression levels and simultaneous multi-factor reprogramming. In preliminary work we have developed a system that increases mRNA lifespan by an order of magnitude. Our single cell analysis of patient TILs pre- and post-expansion has identified two specific pathways deficient in the expanded TIL product that likely contribute to their poor immediate efficacy and absence of memory fate. Both of these will be augmented by TIL mRNA reprogramming. In Aim 1 we will develop a method to enhance post-expansion TIL survival, while in Aim 2 we will improve the production of central memory TILs. We will evaluate the effect of these improvements in TIL production using paired tumor/TIL sets derived from the melanomas from multiple patients by studying tumor-mediated TIL activation and tumor lysis in vitro and in pre-clinical humanized mouse models using single cell analysis and advanced spatial transcriptomics. This application addresses the need to improve response rates to adoptive cell immunotherapies for melanoma and is designed to be translatable to clinical trials in the near future.

NIH Research Projects · FY 2025 · 2023-07

Project Summary/Abstract Excessive alcohol consumption is the third leading preventable cause of death in the U.S. and responsible for 2.7 million years of potential life lost annually. Emergency departments (EDs) provide care for patients with AUD experiencing a variety of alcohol related and unrelated health problems, including illness and injury. Thus, the ED encounter presents a unique opportunity to screen, enhance motivation, initiate medication treatment, and refer to continuation care patients who both seek and do not seek AUD treatment. While combined pharmacological and behavioral therapies for alcohol use disorder (AUD) have demonstrated efficacy in specialty and primary care settings, their effectiveness in the ED setting is unknown, and EDs do not routinely provide comprehensive interventions for AUD. The proposed open label randomized clinical trial (RCT) will evaluate two ED-based intervention models to increase AUD treatment provision and patient engagement. ED patients with moderate to severe AUD (N=240) will be randomly assigned to: (1) Screening, Brief Intervention and Referral to Treatment (SBIRT) (n=120); or (2) SBIRT with ED-initiated medications for AUD (SBIRT+ED- MAUD) (n=120). Gabapentin and extended release or oral naltrexone will be offered as a combination pharmacotherapy in the ED-MAUD component. SBIRT intervention in both study arms will utilize a facilitated referral with direct linkage to continuation AUD treatment following the ED visit. The primary outcome measure will be the rate of AUD treatment engagement assessed on day 30 post randomization in each of the two study groups (Aim 1). The study will also evaluate the between-group difference in the reductions of heavy drinking days from 30 days prior to 30 days post randomization (Aim 2). A statistically significant effect on the primary outcome and a clinically meaningful effect on the reductions of heavy drinking days favoring the SBIRT+ED- MAUD are hypothesized. All enrolled patients will be followed daily on days 1-7 using a brief electronic survey to assess their alcohol cravings, withdrawal symptoms and medication adherence, and with comprehensive follow-up assessments at 30- and 90-days post randomization. The primary outcome, AUD treatment engagement on day 30 post the ED visit, will be based on clinical records documentation obtained from the AUD treatment provider. Alcohol consumption outcomes, medication adherence, the intensity of alcohol cravings and withdrawal symptoms, and other important study outcomes will be based on patient self-report using validated assessment instruments. The planned study sample and the proposed analytical methods will allow for additional meaningful exploratory evaluations of potential differential effects of gender, race, ethnicity, insurance types, and housing instability on the evaluated outcomes. No prospective studies of ED-initiated MAUD interventions have been reported. If successful, the proposed study will provide critically important evidence needed to support a broader dissemination of ED-based interventions for AUD, including MAUD.

NIH Research Projects · FY 2025 · 2023-07

Project Summary In addition to motor control and learning, the cerebellum is intimately linked to cognition. This project is designed to closely examine the cerebellum's role in nonmotor domains, namely, reinforcement learning and statistical learning. We hypothesize that the structure's core computations for sensorimotor learning can be generalized to nonmotor contexts. It is critical to understand how the cerebellum contributes to nonmotor learning – this knowledge will support the development of novel mechanistic and clinical insights into cerebellar function, and human learning in general. Foundational theoretical work has described how the cerebellum typifies an ideal substrate for supervised motor learning. This theory made testable empirical predictions that have been borne out in experiments in animals using tasks such as Pavlovian eyeblink conditioning and vestibular-ocular reflex adaptation, revealing facts about cerebellar sensorimotor processes in exquisite detail. But what about a cerebellar role in other task domains? Here we address this question. The proposed work integrates behavioral, neuroimaging, and computational techniques to develop a new framework for generalized cerebellar learning computations. The research plan centers on three Specific Aims. In Aim 1 we use computationally guided functional neuroimaging (fMRI) to examine the role of the cerebellum in reinforcement learning. We test the idea that the cerebellum processes reward predictions and prediction errors, the core computations of reinforcement learning. We also posit a constraint on cerebellar learning computations, namely that the structure only contributes to learning when the temporal interval between events is brief (i.e., subsecond). Aim 2 takes a similar approach to the domain of visual statistical learning, examining sensory predictions and prediction errors in the cerebellum and further testing the proposed timing constraint. In Aims 1-2 we also measure cerebro-cerebellar connectivity to position the cerebellum within broader task-specific learning networks, and to ask if cerebro-cerebellar connectivity covaries with behavior. In Aim 3 we examine causal contributions of the cerebellum to nonmotor learning, testing a large sample of individuals with cerebellar pathology and contrasting their behavior with matched controls. Computational analyses will be used to detect and characterize the hypothesized deficits. This project proposes a new framework for understanding the contributions of the cerebellum to nonmotor learning and will provide new insight into the broader role of the cerebellum in health and disease.

NIH Research Projects · FY 2025 · 2023-07

Project Summary Opioid use disorder (OUD) has reached epidemic levels in the Unites States, associated with increased rates of hospitalization and drug overdose death, the latter showing a significant steep rise of up to 29.4% in 2020. While genetic risk factors have been identified in recent large-scale genome-wide association studies (GWAS) of OUD, these explain only part of the variance and often map to noncoding regions. Epigenetic modifications have been implicated in the etiology of opioid use disorders (OUD) underlying the gene and environment interplay. We and others have found that alterations of DNA methylation (5mC), one of the most studied epigenetic mechanisms, is associated with OUD in both human peripheral and postmortem brain. However, most of this work has been done in bulk tissues, which obscures the functional role of the cellular diversity in human cells. Further, research is needed to assess additional and novel epigenetic regulatory layers to gain a better understanding of its contribution to gene regulation and its ability to interpret the functionality of GWAS genetic variants in the context of OUD. Here, I offer a novel framework to tackle these gaps and challenges: 1) conduct a simultaneous profiling of DNA methylation, DNA hydroxymethylation, and 3D genome structure in single human nuclei, 2) identify OUD-dependent regulatory signatures within cell types and brain regions, 3) evaluate the crosstalk between the different epigenomic regulatory layers, and 4) construct gene programs to finely map OUD GWAS variants and polygenic signals to function. This comprehensive single-cell multiomics mapping of OUD will examine the dorsolateral prefrontal cortex (DLPFC), amygdala (BLA), and nucleus accumbens (NAcc), part of the addiction circuitry, of human postmortem brain samples collected from the UTHealth Brain Collection datasets and using the VA Brain Bank (NPBB) as a validation cohort. This work is highly innovative and will open new lines of research the genetics and epigenetics of OUD by providing novel mechanistic insights on its gene regulatory structure in the human brain. This proposed study will identify and help inform molecular targets to be used as prevention and treatment efforts for individuals suffering from OUD.

NIH Research Projects · FY 2025 · 2023-07

Genetics is a critical factor underlying human disease, wellness, and lifespan. Genetic research has led to enormous improvements in the prevention, diagnosis, and treatment of a great range of diseases. The long-term objective of the proposed program is to strengthen the national scientific workforce to improve human health. We have designed the Training Program in Genetics (TPG) to provide unified training in modern genetics research for predoctoral students across three campuses and from three main departments at Yale University. It aims to prepare PhD students for leadership positions in science and science-related careers via four key objectives: i) to provide training in rigorous experimental design, new technology and quantitative methods; ii) to foster intellectual interactions amongst geneticists addressing a wide variety of problems and across several departments; iii) to develop communication skills by providing opportunities to present research and by providing feedback on the presentations; iv) to develop leadership skills that are applicable not only in genetics research but also in a variety of other science and science-related careers. We will advocate for these innovations to be adopted by other training programs and therefore impact the university on a larger scale. Students develop skills via a combination of coursework, laboratory research, and a rich variety of carefully designed program-specific activities. The TPG will hold monthly Research in Progress talks, an annual Retreat, an annual Symposium, workshops on R statistics and other topics, and opportunities to discuss topics in genetics with undergraduates in a course for non-science majors. A number of career development opportunities will be provided. The TPG is distinguished from other training programs at Yale by the remarkable wealth of interests of its trainers. Faculty trainers are united by a common focus on genetics but address wide-ranging problems at different levels in a variety of species, providing exceptionally rich training. Junior trainers are mentored by senior trainers, and all take a common evidence-based course on mentoring. Students and trainers are selected via a set of criteria, including their scientific expertise and their commitment to mentoring and supporting student education. The program will be overseen by two Directors with complementary expertise, an internal Executive Committee, and an external Advisory Committee. Success of the TPG will be evaluated regularly according to a detailed plan designed and executed by a professional with expertise in program assessment. The program would welcome seven new students each year and provide stipend and tuition support during years 2 and 3 for 14 slots total per year, with a cohort of ~42 students across ~6 years of training.

NIH Research Projects · FY 2025 · 2023-07

Complex relationships between genetics and non-genetic factors influence health outcomes. The All of Us (AoU) Program and the Million Veterans Program (MVP) include genetic, health and other information on all participants, and therefore provide an opportunity to identify factors contributing to health. However, the AoU program and MVP require their data to stay within local hosting sites, therefore conducting joint analyses on these cohorts requires the development of algorithms that enable privacy-protecting distributed computing (i.e., without revealing individual-level data). There are three important gaps in understanding genetic determinants of health: (1) most studies control for global ancestry, and there is no attempt to model the patchwork of local ancestry characteristic of most individuals. (2) GWAS are primarily conducted using SNPs, while important sources of ancestry-specific genetic variation (tandem repeats (TRs) and the major histocompatibility complex (MHC) interval) are not assayed; and (3) most GWAS do not adjust for other factors. The American College of Medical Genetics and Genomics (ACMG) has published a list of medically actionable cancer and cardiovascular genes recommended for return of incidental findings of pathogenic variants to reduce morbidity and mortality, but having some individuals removed from healthcare follow up due to common obstacles (e.g., access to healthcare services) makes it difficult to distinguish between the genetic and non-genetic factors that contribute to different health outcomes. The goal of the CAST (Center for Admixture Science and Technology) program is to improve the clinical utility of genetic information for all populations in the US. In Aim 1, we will develop and apply multivariate models of disease risk prediction that incorporate local ancestry, complex variants (TRs and HLA types). In Aim 2, we will conduct scalable distributed computing using data from millions of individuals across the AoU and MVP compute enclaves. In Aim 3, we will develop new approaches to characterize phenotypes using electronic health records and surveys from AoU and MVP, assess the impact of including social determinants of health in our models, and prospectively evaluate them with new AoU and MVP participants. To achieve these goals, we assembled a highly interdisciplinary group of researchers with expertise in Genetics, Genome Biology, Data Sharing Policy and Technology, Health Outcomes, Phenotyping, and Statistics.

NIH Research Projects · FY 2025 · 2023-07

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. The goal of the Yale Biophysics Training Program (BTP) is to equip predoctoral trainees with the intellectual and research foundations to become future leaders at the forefront of biophysical and biomedical sciences. The proposed BTP leverages the strengths of our previous 34 year-long program in biophysics training while incorporating substantial new focuses to adapt to the rapidly evolving research enterprise. The BTP is a PhD-track program that offers training in a wide range of biological systems and biophysical techniques to enable understanding the mechanisms of life processes at the molecular level. The BTP combines rigorous research training in a highly interactive environment and a thorough academic program in biophysics with ample opportunities for career and skill development. The program takes advantage of the deep and strong biophysics applicant pool at Yale as well as the extraordinary research strengths of 43 faculty trainers from many departments including Molecular Biophysics and Biochemistry (MB&B), Chemistry, Pharmacology, Immunology, and Cell Biology. BTP Program Directors Yong Xiong and Elsa Yan work together closely to oversee the program and together with four additional faculty, constitute the BTP Executive Committee, which develops new initiatives, evaluates program success based on internal and external reviews, and oversees trainee and BTP faculty evaluations and appointments. The BTP leadership will additionally ensure that our trainees thrive within a supportive environment. The principal training entities are the MB&B Department and the Chemistry Department. Students are admitted to the BTP either directly through the Chemistry Department or from MB&B Department through an umbrella Biological and Biomedical Sciences (BBS) Program, primarily from the Biochemistry, Quantitative Biology, Biophysics, and Structural Biology (BQBS) track. Trainees are selected for BTP appointment in year 2 based on a research focus in biophysics. BTP training involves formal course work, research rotations, teaching, and qualifying exam in years 1-2, with thesis research beginning in the spring of year one. Upon joining a mentor lab, dissertation research is performed with supervision from a thesis committee comprised of at least three faculty that are familiar with the student's research topic and meet regularly to discuss progress. Training is enriched by intensive coaching in rigor, reproducibility, and responsible conduct of research, travel to major biophysics meetings, mentoring, and numerous opportunities for collaboration and interaction. We are also developing special assessment tools and surveys to measure trainee development and guide future improvements. All trainee outcomes will be deposited into an easily accessible databank on the BTP website. The training resources at Yale and the dedicated commitment to training by the mentors, facilitate the BTP goal to produce the next-generation leaders in science. The BTP requests 12 training positions to appoint 6 second-year and 6 third-year students per year.