Weill Medical Coll Of Cornell Univ

NIH Research Projects · FY 2025 · 2022-09

The overall goal of CAP-IT Center for Immunoprevention (CRI) is to pre-clinically delineate, formulate and validate nucleic acid vaccines for precision prevention of individuals with increased cancer risk. The PI is Dr. Lipkin, an established leader in Cancer Prevention who has made several important, clinically translated contributions to the field. Project 1 will develop and validate an immunoprevention vaccine for Lynch syndrome, a genetic cancer predisposition syndrome with highly immunogenic recurrent neoantigens shared among cancers from different patients. Project 2 will develop and validate a nucleic acid immune interception vaccine for patients with lung non-solid nodule (NSN) pre-malignant neoplasms, a lung adenocarcinoma precursor lesion. To achieve these goals, we will use state-of-the-art technologies, including nucleic acid vaccine formulation, computational genomic tumor immunology, spatial genomics and immunopeptidomics. To ensure CRI's scientific rigor and excellence, we have assembled a scientifically outstanding CRI External Advisory Board (EAB). Overall, the CAP-IT CRI will develop state-of-the-art nucleic acid immunoprevention and immune interception vaccines and provide a technologically powerful platform to jumpstart additional CAP-IT CRI vaccine projects. We anticipate that CAP-IT CRI will propel both Lynch syndrome and lung NSN vaccines to NCI PREVENT and CP-NET clinical trials and FDA approval/clinical translation.

NIH Research Projects · FY 2024 · 2022-09

PROJECT SUMMARY/ABSTRACT Invasive aspergillosis (IA) is a life-threatening pulmonary infection of immunocompromised patients caused by Aspergillus fumigatus. While previous work has identified recruited phagocytes as critical cellular players in controlling A. fumigatus infection, a major knowledge gap exists regarding the role of lung structural cells in establishing the anti-fungal environment of the lung. My preliminary data indicates that IL-1 receptor (IL-1R1) signaling promotes neutrophil and monocyte killing of A. fumigatus spores (called conidia) and that IL-1R1 expression on lung structural cells is required for production of key anti-fungal cytokines such as GM-CSF. These data strongly suggest an accessory immune role for structural cells during A. fumigatus infection, although the identity of IL-1/-producing cells and IL-1R1-expressing cells is unknown. I hypothesize that production of IL- 1 and  by recruited and lung-resident phagocytes, respectively, is required for optimal immune cell killing of Af conidia and murine survival and that IL-1R1 expression by structural cells is required for broad production of anti-fungal cytokines by diverse structural cell subsets. I will test this hypothesis with the following specific aims: Aim 1: To investigate the cellular sources of IL-1/ and their contributions to prevention of mortality and efficiency of conidial killing in the A. fumigatus-infected lung. I will identify IL-1/ producing cells in infected mouse lungs using ELISAs, flow cytometry, and immunofluorescence microscopy, in both wild-type mice and mice depleted of candidate producer cell types. I will infect mice deficient in IL-1 or  with a fluorescent A. fumigatus reporter to test the contributions of each cytokine to fungal killing and murine survival. Aim 2: To define a map of IL-1 responsive structural cell types that produce key cytokines modulating the quality and quantity of the anti-A. fumigatus immune response. I will identify IL-1R1-expressing structural cell subsets in the lung using flow cytometry and microscopy. I will test the requirement for IL-1R1 on specific cellular subsets for murine survival and fungal killing by using mice with conditional Il1r1 deletion on three different structural cell subsets. I will test whether IL-1R1 on structural cells is required for anti-fungal cytokine production and determine which structural cells may produce these cytokines. Upon conducting these aims, I will determine the structural and immune cells involved in IL-1R1-dependent crosstalk during A. fumigatus infection. These results will advance our understanding of immunity to a medically- important fungal pathogen. I have designed this training plan for broad training in fungal pathogenesis and cellular immunology. The sponsor's laboratory and the host institution are the ideal environment for conducting this training and contribute to a high likelihood of success in both research and other aspects of training.

NIH Research Projects · FY 2025 · 2022-09

The Next-Gen Oncopathology (NGO) program has the overall mission of training young diagnosticians to meet advances in our understanding of the mechanisms of cancer pathogenesis and new oncological interventional approaches thereby leading the field of pathology into the future. Specialized pathologists have been involved in cancer diagnostics by examining tissues and other specimens since at least the 19th century, and training in pathology has been incrementally structured and subspecialized. Pathology training programs traditionally teach residents to examine tissue under the microscope and analyze laboratory data for diagnosis, with pathology research being largely descriptive. This approach is no longer sufficient, and it is essential that we prepare pathologists to understand and apply advanced technologies to perform more precise and personalized diagnostics in addition to utilizing innovative and improved ways to conduct research and diagnose cancer. The Weill Cornell Department of Pathology and Laboratory Medicine has trained numerous outstanding pathologists in many subspecialty areas, but it is only with the use of an innovative approach incorporating a view towards the future that we will be able to produce leaders that will advance the field of cancer pathology. The NGO program takes a holistic and multidisciplinary approach, where all aspects of a cancer patient are considered, ranging from the tumors themselves, to in vitro and in vivo cancer models, to changes in the patients’ blood and microbial infections. Thus, trainees in both Anatomic and Clinical Pathology (i.e. Laboratory Medicine) will be included, which will be individuals with MD or MD/PhD degrees doing a Pathology Residency or Fellowship, or trainees with PhD degrees doing a clinical fellowship in Laboratory Medicine, who are committed to an academic career that includes cancer research. Our trainees will gain expertise and depth by spending two years in a research laboratory working in one or more of the following major themes: 1) molecular diagnosis and cellular therapies, 2) cancer pathobiology, 3) advanced imaging and 4) tumor microenvironment. The foundational principles of the NGO program will be to ensure that all the pathology projects relate to the study of cancer patient samples as well as the comparative pathology of cancer models. Overarching methodologies that will support all of the projects are: i) biostatistics and data science, ii) machine learning and artificial intelligence, and iii) genomics, epigenomics, proteomics and metabolomics. Faculty in the program have expertise in the major themes and specific methodologies, which will allow for the teaching of foundational skills as well as a highly customized educational plan. This will be accomplished by the establishment of a mandatory NGO Course as well as additional course requirements on data science and career development, which will allow trainees flexibility to design a personalized curriculum with their mentoring committee. We will also leverage the Meyer Cancer Center and the Weill Cornell Clinical and Translational Science Center (CTSC) resources to educate the next generation of pathologists working on cancer.

NIH Research Projects · FY 2025 · 2022-09

Project Summary/Abstract Hypersensitivity Pneumonitis (HP) is an often incurable and potentially progressive fibrotic interstitial lung disease (ILD) with limited treatment options that leads to poor health-related quality of life (HRQOL). Patients with HP experience a profound lack of knowledge about the disease, uncertainty, intense hypervigilance, feelings of anxiety and depression, and marked disruption to their lifestyle and home environment. HRQOL is highlighted by the American Thoracic Society as a priority patient-centered endpoint in ILD research. Despite this, no interventions have been designed to improve the HRQOL of patients living with HP, highlighting a crucial gap in patient centered care. The objective of this proposal is to develop and pilot test a behavioral and educational intervention (“Reimagining Interventions for Support and Education in HP: “RISE-HP”) that targets the key domains of HP-HRQOL and patient knowledge as an innovative strategy to improve the lives of patients with HP. I hypothesize an intervention that delivers peer coaching using cognitive behavioral principles combined with theory-driven patient education will improve HRQOL of patients with HP. To accomplish this objective, I propose the following research aims: 1.) Determine the barriers and facilitators of improving HP- specific HRQOL, patient perceived knowledge gaps, and stakeholder preferences to inform the framework for the RISE-HP intervention 2.) Develop and iteratively refine the novel RISE-HP intervention with stakeholder input. 3.) Conduct a pilot randomized controlled trial to determine the feasibility and acceptability of the RISE- HP intervention. I will work closely with a patient advisory committee through all Aims of the proposal. Findings from this study will lay the groundwork for a multi-center randomized controlled trial to test the effectiveness of the RISE-HP intervention. I will expand on my prior training in observational study design and analysis to develop foundational skills to become an independent investigator with expertise in stakeholder-engaged intervention development, qualitative research methods, behavioral and educational interventions, and conduct of real-world clinical trials with assessment of implementation outcomes. I will be mentored by three internationally recognized clinician scientists, Dr. Monika Safford, Dr. Fernando Martinez, and Dr Robert Kaner. Together we designed a career development plan for me to gain skills through experiential leaning by carrying out the research aims supplemented by didactic work and additional career development benchmarks. By conducting the proposed research, I will advance toward my long-term career goal of becoming an independent investigator focused on patient-centered outcomes research in ILD, specifically by developing and testing interventions that improve HRQOL. This proposal will advance the ILD field by developing a novel patient-centered intervention aimed at improving HRQOL of patients with HP and allow me to build the first HP- specific multisite infrastructure for a larger national hybrid type I effectiveness-implementation trial.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY/ABSTRACT CMS expanded telehealth coverage for Medicare beneficiaries in March 2020, removing multiple barriers to the provision of telehealth in skilled nursing facilities (SNFs). While telehealth has the potential to reduce potentially avoidable hospital readmissions and emergency department visits for patients in SNFs, there is very limited evidence on the impact of telehealth provision for Medicare beneficiaries in SNFs. Furthermore, although roughly 25% of Medicare beneficiaries in SNFs have a diagnosis of Alzheimer's disease and related dementias (ADRD), there is no population-level evidence on the impact of telehealth provision in SNFs for beneficiaries with ADRD. Although telehealth may improve access to necessary specialty care for patients with ADRD, there are numerous ADRD-specific barriers to telehealth use. The overall objectives for this proposal are to examine telehealth growth and the effect of telehealth provision on utilization, cost, and quality of care for Medicare beneficiaries with ADRD in SNFs and for beneficiaries generally in SNFs, and to examine facilitators of telehealth provision in SNFs. Through the proposed training plan, which includes a combination of formal coursework, workshops, and clinical rotations, as well as a multi-disciplinary mentorship team of NIH-funded investigators, the applicant will gain clinical knowledge on the treatment of PAC patients, with a focus on patients with ADRD, expertise in qualitative and mixed methods, and an understanding of telehealth implementation. Dr. Yu will use the methods and content knowledge gained through these training activities to achieve the following specific aims: (1) Examine the patterns of telehealth use for all SNF patients and for SNF patients with ADRD before and after the expansion of Medicare coverage, and assess the relative change in SNF telehealth and in-person visits; (2) Estimate the relationship between SNF telehealth provision and utilization, cost, and quality of care for all SNF patients and for SNF patients with ADRD; and (3) Identify SNF characteristics associated with telehealth provision, factors supporting or hindering telehealth provision in SNFs, and telehealth tools and technologies for patients with ADRD. This application is innovative because it leverages a quasi-experimental approach to estimate the causal effect of telehealth use, as well as a mixed methods approach to provide nuanced insights into telehealth provision in SNFs, including current and emerging uses of telehealth in SNFs for patients with ADRD. The proposed research is significant because it will provide new, critical evidence on the impact of telehealth use for SNF patients, with a focus on patients with ADRD and on how telehealth is provided to patients with ADRD, which may inform telehealth coverage policies and targeting of telehealth investments in PAC. This K01 investigator patients Award will provide Dr. Yu with the training and mentoring needed to become an R01-funded independent leading a research program on telehealth use for older adults in PAC settings, with a focus on with ADRD.

NIH Research Projects · FY 2025 · 2022-09

Project Summary/Abstract Cardiovascular disease (CVD) accounts for one of every three deaths each year in the U.S. A substantial pro- portion of patients with cardiovascular disease develop myocardial dysfunction. Imaging tools that permit early detection of abnormal hemodynamics and/or mechanics provide an opportunity to initiate targeted therapeutics and diminish the burden of disease. Mice are the most common model organism for translational CVD studies of the mammalian heart. Ultrasound (US) is now extensively used in small animals to obtain cardiac functional parameters. However, advanced US intracardiac vector-flow imaging techniques that are gaining traction for hu- man CVD, such as cardiomyopathies, have yet to translate to preclinical use, thus, limiting the functional cardiac parameters that can be obtained from mice. The ability to employ US vector-flow methods to simultaneously re- solve complex, intracardiac blood flow patterns and cardiac mechanics at sub-millisec temporal resolution, prior to overt structural and functional abnormalities, would add a new preclinical tool to study the interplay between blood flow, cardiac mechanics and adaptation in CVD mouse models. The goal of this project is to develop a novel, 30-MHz, 2D CMUT, row-column (RC) high-frequency-ultrasound array and a plane-wave vector-flow imaging approach capable of sub-ms, full-frame image capture for intracardiac imaging in mice. Unlike a standard linear array, the 2D CMUT array will allow dynamic, hands-free selection of the optimal scan plane and the ability to acquire data in orthogonal image planes. In addition, the CMUT array will allow us to collect data in adjacent planes to provide a 3D view of flow dynamics within the murine heart. To validate our system and demonstrate the utility for small-animal imaging, we will study intracardiac left ventricle (LV) blood flow patterns in two highly related mouse strains that nonetheless display divergent responses (progressive hypertrophy vs. dilatation and failure) to abnormal pressure overload induced by the well-established model of transverse aortic constriction (TAC). We hypothesize that our vector-flow system will be able to quantify abnormal left ventricle flow patterns relative to sham control mice and that we will be able to detect flow disruption prior to changes in traditional functional echo or strain measures. Importantly, we also hypothesize that distinct flow pattern signatures can be identified early in the course of disease that will permit discrimination between hearts that are destined to develop progressive hypertrophy vs. dilation. The ability to detect subtle phenotypic changes in common mouse models of CVD that are a result of early-stage diseases or therapies may translate to earlier and more aggressive treatment of patients at highest risk of pressure-overload induced heart failure.

NIH Research Projects · FY 2025 · 2022-09

This project focuses on cortical mechanisms in areas V1, V2, and V4 (V1-2-4) underlying the information- processing roles of saccades and fixational eye movements (FxEMs: microsaccades and drift) in vision. Both saccades and microsaccades are followed by drift. Sequences of saccade/drift and microsaccade/drift cycles, both of which we will refer to as saccade/drift cycles (SDC’s), are believed to be critical to gathering information about visual scenes and the objects within them. We will record single-unit and local field potential (LFP) activity from the foveal projection in areas V1-2-4 simultaneously while monkeys perform match-to-sample tasks for shape or texture, with shapes filled with texture, to understand the role of SDC’s in cortical processing during active vision. Through the use of gaze-stabilization, we will be able to disrupt the retinal input to the cortex during the task to probe selectively how SDC’s control processing of shape and texture in early visual areas. In active vision, the SDC maps spatial information into temporal patterns of neural activity. Recent modeling and psychophysical work have determined that the initial transient phase of the cycle encodes coarse features, while the later, more prolonged period of drift is critical for extracting fine details. We are interested in how the transition from coarse to fine processing in the SDC is implemented in local and inter-areal cortical networks. We hypothesize that processing in these networks during the SDC begins with a phase of transient feedforward activity followed by a longer phase of recurrent and re-entrant activity that coincides with gamma oscillations in the networks. We hypothesize that shape is captured in the initial phase of the SDC and finer features of the shape’s border and the region within the shape by the recurrent phase of processing during drift. We also suggest that the cortex uses sequences of SDC’s to accumulate information and that the organization of networks within the cortex, in terms of their hierarchy and temporal frequency band for communication, depends on whether the sequence is dominated by saccades and drift (looking) or by microsaccades and drift (fixating). In AIM 1, we focus on activity phase-locked to the SDC where the match to sample for shape or texture is fixed for an entire day’s session. The SDC’s in this task will be dominated by microsaccades/drifts. We will ask if accurate matches for shape coincide with stronger SDC transients in the network and if accurate matches for texture produce robust gamma coherence that emerges later in the SDC. In AIM 2, we investigate sequences of SDC’s in periods of looking and fixating for a match-to-sample task where the monkey is given a cue on every trial for the correct match of shape or texture. Information is gained across the trial through saccades and FxEMs, and we ask how the dynamics of V1-2-4 network activity, phase-locked to these sequences, reflect performance and task. Gaze-stabilization will be used in both AIMs to impact cortical processing of the sample stimulus. How the SDC’s modulate the causal relationships between cortical areas and the dynamics of those interactions will be examined through a new method of analysis, frequency-extracted hierarchical decomposition.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY Islet transplantation offers a potential cure for Type 1 diabetes (T1D). Wide adoption of this promising therapy requires abundant islet supplies and effective immune protection. My laboratory and others showed that it was feasible to derive insulin-secreting cells from gastrointestinal (GI) tissues. However, it has not been possible to mass-produce islet-like organoids from human GI tissues for detailed assessment of their translational potential. In preliminary studies, we established methods to culture human gastric stem cells (hGSCs) from biopsy or autopsy samples that can be expanded to billions. We developed a scalable 2-step method to produce thousands of GINS (Gastric Insulin Secreting) organoids by transient activation of NGN3 and stable expression of PDX1 and MAFA (collectively referred to as NPM factors). GINS organoids acquired glucose-stimulated-insulin-secretion (GSIS) within 10 days, and upon transplantation, rapidly reversed diabetes in mice and maintained normoglycemia for over 3 months, with no tumor formation. Human GINS organoids thus have favorable attributes as a potential cell product for T1D treatment. GINS organoids contain 25% of cells that closely resemble pancreatic β-cells but a paucity of GCG+ and SST+ cells. Human islets have 50-75% β-cells, 25-35% α-cells, and 5% δ-cells. Both α- and δ- cells exert paracrine effects on β-cell section. In this project, we aim to develop new clonal hGSC lines and novel nanoparticle-based mRNA transduction method suitable for mass production of organoids that closely mimic human islets in cell composition and function. These studies are based on preliminary data indicating that hGSC clonal lines are markedly different, with some predominantly producing β-like or α-/δ-like cells. Their differentiated progenies can thus be combined to yield islet- like organoids. We will further study the clonal lines for chromatin features and PDX1/MAFA genomic binding to gain mechanistic insight in GINS formation. Together, these studies constitute a major step in advancing the long-term goal of developing GINS organoids for T1D treatment.

NIH Research Projects · FY 2024 · 2022-08

Project Summary Alzheimer’s disease (AD) is one of the most common forms of dementia, affecting one in ten people over the age of 65 and nearly half of people over the age of 85. AD is currently untreatable, posing a significant health concern. Many attempted treatments for AD target amyloid-beta (Ab) plaques, but these treatments have all failed in clinical trials1,2. Emerging evidence shows that tau pathology may play a causal role in the development of AD. Inflammation prompted by microglia may precede the spread of pathogenic tau3-6, and most AD risk genes are found in microglia, supporting a significant role for inflammation in disease7,8. Inflammation requires metabolic reprogramming to provide the energy and substrates needed for activation9,10, and mitochondrial dysfunction could contribute to aberrant inflammatory responses in AD11. The APOE4 risk allele along with the R47H variant of the microglial Trem2 receptor both display large effect sizes in increasing AD risk. APOE4 is found in approximately 20% of the population, whereas the R47H mutation is much rarer, representing less than 1% of the population12. The APOE3 allele is considered neutral to disease risk and is often used as a control comparison in experiments. APOE is a known ligand of the Trem2 receptor, and Trem2 activation robustly increases microglial APOE expression, as well as affecting cellular metabolism and inflammation. Activation of the microglial Trem2-APOE pathway is associated with heightened inflammation13,14. However, the mechanistic underpinnings of the pathway are not well understood, and there has been little research on the interactions between risk variants R47H and APOE4. My preliminary data indicates that R47H/+ has a remarkable differential effect on the APOE3 background compared to the APOE4 background, such that R47H with APOE3 (R47H-E3) has heightened inflammation in response to tau and increased mitochondrial respiration, but R47H with APOE4 (R47H-E4) has low inflammatory response and decreased mitochondrial function. This differential response is accompanied by enhanced AKT activation in R47H-E3 but reduced AKT activation in R47H-E4, suggesting potential mechanistic involvement in these phenotypes. I hypothesize that alterations in AKT signaling drive the differential effects of R47H on mitochondrial respiration and inflammation in the E3 vs. E4 background. In this proposal, I aim to further elucidate the interactions of R47H with different APOE genotypes to affect microglial metabolism and inflammation, both in vitro using a primary microglia model and in vivo using a tauopathy mouse model. I will then explore the potential mechanistic involvement of AKT in this pathway using AKT inhibition. These studies will provide a better understanding of the function and mechanisms of the disease-implicated Trem2-APOE pathway in microglia, providing novel targets for the treatment of AD.

NIH Research Projects · FY 2025 · 2022-08

SUMMARY This proposal seeks Dr. Angeles Duran’s salary support as a Research Specialist to support Dr. Jorge Moscat’s research program at the Weill Cornell Medicine Department of Pathology and Laboratory Medicine to study the role of the tumor microenvironment (TME) in colorectal cancer (CRC). Dissecting the role of these complex cellular interactions requires scientists with an in-depth understanding of the biology of these processes, but also with the required technical expertise in in vivo mouse models that faithfully recapitulate human disease, as well as the necessary bioinformatics tools to interrogate the TME of these models at the single-cell level. Therefore, with this Research Specialist Award, we intend to provide stable research opportunities for the exceptional scientist, Angeles Duran, to develop impactful research in this area of expertise. She has made seminal contributions in signaling, inflammation, metabolism and cancer and has a strong interdisciplinary training that will be critical for the success of the project. She will contribute to the research program focused on defining the molecular and cellular mechanisms that drives mesenchymal CRC, a desmoplastic and of poor prognosis type of cancer. With her expertise in cancer biology and her capacity to apply novel mouse models and bioinformatics approaches, she is filling a unique niche within the Moscat lab that will provide continuity, stability, and detailed scientific knowledge to achieve the aims of the NCI-funded grants. She will support this project with scientifically impactful in vivo models and bioinformatics approaches. Dr. Duran’s long-time expertise and dedication will advance our understanding of the role of TME in cancer progression to help design more effective therapies.

NIH Research Projects · FY 2026 · 2022-08

Project Summary/Abstract: The objective of this Mentored Clinical Scientist Career Development Award is to elucidate the underlying mechanisms by which gut microbes regulate hepatic gluconeogenesis and thereby coordinate host nutrient homeostasis in health and disease. Non-alcoholic fatty liver disease (NAFLD) is the most-prevalent chronic liver disease worldwide and can progress to cirrhosis and liver cancer. The absence of approved pharmaceutical treatments for NALFD identifies a significant unmet need. Whereas the gut microbiome contributes to NAFLD, the underlying mechanisms are incompletely defined. Our published and preliminary data demonstrate that gut microbes play a key role in regulating hepatic gluconeogenesis through portal vein metabolites, providing a clear rationale for this research. We propose the central hypothesis that specific biologically-active microbial metabolites are transported by the portal circulation to the liver, where they downregulate hepatic gluconeogenesis in health, and that ultra-processed western diets disrupt this pathway to contribute to the excess glucose production observed in NAFLD. Specific Aim 1 will identify the specific microbes and downstream metabolites that regulate hepatic gluconeogenesis. Mice will be colonized with defined microbial consortia and in vivo glucose production assays and in vitro primary mouse hepatocyte cultures will determine the specific microbial metabolic components that control hepatic glucose production. Mice with diet-induced hyperglycemia and NAFLD will be colonized with specific microbes or administered metabolites to restore normal hepatic gluconeogenesis. Specific Aim 2 will define the maladaptive changes in gut microbiome function that contribute to excess hepatic gluconeogenesis in human NAFLD. Donor stool from patients with NAFLD and controls will be used to create mice with humanized gut microbiomes. Portal vein serum metabolomics and microbial whole genome sequencing will be used to identify microbes and microbial-metabolites that contribute to excess hepatic gluconeogenesis in human NAFLD. This research is significant because it will identify novel mechanisms by which the microbial component of the gut-liver axis regulates hepatic gluconeogenesis in health and disease. This research project will be performed in the context of a comprehensive career development plan that will permit the investigator to acquire expertise in metabolomics, microbiome engineering, and bioinformatics analysis. The work will be conducted at Weill Cornell Medical College, which together with The Rockefeller University and Memorial Sloan Kettering Cancer Center constitutes the highly stimulating Tri-Institutional research network. Seminars and specialized coursework will augment tailored guidance from the candidate’s co-mentors, as well as from a distinguished advisory committee with complementary expertise. The candidate’s ultimate goal is to become an independent investigator whose research program integrates expertise in the gut microbiome with hepatic metabolism in order to advance the management of chronic metabolic diseases, including NAFLD.

NIH Research Projects · FY 2025 · 2022-08

Project Summary/Abstract This proposal is for a four-year research career development program, focused on the study of the microbiome’s contribution to the regulation of microglial maturation and function including experience-dependent synaptic pruning. The candidate has already been appointed an Instructor in the Department of Medicine at Weill Cornell Medical Center. The proposal is a natural extension of the candidate’s previous research into microglial-neuronal interaction, synaptic plasticity, and behavioral outcomes in mice. It outlines a plan for the candidate to achieve his goal of becoming an expert in the microbial regulation of critical central nervous system processes, extending the training of the candidate in two dimensions, which are reflected in the mentorship of Drs. Conor Liston and David Artis: 1. Identification of microbially-derived signals that alter the maturation and function of microglia, and 2. Alterations in microglial function that regulate experience-dependent synaptic refinement. The proposed experiments and multi-faceted training plan will impart the candidate with a unique combination of skills that will position him to transition into a successful independent career as a physician-scientist studying the contribution of peripheral organ system dysfunction to alterations in cognitive function and affective states. Alterations in the microbiota have been associated with multiple neuropsychiatric disorders in small-scale human correlational studies, and animal studies utilizing germ-free (GF) mice lacking a microbiota from birth, or animals rendered acutely dysbiotic by antibiotic treatment have demonstrated defects in the normal physiology of multiple CNS regions and cell populations including synapse-level changes in the context of experience. Amongst affected cell populations, the CNS tissue-resident macrophage known as microglia have been shown by us and others to be heavily altered in the absence of a normal microbiota. Given the known importance of microglia in regulating the formation, stability, and plasticity of synapses within both the developing and adult mouse brain, they likely represent an important conduit through which microbiota-derived signals regulate normal experience- dependent synaptic plasticity and ultimately animal behavior. The goal of my proposal is to investigate the role of the microbiota in modulating microglial function in the adult brain. Specifically, this proposal investigates how changes to the microbiome alter microglial-neuronal interaction by: 1. Identifying the microbially-derived small molecule signals by which the microbiome alter mouse and human microglial maturation and function in vitro; 2. Testing the role of these metabolites in regulating microglial-dependent synaptic refinement in a model of experience-dependent plasticity. Collectively, these experiments provide novel insight into the role of the microbiome and its metabolites in regulating microglial function including synaptic refinement.

NIH Research Projects · FY 2024 · 2022-08

PROJECT SUMMARY/ABSTRACT The over-arching goals of Dr, Rameau's Beeson application are (1) to develop an easy-to-use, highly accurate bedside clinical decision support tool to identify swallowing dysfunction in older adults using analysis of features of their recorded voice, cough and speech, and (2) to become a leader in the nascent field of geriatric otolaryngology with a focus on management of speech and swallowing issues in older adults with Alzheimer's disease and related dementias (AD/ADRD). Candidate: The applicant, Dr. Anaïs Rameau, is an otolaryngologist at Weill Cornell Medical College (WCMC) who has demonstrated significant research ability and clinical interest in geriatric otolaryngology, especially in the care of older adults with dysphagia. Dr. Rameau's long-term career goal is to become an independent researcher and academic leader in geriatric dysphagia. She already laid significant foundations towards this goal, developing close mentorship relationships, gaining broad research, clinical, management and leadership skills, and experience as PI on multiple institutional and foundation grants. Mentors: To achieve her objectives, Dr. Rameau has engaged an exceptional, transdisciplinary team of mentors, who are highly successful, NIH-funded investigators and well-recognized leaders and experts in their respective fields. Her mentorship team includes Dr. Mark Lachs, Co-Director of the WCMC Division of Geriatrics, Dr. Michael Stewart, Chair of the WCM Department of Otolaryngology – Head & Neck Surgery, and Dr. Sara Czaja, Director of the Center on Aging and Behavioral Research at WCM. Research: In collaboration with bio-acousticians at the Cornell Lab of Ornithology, our research, both in an excised canine model and a human pilot study, has suggested that conventional acoustic metrics of voice and cough sound differ in important ways between patients with and without aspiration risk. These characteristics may serve as biomarkers of dysphagia, and acoustic analysis of the patient's digitally recorded voice and cough has the potential to effectively differentiate between normal and abnormal swallowing. Including multiple characteristics, such as those specifically evaluating oral frailty, and combining the results may increase accuracy of swallowing dysfunction identification, especially in older adults with AD/ADRD who are more prone to silent aspiration. Adding non-linear methods and machine learning to conventional acoustic analysis may also improve accuracy. Dr. Rameau proposes to use these techniques to develop a clinical decision support tool that incorporates analysis of multiple characteristics of a patient's recorded voice and cough to determine their aspiration risk. To increase the potential for use of this tool at the bedside, she will modify it for recordings on a smartphone as part of a mobile application. Upon completion of this research, she plans to submit an R01 to prospectively examine the performance of the clinical decision support tool in a multi-site RCT in large, diverse cohort of older adults.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY The basolateral amygdala (BLA) serves as a neural hub for the integration of various inputs from across the brain to, in turn, control fear and anxiety-related behaviors and the response to chronic stress. Given this central role in neuropsychiatric disease-relevant emotional processing, neuromodulatory G protein-coupled receptors (GPCRs) that can control BLA function have been proposed as targets for the treatment of anxiety disorders and post-traumatic stress disorder. However, due to the complexity of BLA circuits and the lack of tools for spatiotemporally and genetically precise manipulation of GPCRs in vivo, it remains difficult to understand how specific receptors in defined cell types or projections mediate their effects on BLA circuit function and behavior. Here we will focus on an understanding of how metabotropic glutamate receptor 2 (mGluR2) modulates anxiety and fear-related behaviors using recently developed genetically-targeted photopharmacology in conjunction with slice electrophysiology, behavior, fiber photometry and RNA sequencing. mGluR2 is a critical presynaptic G protein-coupled receptor (GPCR) which mediates both rapid synaptic inhibition and the induction of long-term depression (LTD), although connecting these dynamic synaptic processes to behavioral modulation has been challenging. Our preliminary mapping studies using a Grm2-Cre mouse have shown that mGluR2 is enriched in projections from the ventromedial prefrontal cortex (vmPFC) and posterior insular cortex (pIC) to the BLA, motivating our comparative analysis of these two projection classes. We will define the ability of mGluR2 in each projection to control the synaptic strength of cortical connection to BLA pyramidal neurons and interneurons and use our photopharmacological toolset to link presynaptic modulation to behavioral changes across a battery of measures of avoidance to aversive stimuli and auditory fear conditioning (aim 1, aim 2). We hypothesize that depending on the nature of the aversive stimulus (spatial, somatosensory, social) either inputs from the vmPFC or pIC will play primary roles in behavioral control. In aim 3, we will use a dual optogenetic and projection-targeted RNA sequencing approach to define the synaptic and molecular adaptations that occur in each pathway in response to chronic unpredictable stress. Such analysis should inform future studies of novel projection-defined drug targets that can have desired effects on different aspects of fear and anxiety. Together this project will introduce a novel approach to mapping the synaptic and circuit mechanisms of behavioral control by neuromodulatory GPCRs while providing new insights into neuromodulatory control of the BLA by presynaptic mGluR2.

NIH Research Projects · FY 2026 · 2022-08

Overall Abstract: We propose a Tri-Institutional Tuberculosis (TB) Research Advancement Center (TRAC) at Weill Cornell Medicine, Memorial Sloan-Kettering Cancer Center and Rockefeller University. The three institutions are adjacent to each other on a Tri-Institutional (Tri-I) campus in New York City. The purpose of the proposed Tri-I TRAC is to pool the expertise and resources of an outstanding team of 20 senior TB investigators at the three institutions to expand the number of investigators in the field of TB research and to promote innovative multidisciplinary TB research. The senior investigators have broad expertise spanning biochemistry, basic microbiology, mycobacterial genetics, human genetics and immunology, drug discovery, clinical trials, and implementation science. A major focus will be supporting New Investigators (NIs), who we define as senior post-doctoral fellows or junior faculty members who seek an academic career and have not yet received an R01. We also will recruit New to TB (N2TB) Investigators, who are R01 experienced investigators in other scientific disciplines who bring their expertise to study TB. The TRAC will have four Cores. The Administrative Core will provide leadership, financial oversight, communication, and program evaluation. A Developmental Core will fund 4-6 Developmental Project Awards annually of $50,000 each to support NIs and N2TB investigators. Institutional support from Weill Cornell Medicine will fund two of these awards each year. The Clinical Core will build upon long-standing clinical trials collaborations. The Basic and Clinical Science Cores will provide NI and N2TB recipients of Developmental Project Awards mentorship, technical expertise, and scientific resources unique to TB research including access to TB animal models, genetically modified mycobacterial libraries, and biobanked clinical samples. The Basic and Clinical Science Cores will also facilitate sharing of technology and resources between senior TB investigators in order to initiate new lines of collaborative translational TB research. Other activities including an annual symposium, a technology workshop, and travel to TB clinical sites will bolster the pipeline of new TB investigators and generate an environment conducive to multidisciplinary collaboration. There will be no overlap with other NIH research grants, centers, or institutional cores. The TRAC will leverage these existing resources and synergistically expand the number of TB investigators and foster new innovative lines of collaboration. Our goal over 5 years is to have 25 NIs successfully compete for a TB related NIH grants and transition to independence and to attract at least 5 N2TB investigators to TB science. We will also initiate new lines of collaborative translational research to address the five NIAID priorities in TB science with the ultimate goal of improving TB diagnostics, prevention, and treatment and ending morbidity and mortality from TB world-wide.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY The 5-year survival is the lowest for cancers of the pancreas (<10%) among all cancers and the incidence of pancreatic cancer continues to increase. The most common type of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC), followed by pancreatic neuroendocrine tumor (PNET). Pancreatic cancer is usually deadly due to metastatic dissemination and insufficient therapeutics. Factors driving metastasis of pancreatic cancer remains largely unclear. There is an urgent need to understand the biology of pancreatic cancer metastasis and develop new therapeutic strategies. We were the first to report that Receptor for hyaluronan-mediated motility isoform B (RHAMMB), but not the full length RHAMMA, promotes metastasis of PNET. We found that among different splice isoforms, RHAMMB was significantly upregulated in human PDAC, and that higher RHAMMB predicted poorer survival of PDAC. However, whether RHAMMB promotes PDAC metastasis is still unknown and will be determined in this proposal work. Our preliminary data showed that RHAMMB overexpression induced RhoA signaling, migration, 3D spheroid invasion, and lipid droplet (LD) biogenesis in both PDAC and PNET cell lines, while RHAMMB knockdown or pharmacological inhibition of RhoA signaling caused opposite effects. We hypothesis that RHAMMB promotes pancreatic cancer metastasis through RhoA signaling/LD biogenesis and this RHAMMB /RhoA/LD axis represents a novel therapeutic target. To test this hypothesis, we will use multiple experimental systems, including cell lines, orthotopic tumor xenograft, genetically engineered mouse models, and patient-derived xenografts. The findings will be cross- examined. The success of this proposed study will establish the mechanisms by which RHAMMB promotes pancreatic cancer metastasis and translated into new therapeutic approaches for treatment of this devastating cancer.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY Cells must organize their contents spatially and temporally. The microtubule cytoskeleton and its associated molecular motors, dynein and kinesin, are the main system used by cells to move cargos, ranging from protein assemblies to entire organelles, including the nucleus. Dynein (~0.5MDa) is a member of the AAA+ family. Active dynein complexes, the only ones capable of transporting cargo, are ~4MDa and consist of two dynein dimers bound to the ~1.0MDa dynactin complex, and an adaptor protein that links them to cargo. Lis1, another essential regulator of dynein, is necessary for their formation. Previously, we showed how Lis1 regulates dynein’s mechanochemistry. Here, we will focus on understanding how the 90kDa Lis1 dimer helps activate and assemble the 4MDa transport complex. Chromatin, with the nucleosome as its basic unit, provides both a solution to the problem of packaging the genome, and a tool to regulate access to it. Among the factors involved in controlling chromatin dynamics are ATP-dependent nucleosome remodelers, which couple ATP hydrolysis to the non-covalent modification of nucleosome structure. Both remodelers and the modifications they catalyze are very diverse, even though all remodelers use the same mechanism, and conserved catalytic core, to break histone-DNA contacts. I am interested in how this common underlying mechanism is modulated to result in the wide array of outcomes of which remodelers are capable. Previously, we focused on model systems representing two of the four families of “canonical” remodelers. Here, we will focus on Rad26 (the yeast ortholog of CSB), an “orphan” remodeler that uses its remodeling-like activity to act on RNA Pol II to help it overcome obstacles or initiate Transcription Coupled DNA Repair (TCR) when the obstacle is a DNA lesion. We aim to understand how Rad26 helps RNA Pol II recognize a lesion from other obstacles and recruit downstream repair factors. We take a structure-guided approach to addressing fundamental mechanistic questions, with cryo- electron microscopy (cryo-EM) as our main technique. We use the structures we generate to formulate mechanistic hypotheses that can be tested, either in house or in collaboration, using a range of techniques including single-molecule biophysics, biochemistry, and cell biology. We have made major contributions to our understanding of the mechanochemical cycle of dynein and its regulation, and to the functional diversity and regulation of nucleosome remodelers. We are also interested in developing tools to solve challenges we encounter along the cryo-EM pipeline and have made important contributions to cryo-EM grid preparation and data processing in the cloud. We are currently developing approaches to increase the efficiency of data collection.

NIH Research Projects · FY 2024 · 2022-08

PROJECT SUMMARY/ABSTRACT Dr. Sri Lekha Tummalapalli is a nephrologist and health services researcher whose long-term goal is to become a leading national expert studying healthcare policies and delivery system interventions to optimize the quality and equity of care for patients with kidney disease. If awarded, this K08 mentored career development award will provide Dr. Tummalapalli with the necessary protected time and training to develop into an independent physician-investigator. Dr. Tummalapalli will be mentored primarily by Dr. Lawrence Casalino, the Livingston Farrand Professor of Population Health Sciences and an expert in alternative payment models and the organization of the healthcare delivery system. Under the guidance of a multidisciplinary mentorship team, Dr. Tummalapalli will engage in a rigorous training and career development plan in the following 3 areas: (1) qualitative research for evaluating healthcare delivery systems (Dr. Lawrence Casalino), (2) quasi-experimental research designs (Dr. Yuhua Bao) and advanced epidemiologic methods (Dr. Michelle Estrella), and (3) the use of large claims databases to examine quality and equity of care (Dr. Sumit Mohan, Dr. Said Ibrahim). Dr. Tummalapalli will conduct her research and training in the outstanding environment of Weill Cornell Medicine’s Department of Population Health Sciences, surrounded by internationally recognized experts in health services research, health economics, epidemiology, and biostatistics. End-stage renal disease (ESRD) requiring dialysis causes an enormous clinical and economic burden, affecting over 550,000 Americans and costing ~$49 billion annually. Home dialysis is a preferred treatment for ESRD, offering better quality of life than in-center hemodialysis at reduced cost. Yet, uptake of home dialysis is low and there are stark racial/ethnic and socioeconomic disparities in uptake. There is limited understanding of organizational structures and processes that lead to higher home dialysis uptake and reduced disparities. This proposal applies rigorous health services research techniques to examine the ESRD Treatment Choices (ETC) Model, a randomized alternative payment model that incentivizes home dialysis uptake. Leveraging qualitative interviews and national large claims databases, this research aims to (1) Identify changes in structures and processes of care in response to the ETC Model; (2) Identify facility and practice structures and processes of care associated with home dialysis uptake; and (3) Assess the impact of the ETC Model on socioeconomic and racial/ethnic disparities in home dialysis uptake. The knowledge gained in this project is highly likely to influence healthcare policy and the delivery of kidney disease care on the national scale by revealing effective structures of care, processes of care, and policy levers that increase home dialysis uptake and reduce disparities. This work will equip Dr. Tummalapalli with the skills and research experience to become one of the few independent physician-investigators studying nephrology payment and delivery system reform.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY/ABSTRACT Although modern therapies have dramatically improved the outlooks for people living with HIV, they are unable to cure infection, leaving these individuals burdened by a lifelong commitment to antiretroviral (ARV) medication. For any given individual, maintaining lifelong adherence to medication can present substantial challenges. Moreover, many people do not have access to these expensive medications - in particular those living in resource-limited settings. It would therefore be of tremendous value to develop novel therapies that can either cure HIV infection or drive it into remission (a state where levels of virus remain low or undetectable even when one stops taking ARV medication). One approach to achieving either a cure or remission is to reactivate latent (hidden) ‘reservoirs’ of virus and harness the immune system to reduce or eliminate these reservoirs. These ‘kick & kill’ approaches often focus on cytotoxic T-cells (CTL), which are an arm of the immune system specialized in eliminating virus-infected cells. While the ‘kick & kill’ strategy has shown promise in in vitro models of latency, it has not yet been effective in clinical trials. In recent work, we have uncovered an additional barrier to eliminating viral reservoirs by showing that HIV-infected cells are intrinsically resistant to CTL - even when they are forced to show virus to the immune system by latency reversing agents (LRAs). Although this idea of intrinsic resistance to CTL has not been widely considered in the context of HIV, it is well known as a factor that limits therapeutic efficacy in cancer. In this grant application we propose to leverage cutting edge technologies to identify novel mechanisms by which target cells resist elimination by CTL. These approaches are expected to yield a large number of ‘hits’, for which we will perform high-resolution mechanistic characterizations. We will then study samples from people living with HIV to determine which of these mechanisms of resistance play roles in HIV persistence in vivo. Finally, we will directly test whether therapies targeting this resistance can allow CTL to kill these ex vivo reservoir-harboring cells. We expect that the outcome of our study will be the identification of novel targets for the development of therapies aimed at curing HIV infection or enabling remission. More broadly, we anticipate that the mechanisms identified here will provide fundamental insights into the biology of CTL with implications for cancer & other conditions.

NIH Research Projects · FY 2025 · 2022-08

SUMMARY Precise and dynamic control of gene expression is a balancing act between production and destruction. Although noncoding RNAs are critical regulators of gene expression with important roles in development and disease, our understanding of their destruction is still in its infancy. One of the reasons for this gap in knowledge is that some noncoding RNAs, like microRNAs and circular RNAs, are resistant to the known pathways that destroy protein- coding RNAs. Here I present my plan to identify how these two types of noncoding RNA are destroyed. MicroRNAs (miRNAs) are protected from degradation by their effector protein Argonaute. One way to degrade miRNAs is through target-directed miRNA degradation (TDMD), which occurs when a highly complementary viral or artificial RNA interacts with the miRNA. My postdoctoral work identified two of the first examples of endogenous targets that induce miRNA degradation, which also led to our discovery of an E3 ubiquitin ligase that mediates TDMD and the identification of 48 additional miRNAs (likely an underestimate) subject to TDMD. Our working model now is that the binding of highly complementary targets to the Argonaute–miRNA complex leads to recruitment of the E3 ligase, ubiquitination and proteosomal degradation of Argonaute, and release and degradation of the miRNA. With the discovery of TDMD effector proteins and the broad influence of TDMD on miRNA stability, a major gap is identifying the target RNAs that induce TDMD. A related problem is understanding why some targets are better than others. We will address these gaps by answering two questions: 1) Which endogenous RNAs induce miRNA degradation? 2) What are the pairing rules and cis-acting elements that promote TDMD? To do so, we will use transgenic mice, engineered cell lines, genome-wide approaches, and classic molecular biology techniques. Our second area of research is understanding how circular RNAs (circRNA) are degraded. The poster child of post-transcriptional circRNA regulation is Cdr1as, a conserved circRNA that is highly expressed in neurons and limits spontaneous synaptic vesicle release. Cdr1as contains a single near-perfect binding site that can be sliced by Ago2-loaded miR-671 and >70 seed sites for miR-7. Previously, I showed that Cdr1as can be regulated by the independent and cooperative actions of miR-671 and miR-7. How miR-7 induces destruction of Cdr1as is unclear as circRNAs should be resistant to miRNA-mediated deadenylation and decapping. Here, we will answer two questions: 1) How is Cdr1as degraded? 2) How are other unstable circRNAs degraded? The outcomes of our research will be the identification and improved understanding of dedicated pathways for degrading noncoding RNAs. These pathways have potential for broad impact as they are likely employed in diverse cell types and organisms and in response to a variety of stimuli.

NIH Research Projects · FY 2025 · 2022-07

ABSTRACT: Tuberculosis (TB) is a leading cause of maternal mortality worldwide, especially among women with HIV. Of the 1.3 million pregnant women living with HIV, 85% use combined anti-retroviral therapy (cART), which should significantly decrease their risk of TB. Yet pregnant women with well-controlled HIV still have a 2- 3 times greater incidence of TB than pregnant women without HIV. There is an urgent need to identify the immune impairment responsible for the increased risk of TB in these women. Gestational diabetes (GDM)– which affects 16% of pregnancies globally, and up to 40% of pregnancies in TB- endemic India–likely contributes to the increased risk of TB in pregnancy, especially for women with HIV. We base this hypothesis on the known association between HIV, diabetes (DM) and TB in non-pregnant populations and our preliminary data on HIV, GDM and TB in pregnancy. We found HIV increases GDM prevalence, and GDM impairs the host immune response to M. tuberculosis (Mtb). In partnership with BJ Government Medical College in India (BJGMC), we propose a longitudinal study to fully describe HIV’s effect on GDM risk, and GDM’s effect on the immune response to MTB in pregnancy. BJGMC has conducted NIH clinical research for over 20 years with expertise in HIV and TB in pregnancy. We will enroll 2nd trimester women from the antenatal clinic at BJGMC in Pune, India, with additional visits at 3rd trimester, delivery, 6 weeks, 6 months, and 12 months postpartum. Women will be screened for GDM at enrollment with an oral glucose tolerance test. A subset comprised of all women diagnosed with GDM, and a matched number of women without GDM, will have additional blood and placenta samples collected for flow cytometry and cytokine studies. Enrolled women will be screened for active TB at each visit. Our specific aims are to: 1. Determine the effect of chronic HIV-induced inflammation on glucose metabolism during pregnancy and GDM prevalence. We hypothesize that women with HIV will have double the prevalence of GDM compared to women without HIV. We further hypothesize that elevated plasma TNF-a levels and decreased placental GLUT4 will be associated with GDM in women with HIV. 2. Determine the effect of GDM on the CD4+ and CD8+ T-cell response to Mtb and incident TB. We hypothesize that women with GDM will have a significantly higher incidence of active TB than women without GDM. We hypothesize that women with GDM will have suppressed Mtb-specific memory CD4+ and CD8+ T-cell function, with a decreased ability to activate macrophages, compared to women without GDM. This will be the first study to determine if the pathophysiology of GDM is different in women with HIV and to delineate the TB-specific clinical and immune sequelae of GDM for pregnant women. The results of this study will identify pregnant women at the highest risk for active TB, improve targeted GDM screening and TB prevention and potentially identify novel targets for GDM prevention and treatment.

NIH Research Projects · FY 2024 · 2022-07

PROJECT SUMMARY/ABSTRACT Each year there are 1.5 million skilled nursing facility (SNF) stays for post-acute care among Medicare fee-for- service beneficiaries with Alzheimer’s disease or related dementias (ADRD), representing over 60% of beneficiaries who receive care in SNFs. ADRD patients often face unique challenges, including an inability to describe their diagnoses and symptoms or to participate in care planning, which may contribute to a higher likelihood of SNF use following hospitalization and poor outcomes. Following hospitalization, ADRD patients are four times more likely to be discharged to a SNF compared to patients without ADRD. SNF patients with ADRD have worse outcomes than other SNF patients, including higher re-hospitalization rates, longer SNF stays, and a lower likelihood of being discharged back to the community. Insufficient information-sharing capabilities between the SNF, the hospital, and other providers are thought to contribute to the frequency of these events. SNFs were not eligible to receive incentive payments through the Medicare and Medicaid EHR Incentive Programs that led to widespread adoption of health information technology among hospitals and physicians. HIE participation is now being actively promoted by policymakers as means to improve the quality of care in SNFs. However, there is no evidence of its ability to do so for SNF patients with ADRD. This is likely due to a lack of available data on SNF participation in HIE that includes key information, such as dates of HIE participation. In this project, a novel data source will be used that includes dates of HIE participation for all SNFs participating in HIE in New York State over an eight-year period (2012-2019). These data will be merged with a 100% sample of Medicare claims for all beneficiaries in the state who received care in SNFs during the study period to examine the relationship between SNF participation in HIE and the quality and the cost of care for patients with ADRD. The relationship between SNF participation in HIE and the quality of care will also be examined specifically for dual-eligibles and racial minorities with ADRD, who are more likely to receive fragmented care of lower quality compared to other Medicare beneficiaries. Our research design utilizes a difference-in-differences framework using the differential timing of SNF participation in HIE and incorporates an instrumental variable based on a patient’s residence and the differential distance between the nearest SNF with HIE and the nearest SNF without HIE. The robust study design will allow estimation strongly indicative of causation. The results of the proposed project will be important regardless of our findings. It will be the first investigation of whether HIE participation among SNFs (1) improves the quality of care, (2) lowers health care costs, or (3) reduces income and racial disparities in the quality of care for ADRD patients. The information will be useful to policymakers, SNF and hospital executives, physicians, patients, and leaders of health information exchanges.

NIH Research Projects · FY 2025 · 2022-07

Project Summary/Abstract The structural maintenance of chromosomes (Smc) 5/6 complex plays a critical role in tumor suppression and the repression of tumor-causing viruses, such as the hepatitis B virus. Smc5/6 exerts these clinical functions by promoting faithful genome replication, coordinating DNA repair, and silencing extra-chromosomal DNA. However, there is little understanding of how Smc5/6 operates as a molecular machine, hindering our ability to intervene in Smc5/6’s health-related functions. Our central hypothesis is that Smc5/6 operates as a dynamic molecular machine that compacts DNA, intrinsically binds to DNA fork junctions, and co-localizes with replication factors. The long-term goal of this research is to understand how defects in Smc5/6 promote genome instability and malignant transformation. This project’s immediate objective is to elucidate the biophysical properties of the Smc5/6 complex by utilizing correlative single-molecule fluorescence and force microscopy, which combines optical tweezers, automated microfluidics, and multi-color confocal microscopy. In Specific Aim 1, Smc5/6’s DNA compaction abilities will be assayed on individual DNA tethers. The effect of the subunits of Smc5/6 and ATP will be systematically tested. The outcome of this work will define the role of each of these components on Smc5/6’s DNA compaction behavior. In Specific Aim 2, the binding behavior and dynamic movement of fluorescently-labeled Smc5/6 will be monitored on double-stranded DNA, single-stranded DNA, and fork junctions in real time. In Specific Aim 3, Smc5/6’s interactions with replication factors will be defined by a first-of-its-kind in vitro reconstitution of the eukaryotic replisome. Overall, this project will: (1) consolidate our understanding of Smc5/6 at the molecular level; (2) yield important insights into how eukaryotes maintain genome integrity and suppress tumors; and (3) potentiate new strategies to modulate Smc5/6’s physiological functions as a tumor suppressor and host restriction factor. Dr. Xiaolan Zhao, an expert on Smc5/6 biology who has a proven track-record for training successful scientists, and Dr. Shixin Liu, an expert on single-molecule technology who practices active mentorship, are co-sponsoring this proposal. The research efforts will take place at the Rockefeller University within the deeply supportive Tri-Institutional MD- PhD Program. This proposal and fellowship is an important career milestone for dual-degree students seeking to become independent investigators.

NIH Research Projects · FY 2024 · 2022-07

PROJECT SUMMARY Complex structural variants (SVs) are a class of mutations consisting of clustered DNA copy number changes and rearrangements. These alterations can produce driver mutations in cancer but have been underexplored due to the analytical limitations of bulk short read sequencing. There is an urgent need for new computational tools that can apply long-range and single cell genomic profiles to structural variant analysis. Genome graphs are a computational framework that can be extended to these new data modalities to study the allelic structure and evolution of complex SVs. Recent genome graph analysis of pan-cancer whole genomes by our lab identified a novel complex structural variant pattern termed pyrgo. Pyrgo consist of “towers” of clustered tandem duplications and are enriched in prostate and ovarian adenocarcinomas. In Aim 1, we will construct haplotype graphs to characterize the allelic structure of pyrgo. Haplotype graphs represent allele-specific genomic segment and junction copy numbers and will be inferred from long range profiling data. Using these graphs, we will characterize the parental and somatic allele structure of pyrgo duplications in pan-cancer genomes. We will identify associations between allelic structure and cell-of-origin, prior systemic therapy, and genomic features such as chromatin loops and replication timing. In Aim 2, we will construct single cell genome graphs that recapitulate the evolution of pyrgo. Single cell genome graphs are a set of phylogenetically linked genome graphs representing the structural variants present in individual cells, along with the ancestral subclone in which each aberrant genomic junction first arose. These graphs will be inferred from single cell whole genome profiles. We will use single cell genome graphs to model the acquisition of tandem duplications comprising pyrgo during tumor evolution in ovarian adenocarcinoma tissue samples.

NIH Research Projects · FY 2025 · 2022-07

ABSTRACT: The goals of this K24 proposal are to train clinical investigators in the conduct of patient-oriented cardiovascular disease (CVD) research primarily in Haiti, with a new project in Tanzania and to conduct a new study on environmental lead exposure and CVD risk factors in Haiti (Aim 1). The training also leverages four currently funded CVD research projects in Haiti (Aims 2-5), and a funded CVD research project in Tanzania (Aim 6). United States trainees will spend ~50-60% of their time at international research sites in Haiti and Tanzania, which have onsite Weill Cornell faculty, long-standing international collaborators, and outstanding environments for research training. The common theme of the projects is patient-oriented CVD research in the areas of clinical epidemiology, clinical trials, CVD-infectious diseases, and implementation science. The projects include: 1. Environmental lead exposure and CVD risk factors in Haiti 2. Clinical epidemiology of CVD risk factors, diseases, and poverty-related social determinants in Haiti 3. Randomized clinical trial of early hypertension treatment among persons living with HIV 4. COVID-19 and cardiac dysfunction 5. Implementation of hypertensive screening and management 6. Heart failure in Tanzania The focus of research training will be on postdoctoral clinical investigators who have completed their advanced degree training. Dr. McNairy has an impeccable history of excellence in research mentorship and serves in leadership roles in the Weill Cornell Global Health Research Fellowship and the Weill Cornell Women in Global Health Research Initiative. Trainees will be mentored by Dr. McNairy and will participate in research projects in Haiti (Aims 1-5) and Tanzania (Aim 6). These six projects have both clinical and laboratory aspects and offer trainees a broad research experience. Trainees learn through the conduct of their mentored research project and the opportunity to interact with colleagues working on studies other than their own. The K24 award will allow Dr. McNairy to decrease her administrative and clinical responsibilities and commit 50% effort to CVD- related research and mentorship of US trainees. Her long-term goal is to build a world-class CVD global health research and training program to improve CVD-related health outcomes among the world's poorest populations.