Weill Medical Coll Of Cornell Univ

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY Serious mental illnesses (SMIs) including schizophrenia, bipolar disorder, and major depressive disorder disproportionately affect people who are dually eligible for Medicare and Medicaid (“dual eligibles”). The US population with SMI experiences one of the largest health disparities in the US, dying 10-20 years earlier than the overall population. Widespread undertreatment of SMI and comorbid physical health conditions, intertwined with social and economic risks (e.g., low-income, inadequate housing), is a key driver of excess mortality in SMI. Dual eligibles with SMI, with their high concentration of low-income and disability, are a particularly high- need subgroup of the overall US population with SMI. Dual Medicare-Medicaid coverage aims to facilitate access to the array of specialty mental health, general medical, and long-term services and supports (LTSS, like home-based personal care) needed by people with SMI but has fallen short of this goal. Medicare covers all general medical and most specialty mental health outpatient care, inpatient care, and prescription drugs. Medicaid covers intensive behavioral health services excluded from Medicare, like psychiatric rehabilitation and crisis response services, as well as additional inpatient psychiatric days beyond Medicare’s 190-day lifetime limit and some psychotropic medications not covered by Medicare. Medicaid also covers LTSS. Medicare and Medicaid have been poorly integrated to serve dual eligibles, leading to conflicting financial incentives, fragmented care delivery, and complicated administrative processes. Together, these issues create inefficiencies and care patterns that frequently result in sub-optimal care and poor health outcomes among dual eligibles with SMI. Integrated dual-eligible special needs plans (integrated D-SNPs) are a type of Medicare Advantage (MA) plan that contracts with state Medicaid agencies to cover some or all Medicaid services, coordinate Medicare and Medicaid benefits, and streamline administrative processes for dual eligibles. Without integration, Medicare and Medicaid each have a financial incentive to shift costs to the other program, affecting care delivery in ways that may not benefit patients. Integrated D-SNPs aim to address these issues by better aligning financial incentives toward “whole person” care consistent with clinical guidelines and patient preferences. This study aims to fill this gap using novel linked data capturing the entirety of Medicare and Medicaid services for 100% of dual eligibles with SMI from 2018-2027. We will use a concurrent- embedded mixed-methods design integrating a quantitative trial emulation approach with difference-in- differences (Aim 1) and survival (Aim 2) analyses with qualitative study of D-SNP implementation (Aim 3). Aims 1-2 will assess how integrated D-SNP enrollment influences care utilization and quality indicators (Aim 1) and mortality (Aim 2) among dual eligibles with SMI. Aim 3 will characterize integrated D-SNP implementation for dual eligibles with SMI with the goal of identifying promising practices and areas for improvement.

NIH Research Projects · FY 2026 · 2024-12

Project Abstract Atrial natriuretic peptide (ANP) plays a pivotal role in cardiovascular homeostasis, produced by cardiomyocytes as a response to conditions like hypervolemia and hypertension. Its wide array of beneficial effects, including vasodilation, increased natriuresis, diuresis, and its anti-fibrotic and anti-hypertrophic actions within the heart, underscore its physiological importance. These effects are mediated through the atrial natriuretic peptide receptor (ANPR), also known as GC-A. This receptor uniquely integrates the recognition of peptide hormones and the generation of the second messenger cGMP within a single polypeptide chain. The deletion of either ANP or GC-A genes in mice results in elevated blood pressure and a cascade of renal, vascular, and cardiac dysfunctions, culminating in hypertensive heart disease. These findings, corroborated by both mouse genetic studies and the clinical utility of natriuretic peptides, highlight the critical regulatory role of ANP in maintaining cardiovascular equilibrium. Despite this, a comprehensive understanding of the structural mechanisms governing GC-A regulation remains elusive. This proposal is structured around three primary objectives, each aimed at unraveling different aspects of GC-A's structural and functional regulation. Aim 1: Structural basis of GC-A activation by ANP. We intend to delineate the structural changes occurring within GC-A upon ANP binding. This involves elucidating how ANP interaction with the extracellular domain triggers conformational adjustments leading to cGMP production. Aim 2: Regulation by the kinase-homology domain (KHD). The KHD of GC-A is implicated in receptor activity regulation, yet its precise functional role remains to be defined. This aim focuses on understanding how ATP binding to the KHD influences GC-A's activation by ANP. Through structural, biochemical, and functional studies, we will explore the KHD's contribution to receptor regulation and its impact on the receptor's overall activity. Aim 3: Mechanism of cyclase catalytic activity regulation. Despite GC-A's homodimeric structure, suggesting the presence of two catalytic sites, there is ongoing debate about their functional status during receptor activation. This aim seeks to clarify whether one or both catalytic sites are operational and to understand the conformational dynamics that enable GTP conversion to cGMP. Our proposed research is poised to significantly advance our understanding of GC-A's structure-function relationship and its regulatory mechanisms. The implications of this work extend beyond basic science, offering potential strategies for the development of targeted therapeutic interventions to modulate GC-A activity in cardiovascular diseases.

NIH Research Projects · FY 2025 · 2024-12

SUMMARY FOXP1 syndrome (FOXP1S) is a rare neurodevelopmental disorder causing severe language impairment, motor delays, visual-motor integration deficits, complex psychiatric presentations, repetitive behaviors, sensory impairment, and Autism symptoms. The major pathogenicity mechanism is haploinsufficiency and most identified mutations lie within the DNA binding domain resulting in loss of transcriptional repressor activity. However, the direct binding targets of FOXP1 in neural cells are yet to be elucidated. Our goal is to further our understanding of the disease mechanisms underpinning FOXP1S by determining the transcriptional networks regulated by FOXP1 in human cortical neural progenitor cells (NPCs) and neurons. In other systems, Foxp1 regulates cell cycle dynamics and differentiation by influencing glucose homeostasis, metabolism, angiogenesis, and response to hypoxia. FOXP1 has been shown to contribute to multiple cancers and has been identified as a druggable target as well as a prognostic biomarker. During mouse and human cortical development, Foxp1 is expressed by NPCs and neurons and several studies have sought to determine its role in these different cell populations. In NPCs, Foxp1 promotes symmetric divisions, promoting self-renewal and the generation of early born neurons. In neurons, Foxp1 has been shown to play roles in neuronal differentiation, migration, and morphology. Whilst it has been classified as a transcriptional repressor, evidence supports a role for Foxp1 as a transcriptional activator during brain development. Given its expression in these two distinct cell populations, and our long-term aim to develop an in vitro model of FOXP1S it is important to determine the cell-type specific targets of human FOXP1. Our specific aims are to 1) identify the direct binding targets of FOXP1 in human cortical neural progenitors and neurons and 2) determine the transcriptional changes of direct targets in FOXP1 deficient human cortical NPCs and neurons. Using wildtype and FOXP1 homozygous mutant human induced pluripotent stem cells (iPSCs) we will generate cortical NPCs and neurons using the Dual SMAD inhibition directed differentiation methods. For Aim 1, using CUT&RUN followed by DNA sequencing, we will identify FOXP1 binding motifs in NPCs and neurons, using FOXP1-/- cells to distinguish genuine peaks from background noise. For Aim 2, we will perform bulk RNA Sequencing with wildtype and FOXP1-/- iPSC-derived NPCs and neurons to identify the transcriptional changes of direct target genes (identified in Aim 1) in the absence of FOXP1. This will enable us to determine whether FOXP1 acts as a transcriptional repressor or activator. The experiments outlined in this proposal will enable us to address the fundamental role of FOXP1 in cortical development, and place FOXP1 within transcriptional networks that will inform future studies aimed at developing a 3D in vitro model of the rare disease FOXP1S and identifying therapeutic targets.

NIH Research Projects · FY 2026 · 2024-12

ABSTRACT Parkinson's Disease (PD) is the second most prevalent neurodegenerative disorder all over the world. It is estimated that PD affects 2-3% of people older than 65 years. The underlying etiology and pathophysiology of PD remain unclear to date. Furthermore, PD patients show great heterogeneity in disease progression throughout the PD course, which is a critical factor that hinders therapeutic development. This creates challenges in finding effective disease-modifying treatment or prevention strategies. To overcome the challenges, massive resources for PD study have been built up and become available for research, including clinical, multi-omics, and neuroimaging data generated from well-designed research initiatives such as the Parkinson's Progression Markers Initiative (PPMI) and the Parkinson Disease Biomarkers Program (PDBP); general data sources in biology such as protein-protein interactome network data and functional genomic data; a comprehensive biomedical knowledge graph (BKG) we built; and continuously increasing volume of real-world patient data (RWD). Integrative analysis of these massive and heterogeneous data poses considerable challenges to conventional computational approaches for deriving valuable and reliable insights. Despite the numerous efforts to develop novel machine learning (ML) algorithms for analyzing these data, they typically focused on one or a few data types. Therefore, there is a critical need to develop ML methods to perform integrative and effective analyses of heterogeneous PD data sources to derive comprehensive insights. This project aims to build such a pipeline with three specific aims. Aim 1 identifies progression subtypes of PD through integrative modeling of longitudinal clinical, transcriptomic, and neuroimaging data of participants in the PPMI and PDBP cohorts. Aim 2 identifies gene modules that govern the differential PD progression through integrative analysis of multi-omics data with network medicine and ML. Aim 3 evaluates and validates the gene modules as drug targets through in-silico drug repurposing with multi-omics, BKG we built, and real-world patient data, respectively. In sum, this pipeline will perform integrative analysis on the longitudinal clinical data, transcriptomics data, and neuroimaging data, as well as whole-genome/exome sequencing data from the PPMI and PDBP cohorts, publicly available human interactome data, functional genomic data, drug-perturbation multi-omics data, our BKG, and the real- world EHR data from the INSIGHT network (covering ~12 million patients across New York City's Five health systems and the greater metropolitan area), the Cleveland CIinic EHR database (covering ~11 million patients extracted from IBM Explorys), and the Temple Health EHR (covering ~1.2 million patients).

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY/ABSTRACT Aggregation of α-Synuclein (αSyn) in brain Lewy bodies (LB) is a key pathological feature in Parkinson’s dis- ease (PD) and Alzheimer’s disease related dementias (ADRD) including Lewy body dementia (LBD). The neu- rodegeneration that leads to PD and LBD precedes diagnosis by up to a decade or more, with constipation being one of the earliest symptoms. LBs are found also in the enteric nervous system, which, unlike the brain, is readily accessible through routine screening colonoscopy. Yet, the initial events leading to αSyn aggregation remain unclear. While no single biomarker is sufficiently specific so far for routine use in the diagnostic or prognostic disease evaluation, αSyn has emerged as a leading therapeutic target because it is a central player in PD and ADRDs. αSyn binding to synaptic vesicle membranes defines its physiological and pathological roles. We found that a reduction in synaptic vesicle binding in the brain is predictive of αSyn aggregation. Yet, a detailed biochemical analysis of αSyn membrane binding in the gut has never been done. The objective in this application is to determine changes in synaptic vesicle-binding of αSyn in neurons of the ENS and the brain. The central hypothesis is that changes in synaptic vesicle-binding of αSyn can serve as an early bi- omarker of PD and ADRD such as LBD. This hypothesis will be tested in two specific aims: 1) Identify the GI area with the most prominent changes in synaptic vesicle-binding of αSyn; 2) Establish a timeline of changes in synaptic vesicle-binding of αSyn. Under the first aim, four gut areas of 10-month-old αSynBAC mice, a mild synucleinopathy model, and fresh biopsies taken from similar areas in humans during routine screening colon- oscopy will be analyzed by subcellular fractionation and quantitative immunoblotting, and immunohistochemis- try. Under the second aim, motor and GI function will be assessed in αSynBAC mice at weekly intervals from 1 month of age (before onset of symptoms) and 3 months of age (when symptoms are present). Changes will be correlated with total and membrane-bound levels of αSyn in the brain and gut of these mice, and with changes in neuron density, synapse density and gliosis. Same readouts will be applied to gut biopsies from subjects with severe and mild PD and subjects at risk for developing PD. This study is expected to show a reduction in synaptic vesicle-binding of αSyn as a function of disease severity in the gut of human subjects and our αSyn- BAC mice, and that this reduction can be utilized as an early prodromal disease biomarker. This research is in- novative because it represents the first biochemical assessment of αSyn in the neurons of the gut and because of our use of fresh biopsies taken during routine cancer screening colonoscopies, enabling biochemical frac- tionation. This work is significant because it will lead to a better understanding of pathogenic changes in αSyn, may provide a better understanding of neuronal vulnerability in the gut and brain, and may lead to the devel- opment of a new biomarker for PD and ADRDs/LBD, targeting prodromal disease.

NIH Research Projects · FY 2026 · 2024-12

Diabetes and diabetes-related complications are disproportionately more prevalent among Hispanic men. The Diabetes Prevention Program (DPP) is an intensive lifestyle intervention that effectively reduces the risk of diabetes; however, Hispanic men are relatively underrepresented in the program and less likely to remain engaged in it, which decreases the likelihood of reaching the program’s 5% weight loss goal. Federally Qualified Health Centers (FQHCs) serve many Hispanic adults but have been understudied as settings to test implementation strategies to potentially address health disparities experienced by Hispanic men with diabetes. The proposed K23 career development award will equip Dr. Christopher J. Gonzalez with scholarly training and practical experience as he becomes an independent clinician-investigator conducting implementation trials that reduce health disparities faced by Hispanic men with diabetes. It will enable him to develop, implement, and evaluate FUERTE (Federally qUalified health centers Engaging Hispanic men at Risk for diabeTEs), a multi-component implementation strategy for FQHCs to facilitate referrals of Hispanic men to the DPP and to support their continued engagement in the program. FUERTE is anticipated to include i) information sessions for providers, ii) direct outreach to DPP-eligible Hispanic men, and iii) tailored content, delivered through WhatsApp, meant to increase the DPP’s relevance and acceptability to Hispanic men enrolled in the program, while encouraging additional peer support. First, (Aim 1) qualitative interviews with 30 stakeholders at FQHCs will identify barriers to referring and supporting Hispanic men at FQHCs to the DPP, informing the development of a theory-driven implementation strategy that facilitates DPP referrals and supports engagement of Hispanic men in the DPP. Second, (Aim 2) incorporating stakeholder feedback, focus groups with DPP-eligible Hispanic men at an FQHC will facilitate user-centered content development for the multi-component implementation strategy. Third, (Aim 3) the multi-component implementation strategy will be piloted in a real-world hybrid implementation trial among 40 DPP-referred Hispanic men at an FQHC and assessed for feasibility using the evaluative components of the RE-AIM (Reach, Efficacy/Effectiveness, Adoption, Implementation, and Maintenance) framework. DPP participation, weight change, and A1C change will be assessed. Through formal didactics and training from a team of experienced mentors and multidisciplinary advisors, Dr. Gonzalez will acquire knowledge and skills in implementation theory, stakeholder-engaged intervention design, cultural adaptation, user-centered design, real-world trials, and implementation evaluation. His environment at Weill Cornell Medical College and Settlement Health, an FQHC where Dr. Gonzalez practices internal medicine and with whom he has partnered for this research, is ideal to support his training, complete the proposed aims, and achieve his goal of becoming an independent clinician-investigator and apply for an R01 testing the implementation strategy developed and piloted in this award in a future large-scale multi-site trial.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY Normal mineral homeostasis is regulated by the actions of parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and vitaminD on the intestine,kidney andbone. Vitamin D is counter regulatedby PTHand FGF23: PTH increases andFGF23 decreases circulatinglevels of thebiologically active formof vitamin D, 1,25-dihydroxyvitamin D (1,25D), via opposing actions on the 1,25D-synthetic enzyme, CYP27B1 (1α-hydroxylase), and the 1,25D- catabolic enzyme, CYP24A1 (24-hydroxylase). Despite compelling genetic and physiological evidence in humans and animals that point to the critical importance of CYP24A1, most prior research of vitamin D in health and in chronic kidney disease (CKD) focused on 1,25D synthesis by CYP27B1; much less attention has been devoted to 1,25D catabolism by CYP24A1. To advance research of CYP24A1, we developed new lox-P mice that enable tissue-selective and inducible deletion of Cyp24a1. We will use this novel mouse line to test our overarching hypothesis that tissue-specific effects of CYP24A1 in the kidney and intestinecontribute to normal and disordered mineral homeostasis. Since the kidney is the main regulator of circulating 1,25D, we hypothesize that kidney- specific Cyp24a1 deletion will increase serum 1,25D and downstream vitamin D receptor (VDR) activity in all tissues, including the intestine and kidney. In CKD, this will cause hypercalcemia that suppresses PTH, but will further harm kidney function due to 1,25D intoxication. In contrast, since the intestine does not contribute meaningfully to circulating1,25D, we expect intestine-specific Cyp24a1 deletion to increase1,25D and VDR activity only in the intestine. Resultant increases in intestinal calcium absorption will suppress PTH, which will lead to decreased serum 1,25D and thus, decreased VDR activity in the kidney. As a result, we hypothesize that inhibiting intestinal CYP24A1 in CKD will attenuate secondary hyperparathyroidismwithout causing hypercalcemia or further kidney toxicity. In Aim 1, we will investigate the effects of CYP24A1 in normal mineral homeostasis by studying mice with deletion of Cyp24a1 from the kidney (Six2Cre-Cyp24flox), intestine (VillinCreERT2-Cyp24flox) and globally (UBCCreERT2-Cyp24flox). In Aim 2, we will test our hypothesis that inhibiting intestinal CYP24A1 will attenuate secondary hyperparathyroidism and downstream complications of CKD without worsening CKD. In Aims 1 and 2, readouts of effect will include longitudinal physiological measures of mineral homeostasis and kidney function, and expression of VDR target genes in the kidney and intestine; in Aim 2 we will also assess cardiac structure and function, and kidney, bone and vascular histology. In Aim 3, we will define the molecular mechanisms of CYP24A1 regulationin enterocytes usingpharmacological and genetic approaches in mouseand humanintestinal organoids. Readouts of effect will include cell signaling assays and expressionof Cyp24a1 and VDR target genes. By defining the tissue-specific effects and molecular regulation of CYP24A1 using our new mouse models, we will uncover novel therapeutic strategies for CKD and other syndromes of disordered mineral homeostasis.

NIH Research Projects · FY 2026 · 2024-11

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer, often diagnosed in late stages and with few to no effective treatment options. Understanding the molecular and cellular changes that drive the genesis of PDAC will help define therapeutic opportunities to improve clinical outcomes. The current dogma of PDAC initiation posits that activating mutations in the KRAS oncogene drive cell lineage transformation and proliferation to convert normal pancreatic acini into ductal-like pancreatic intraepithelial neoplasia (PanIN). Our understanding of this process is derived largely from the KrasLSL-G12D mouse model that mimics this near-ubiquitous mutational activation of KRAS in PDAC. However, KRASG12D mutations account for only half of all KRAS mutations. The other cases are driven by KRASG12V (~25%) and KRASG12R (~15-20%) mutations; interestingly, KRASG12R mutations are rarely observed in other cancer types and could reveal PDAC-specific vulnerabilities. In contrast to the commonly accepted disease initiation paradigm, we recently showed – using novel KRAS mouse models - that induction of KRASG12R mutations in the pancreas do not drive acinar-to-ductal metaplasia and PanIN development like KRASG12D, but in the context of cooperating genetic alterations (e.g., p53 loss) in ductal-derived organoids can promote aggressive PDAC, suggesting there are either non-canonical or cell-of-origin-dependent routes to PDAC in G12R mutant cancers. In parallel, we have also used temporally regulated KRASG12D murine models to reveal the requisite chromatin and transcriptomic changes that drive lineage plasticity in nascent pancreatic neoplastic lesions, suggesting that the G12R mutant is deficient in its ability to initiate this epigenetic reprogramming. Molecular characterization of the G12R mutant points to a specific defect in RAC1 signaling because of an inability to upregulate the key RAC1 GEF Vav1. Translational studies from our group have also identified an enrichment of G12R mutations in early-stage disease, with these tumors featuring less frequent lymph node metastases and improved clinical outcomes, including both disease-free and overall survival. Given these data, we hypothesize that the KRASG12R mutation in PDAC has distinct molecular features, oncogenic potential, cooperativity with tumor suppressor loss, and therapeutic vulnerabilities. In this proposal, we will define the role of PDAC-associated KRAS variants by (1) deciphering how cell lineage impacts neoplastic transformation and molecular evolution of epithelial cells in the KRASG12R and KRASG12V mutants; (2) defining the oncogenic factors required for KRASG12R mutant PDAC; and (3) delineating the molecular dependencies and therapeutic responses in KRASG12R and KRASG12V mutant disease. By exploiting our animal models systems, molecular framework for understanding cell lineage and transformation in the pancreas, patient- derived organoids, and in vivo editing technologies this work will define how specific KRAS mutations shape the progression to malignancy and the responses to therapeutic interception.

NIH Research Projects · FY 2026 · 2024-11

PROJECT ABSTRACT Novel pathogens (e.g., SARS-CoV2, monkeypox, respiratory syncytial virus, and influenza) are constantly emerging, creating an urgent, unmet need to identify strategies that enhance immunological memory. Our previous work demonstrated that caloric restriction (CR) is a nutritional intervention that enhances immunological memory in mice, resulting in 500-fold greater pathogen control (Collins N, Cell, 2019 and Han SJ…Collins N*, PNAS, 2023). However, the molecular determinants, signaling pathways, and cell-cell interactions involved are unknown. The objective of this proposal is to generate fundamental mechanistic information that fills these gaps in knowledge, which will advance the field and ultimately reduce the burden of infectious diseases by (i) revealing how CR can be utilized to enhance pathogen- and vaccine-elicited immunological memory, and (ii) leading to the development of novel therapies that pharmacologically mimic the immune-enhancing effect of CR. Our recent publication indicated that CR enhances immunity by increasing memory CD8+ T cell-derived IFN and gut microbiota-derived acetate, which converge on myeloid cells to enhance their capacity to kill pathogens. Our preliminary metabolomics data first show that CR potently modulates systemic nutrient abundance. Memory CD8+ T cells metabolically adapt by switching their intracellular signaling pathways to promote the utilization of nutrient sources that are abundant in this setting, as shown by preliminary single-cell RNA-seq and flow cytometry results. The metabolic state adopted by memory T cells during CR has been shown to enhance their function, providing a potential explanation for increased IFN production. A second essential effect of CR demonstrated by metagenomics sequencing in our recent publication is a ~1000-fold enrichment of the commensal Bifidobacteria that produce the short-chain fatty acid acetate. Ex vivo data indicates that the combination of IFN and acetate is essential to enhance the ability of myeloid cells from mice on CR to kill pathogens. Further, our RNA-seq identified that myeloid cells upregulate multiple genes related to pathogen killing in vivo during CR. This proposal builds on our recent publication and extensive preliminary data and will test the central hypothesis that CR induces memory CD8+ T cell metabolic rewiring to enhance the production of IFN, which combines with Bifidobacteria-derived acetate to increase the capacity of myeloid cells to kill pathogens. Based on our new data, this proposal will determine if (i) CR-induced metabolic reprogramming is essential to enhance memory T cell IFN production, and (ii) how the combination of memory T cell-derived IFN and microbiota-derived acetate enhances myeloid cells in this context. Altogether, we will define how CR enhances and promotes cooperation between distinct immune cells for increased pathogen control. This will be essential to achieving our long-term goal of reducing the burden of infectious disease by optimizing immunological memory.

NIH Research Projects · FY 2026 · 2024-11

Abstract The gut microbiome plays a critical role in the development of the immune system during the first year of life. Contact between immune cells and commensal microbes during early life helps to fine-tune this balance, and early-life perturbations to the microbiome have been linked to later susceptibility to a wide range of health issues, from gastrointestinal disorders such as irritable bowel syndrome or inflammatory bowel disease, to respiratory conditions including asthma and chronic obstructive pulmonary disease. The gut microbiome in premature infants has been well described to be significantly altered, with over-abundance of opportunistic Gram-negative Enterobacteriaceae. Premature infants are at higher risk for adverse outcomes to respiratory infections such as respiratory syncytial virus (RSV) due to their immunocompromised state and incomplete lung development. We hypothesize that the altered state of the premature microbiome affects the ability of the immune system to effectively deal with infection. Our preliminary data suggest that the altered gut microbiome in premature infants induces neutrophil-biased immune responses but weaker anti-viral interferon and antibody responses; the combination of both may contribute to more severe RSV-induced lung injury in premature infants and increase the risk of asthma in later life. This proposal aims to define the contributions of the altered gut microbiome to the outcome of RSV infection in preterm infants, and to identify metabolites that might be used to “normalize” the respiratory immune responses to RSV infection in premature infants and improve their lung functions.

NIH Research Projects · FY 2025 · 2024-09

Project Summary Cell migration is critical for animal development, homeostasis, and is altered in many diseases. During migration, a cell’s ability to change direction is essential for processes such as wound healing, immune surveillance, and tissue morphogenesis. The polarization of cells and the key feedback loops maintaining this polarization allow for faithful execution of cell migration, however, little is known about how cells remain able to integrate new information to change its direction. The experiments outlined in this proposal are designed to dissect the mechanisms by which cells regulate key signaling pathways to control navigation. I will focus on PI3K, Ras, and Rac signaling, which are active at the front of migrating cells, and membrane-proximal F-actin (MPA) – which is localized to the rear. Many of these components have been shown to maintain their polarized activity through positive feedback but it is unclear how exactly negative feedback and crosstalk of these signaling pathways promote directional change. A better understanding of signaling feedback for these pathways will not only increase our understanding of how cells maintain faithful cell migration but are likely to shed light on several other biological processes such as cell division, polarity, and trafficking where these pathways also play critical roles. In Aim 1, the canonical signaling pathways involved in cell migration signaling at the leading edge, such as phosphatidylinositol-3 kinase (PI3K) and Ras signaling will be reinforced to determine the role of signaling feedback in migration speed, turning, and chemotaxis. Negative feedback signaling onto these pathways has been proposed as a mechanism to promote cell responsiveness to stimuli change-of-direction, but the consequences of preventing such negative signaling feedback remain unknown. This will be tested using unbiased front-localizing PIP3-binding domain to recruit protein fragments designed to augment endogenous cell signaling. I will also use fluorescence live-cell biosensors to determine if reinforcement of PI3K and Ras alter the ability of other signaling pathways to regulate cell turning. In Aim 2, I will determine how membrane-proximal F-actin (MPA) regulates cell migration speed, turning, and chemotaxis. Our laboratory has recently shown that areas high in MPA are restrictive to protrusion generation but the mechanism by which this occurs is still unclear. The experiments in this aim will determine how MPA recruitment to the front of the cell alters migration speed, as well as key signaling pathways, such as RhoA and Rac1, that regulate turning and chemotaxis. I will combine the use of high throughput quantitative microscopy, fluorescent biosensors, micropatterned migration substrates, 3D matrices, and cell tracking analysis to address these aims.

NIH Research Projects · FY 2025 · 2024-09

Abstract In Alzheimer's disease (AD), tau accumulation begins in the perirhinal cortex (PC) and spreads to the entorhinal cortex (ERC) and hippocampus (regions in the Braak I-II stages). Although [18F]MK6240 is a promising PET radiotracer with a binding pattern that mirrors tau progression in AD, in vivo neuroimaging of the ERC/PC is hindered by the poor spatial resolution of PET and meningeal dura \spill-in" artifacts (also known as partial volume e ect or PVE). To address these challenges, we propose the development and clinical translation of our ultra-high resolution and upright Prism-PET brain scanner with integration of our ultra-high resolution electromagnetic motion tracker (EMMT). As new amyloid- targeting treatments for AD, such as lecanemab, become widely used, the need for PET scans may increase by a factor of 20, posing a major challenge for health systems to meet this demand, particularly outside of major metropolitan centers. In addition to having the highest spatial resolution, our Prism- PET/EMMT system is cost-e ective, upright, and portable and can be easily attached to CT scanners in the community, thereby increasing community access to brain PET imaging. We hypothesize that in Alzheimer's disease (AD), PET imaging of Braak I-II brain regions using [18F]MK6240 tau radiotracer and Prism-PET/EMMT scanner may be the earliest biomarker for detecting tau aggregation and AD severity in asymptomatic individuals. Given our promising preliminary experimental results, we aim to accomplish the following tasks: (Aim 1) Integration of Prism-PET with EMMT and conversion to upright position; (Aim 2) High resolution motion-compensated reconstruction (HRMR) followed by CT-based and CT-less attenuation correction; (Aim 3) Anthropomorphic phantom imaging and initial Tau-PET human validation; and nally (Aim 4) In vivo quantitative assessment of tau deposition in ERC/PC in amyloid-positive subjects with early mild cognitive impairment (MCI), using both supine and upright Prism-PET/EMMT scanning with the [18F]MK6240 tracer.

NIH Research Projects · FY 2025 · 2024-09

PROJECT ABSTRACT: Hepatitis C virus (HCV) during pregnancy predominantly affects people who inject drugs. The rates of perinatal HCV and maternal to child transmission are rising in concert with the current injection drug use crisis. Testing for HCV in the perinatal period has been inadequate, as has testing of infants born to mothers infected with HCV. To improve testing rates, several professional societies released guidance recommend universal HCV testing with each pregnancy in spring of 2020. However, screening recommendations are not universally followed, and may not be applied equitably across populations. Additionally, we do not know whether an increase in testing ultimately leads to the desired downstream outcomes of linkage to care, treatment, and identification of infants at risk for perinatal transmission. In this proposal, we will use national Medicaid and commercial claims data to examine HCV testing and treatment among pregnant and postpartum women and their infants. Specifically, we will 1) determine whether the testing guideline change was associated with increased HCV testing rates among pregnant women compared to non-pregnant reproductive age women; 2) determine whether the guideline change was associated with increased postpartum HCV linkage to care and treatment as well as other aspects of maternal care, and 3) determine whether the guidelines were associated with increases in appropriate HCV testing and diagnoses for infants born to HCV-infected mothers in Medicaid. In each aim, we will examine variation in the implementation of HCV testing, identifying targets for further public health and policy intervention. Understanding the landscape of HCV testing for the perinatal population is critical for eliminating HCV and improving the lifetime health of people who use drugs.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY Overview: The proposal aims to advance the science of geriatric palliative care by assessing the feasibility and acceptability of implementing radio frequency (RF) sensors to capture cardiopulmonary measures in nursing home (NH) patients with Alzheimer's Disease and related dementias (ADRD) and using machine learning to help predict when a patient may be experiencing an episode of respiratory distress. Background: In NH patients with advanced ADRD, respiratory distress is common and can occur in up to 80% of patients. Respiratory distress can lead to negative patient outcomes such as increased suffering, poor quality of life, and unwanted care transitions. Given that ADRD approximately patients make up 48% of all NH residents, with 60% of those having moderate to severe cognitive impairment,it is critical that we find ways to better identify and detect respiratory distress in this vulnerable patient population. Research plan: The proposal aims to (1) assess the feasibility and acceptability of implementing RF sensors to capture cardiopulmonary waveforms in NH patients with advanced ADRD and (2) develop a machine learning algorithm that will autonomously detect and predict respiratory distress using collected cardiopulmonary recordings. Furthermore, interviews will be conducted with NH staff and legal authorized representatives of patients with dementia to gain insight into the potential use and challenges of implementing RF sensors to help in the detection and prediction of respiratory distress in patients with advanced ADRD. Environment: The study team is a distinguished group with expertise in geriatrics, palliative medicine, pulmonary medicine, and biosensor technology/artificial intelligence. By combining the resources at Weill Cornell Medicine, Cornell University, Archcare, the proposal has the potential to lead to advances in how respiratory distress is monitored and detected in NH patients with ADRD, with the goal of reducing patient suffering and burdensome care transitions.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Large-scale longitudinal microbiome studies are increasingly common as they allow investigators to study temporal patterns of the microbiome, elucidating the forces that shape the microbiome and enabling the development of microbiota-based interventions. Unfortunately, despite the potential of longitudinal microbiome studies, few methods exist for analyzing these studies. Also, the few extant tailored methods are limited, either failing to accommodate the characteristics of microbiome data or failing to properly accommodate the longitudinal structure, leading to potentially spurious findings. This proposal aims to fill the critical gaps in methodology by addressing four major areas. Specifically, we aim to develop a comprehensive and coherent suite of statistical tools for (1) addressing batch effects in longitudinal microbiome data – a pressing problem as studies are getting bigger or integrated; (2) improved identification of individual taxa associated with crucial biomedical exposures or outcomes over time; (3) identifying microbiome interaction network dynamics between taxa within longitudinal microbiome data; (4) visualizing the longitudinal microbiome data. These approaches are all based on rigorous prior data emphasizing the importance of the problems as well as the limitations or absence of existing strategies. Our work is motivated by and will directly enable analyses within three important longitudinal microbiome profiling studies: few studies have the combination of large cohorts of patients with numerous follow-ups and rich covariates. Consequently, our methods have the potential to accelerate understanding of the roles of the microbiome in diseases and therapeutics, especially in the motivating studies that include populations of infants with diabetes and immunocompromised individuals (patients undergoing kidney or bone marrow transplant). Ultimately, the deployment of our methods could guide the design and development of novel microbiota-based preventive and therapeutic interventions.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract Over 1 in 10 older adults is the victim of elder mistreatment. Rates of mistreatment are even higher among older adults with dementia. Care of those with dementia often is the responsibility of unpaid family and friends, with over 11 million unpaid caregivers providing support for individuals with Alzheimer's disease and related dementias. While many caregivers report positive aspects of caring for their loved one, it is also associated with increased burden and distress. Little research has examined the phenomenon of elder mistreatment among individuals with dementia and their caregivers. The objectives of this K01 project propose to create and validate a new measure of elder mistreatment, adapted to the specific experiences of dementia caregivers and their care recipients. Such knowledge is necessary to inform intervention and policy to reduce mistreatment among those with dementia and their caregivers. Dr. Hancock will complete 5 training goals to enable him to become a successful, independent researcher, capable of creating and validating new measures and designing and implementing interventions. First, he will increase his knowledge and expertise in the fields of elder mistreatment and dementia family caregiving. Second, he will develop the skills necessary to create a new measure, translating from related research and soliciting and analyzing qualitative data from key stakeholder interviews. Third, he will seek advanced quantitative training in the validation of newly created measures. Fourth, he will obtain skills and knowledge necessary to translate research into an intervention and the acquire the skills necessary to lead and run an NIH funded intervention project as PI. Fifth, he will develop skills in independent grant writing and academic leadership. The two proposed research aims are designed to complement the training goals. The first aim proposes to develop and refine a measure of elder mistreatment among dementia family caregivers. Aim 1a will develop items and establish content validity of a new measure of elder mistreatment, using feedback from key stakeholders including caregivers and geriatric professionals. Aim 1b will pilot test the items generated in Aim 1a to inform measure creation. Aim 2 proposes to validate the measure created in Aim 1. Aim 2a will seek to validate the psychometrics properties of the newly created measure. Aim 2b will seek to examine prevalence and incidence of elder mistreatment among dementia caregivers. Further, this sub-aim will seek to examine correlates and predictors of mistreatment, to identify potential intervention targets to reduce mistreatment. The proposed training plan and research proposal is well aligned with the NIA's initiative to develop and train research scientists in aging. Moreover, it aligns with NIA's interests in promoting well-being, through intervention, of dementia family caregivers. Finally, this proposal aligns with a recent funding announcement which focuses on measurement of elder mistreatment.

NIH Research Projects · FY 2025 · 2024-09

Abstract. Type 2 diabetes (T2D) is a polygenetic disease marked by impaired insulin secretion in pancreatic islet cells. Although genome-wide association studies (GWAS) have identified many T2D-associated genetic variants/genes, understanding the molecular mechanism and cellular consequence of GWAS identified hits remains challenging. In addition, little is known about the interaction network of GWAS identified T2D genes/variants. Recent advances in human pluripotent stem cells (hPSCs) and CRISPR-based technologies have enabled in vitro model systems for exploring the impact of T2D-associated genes and genetic network on islet dysfunction. In our recent study, we generated a panel of individual isogenic KO hESCs across 20 T2D effector genes. We systematically evaluated the impact of each KO on β cell differentiation efficiency, insulin production and secretion, and β cell survival. We performed allelic imbalance analysis and prioritized 18 T2D associated SNPs, two of which are located at RFX binding motifs. Furthermore, scRNA-seq analysis of human islets revealed the decreased expression of RFX3 and RFX6 in T2D islets. Finally, qRT-PCR analysis showed decrease expression of RFX3 and RFX6 in seven T2D-KO hESC-derived INS-GFP+ β-like cells. Here, we propose to use isogenic hPSC-derived islet organoids and human islets to systematically evaluate the molecular cascade involving T2D effector genes-RFX3/6-T2D variants in human islet cell generation, survival, and function under both healthy and T2D conditions. Three aims were proposed. In Aim 1, we will establish inducible KD hESC lines to assess the individual and synergistic effects of RFX3/6 on human islet cell generation, function, and survival. In Aim 2, we will decode the T2D effector genes-RFX3/6 signaling cascade in human islet cell damage in T2D conditions. In Aim 3, we will decipher the RFX3/6-T2D variants signaling cascade. This proposal aims to systematically evaluate the molecular cascade involving T2D effect genes-RFX3/6-T2D variants in human islet cell, generation, survival, and function. This study will establish a comprehensive pipeline for defining the biological function of T2D effector genes, prioritizing and validating the T2D variants, finally mapping the interactive network of T2D associated genes/variants in disease relevant tissues. This will not only address several challenges encountered in current T2D GWAS studies, but also shedding light on new insights into T2D disease progression.

NIH Research Projects · FY 2025 · 2024-09

MECHANISMS OF MOTOR SUPERPERFORMANCE: ABSTRACT Clinical experience and world population-level data indicate that most neurological disability stems from motor dysfunction. Yet, spontaneous superperformer mutations occur in a variety of persons and animals, illustrating that the intrinsic motor capacity of the organism can be augmented. We set out to identify similar mutations by rotarod screening of 32,726 laboratory mice harboring chemically induced random mutations with the goal of mechanistically explaining motor superperformance. In this context, we have discovered that a point mutation in an unsuspected gene, Rif1 (Replication Timing Regulatory Factor 1), converts a single mouse residue to the primate one and confers supernormal motor ability. Using clustered regularly interspaced short palindromic repeats (CRISPR) Rif1-mutant mice, we have determined that this superperformance is a motor-selective phenotype manifest upon several motor tasks but devoid of other effects upon various rigorous behavioral and longevity analyses. Rif1-mutant mice also exhibit enhanced recovery from stroke in the motor cerebral cortex. The superperformance mechanism is unknown: although Rif1 participates in DNA repair and in transcriptional regulation via G4 folded DNA structural stabilization, little is known about its function in the nervous system. There is precedent that DNA repair may be associated with synaptic transmission strength, while DNA G4 regulation could enhance the transcription of genes active in the motor system. We have strengthened this hypothetical framework by identifying several consequences of the Rif1 mutation: a) Altered Purkinje cell firing regularity and local field potential changes in mouse cerebellum, which can influence movement precision, with change of these neurophysiological parameters upon locomotion on a treadmill; b) Increased cellular resistance to DNA-damaging radiation; c) Increased cell resistance to G4 stabilization; d) Overexpression of a fraction of the cerebellar (but not forebrain or spinal cord) synaptic transcriptome including potential Rif1 mutation mediators such as Kcnma1, Kif5c and Nab2; e) These transcripts may be relevant to the phenotype because we show that their loss of function degrades motor performance, whereas f) Cerebellar injection of adenovirus-containing Nab2 induces superperformance. Thus, we will expand current cerebellar learning conceptions by postulating that the Rif1 mutation facilitates DNA repair and/or loosens G4 DNA folding leading to upregulation of synaptic transcripts, with either one or both mechanisms modifying the range or precision of cerebellar synapse activity that underlies movement control. To this effect, we will conduct neurophysiological studies, study the function of native RIF1, manipulate Nab2, Kcnma1 and Kif5c expression levels, and investigate DNA repair and DNA G4 regulation to test which of these mechanisms enable the superperformance phenotype. We will also investigate if enhanced stroke recovery also partakes from the same cerebellar neurophysiological mechanism to enable future work on this important observation.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract Evidence-based medicine (EBM) requires collecting and ranking relevant evidence according to its epistemological strength, aiming to identify the most suitable evidence to inform guidelines and policies. This process generally prioritizes strong evidence from randomized clinical trials (RCTs), cohort studies, systematic reviews, and meta-analyses. However, the volume of scientific literature being published in peer-reviewed journals is increasing exponentially. This makes it extraordinarily financial and societal costly for scientists to obtain a reasonably precise, cumulative overview of the conceptual structure of the literature about a certain scientific topic, and to identify potential new research opportunities. It also presents a challenge for practitioners and policymakers in assimilating and understanding the prevailing findings, further slowing down the translation from biomedical discoveries to improved health outcomes. It is imperative to develop scalable methods for efficient clinical evidence extraction and summarization. Responding to PA-23-034, this project will develop and validate a novel informatics framework to extract computable Population, Intervention, Comparison, and Outcome (PICO) elements and summarize them from publications of interventionaland observational studies. While the framework can be applied to any type of condition, the focus will be on 23 clinical domains, such as neurological, respiratory, digestive system, cardiovascular, and mental health conditions, because they are extremely common and affect people of all ages, races, and socioeconomic statuses. Our extensive preliminary data show that we can effectively employ deep learning (DL) and natural language processing (NLP) methods to extract PICO elements from the clinical trial registries and RCT publications in PubMed. We can also perform zero-shot clinical evidence summarization across six clinical domains. These studies lend further support to the feasibility of the proposed research. Based on our preliminary data and our experience with an interdisciplinary team, our specific aims are: (1) Systematically design and data-driven evaluate a computable PICO ontology; (2) Extract multi-granular PICO elements from study publications; (3) Generate rational-based evidence summaries; and (4) Develop and validate the EBM toolkit via a user-centered design. The research proposed in this project is novel and innovative because it will produce and rigorously test new solutions to improve computable EBM. Successful completion of these aims will empower the general public, stakeholders in EBM, and public health policymakers to efficiently discover and summarize pertinent medical evidence, thereby facilitating well-informed healthcare decision-making.

NIH Research Projects · FY 2024 · 2024-09

Major depressive disorder is a leading cause of disability. Two FDA-approved treatments—and ketamine and accelerated repetitive transcranial magnetic stimulation targeting the left dorsolateral prefrontal cortex (DLPFC)—have emerged as highly effective alternatives to first-line antidepressants, capable of delivering rapid antidepressant effects even for treatment-resistant depression (TRD) cases. Clinicians who are choosing between ketamine and rTMS usually rely on a trial-and-error approach that can take months. Biomarkers for informing this key clinical decision point have the potential to transform the management of TRD by rapidly matching individual patients to the treatment most likely to benefit them. Leveraging recent technical advances and building on an extensive foundation of preliminary data establishing the feasibility of predicting accelerated rTMS and ketamine treatment outcomes, we propose a two-phase project aimed at developing, optimizing, and testing a new approach to selecting the most effective treatment for individuals with TRD. Individual differences in treatment outcomes can be understood in part by considering the antidepressant mechanisms of action underlying these very different treatments and how they interact with neurobiological heterogeneity in TRD. Our central hypothesis is that individual differences in antidepressant responses to rTMS and ketamine are due in part to heterogeneity in the neurobiology of depression. We hypothesize that whereas connectivity deficits involving the prefrontal cortex are a marker of TRD patients who are likely to respond to ketamine- induced synaptogenesis, intact connectivity between the DLPFC stimulation site and downstream targets in the anterior cingulate and insula will be associated with enhanced rTMS responses. In the UG3 phase, we will use state-of-the-art machine learning methods to optimize statistical classifiers (“neuroimaging biomarkers”) for predicting antidepressant responses in individual patients. We will enhance model performance by a) refining a subtyping procedure we developed; b) incorporating precision functional mapping of network topology; and c) optimizing for robust and reproducible results in held-out data. In parallel, we will validate our biomarker approach in a prospective pilot study, validating the reliability, acceptability, and feasibility of fMRI biomarkers. In the UH3 phase, we evaluate the efficacy of this approach in a prospective clinical trial, randomizing to receive DLPFC-rTMS or ketamine, informed by our biomarkers, and evaluate their utility for supporting new, highly scalable models for predicting outcomes without the need for fMRI data in a subset of individuals.

NIH Research Projects · FY 2026 · 2024-09

Dementia is a disease characterized by a loss of memory and other cognitive functions that is severe enough to interfere with daily living. In 2023, an estimated 6.7 million Americans who are 65 years and older are living with dementia (Alzheimer's disease or related dementias, ADRD). Approximately one-third of people living with dementia (PLWD) have highly “fragmented ambulatory care,” or care diffusely spread across many ambulatory providers. In one national study, PLWD who had highly fragmented ambulatory care had an average of 16 ambulatory visits to 7 different providers in a given year, compared with 11 visits to 3 providers for those with the least fragmented care. Having multiple providers may be clinically appropriate, but it creates challenges, because providers do not consistently communicate with each other, even in the era of electronic health records. When providers do not communicate with each other, harm for patients can follow. Fragmented ambulatory care may be an overlooked but modifiable contributor to some key problems in healthcare delivery, such as delayed or missed diagnoses of dementia (including racial disparities in dementia diagnoses). Similarly, fragmented care may be leading to more prescribers of medication and more polypharmacy (i.e., the use of ≥5 medications), which may be contributing to excess emergency department visits and hospitalizations among PLWD. Filling these gaps in knowledge is necessary for informing the design of future interventions. The proposed project, “Understanding Ambulatory Care Utilization in Alzheimer's Disease and Related Dementias (ACUA),” will illuminate the role of fragmented care in the diagnosis of dementia and in the care of PLWD, while identifying novel opportunities for intervention. Aim 1 will involve secondary analyses of two NIA- funded cohort studies linked to claims (the Health and Retirement Study [N ≈ 3,425] and the REasons for Geographic and Racial Disparities in Stroke study [N ≈ 3,235]), to determine whether fragmentation is associated with delayed or missed diagnoses of dementia, including racial disparities in diagnoses. Aim 2 will involve secondary analyses of national Medicare claims (100% sample) to determine whether fragmentation is associated with more unique prescribers of medication and whether that, in turn, leads to more polypharmacy and excess emergency department visits and hospitalizations (N ≈ 4.5 million). Aim 3 will consist of one-on- one semi-structured interviews with a variety of stakeholders who are involved in dementia care, to determine their preferences regarding who should address fragmented care for PLWD, when, and how (for example, whether the goal of future interventions should be to decrease unnecessary fragmentation or to ameliorate its adverse effects) (N ≈ 50). This project will generate robust, data-driven insights, which will enable future development of novel interventions to improve ambulatory care and outcomes for PLWD.

NIH Research Projects · FY 2025 · 2024-09

Expanded Medicare coverage for telehealth services in 2020 has removed many of the barriers to telehealth provision in nursing homes (NHs). For NH residents with Alzheimer's disease and Alzheimer's disease-related dementias (ADRD), who make up over 60 per cent of NH residents, increased telehealth provision may allow more timely access to specialty care at the end of life (EOL) and provide clinicians and caregivers with an important layer of audiovisual information to make informed patient-centered decisions. However, EOL care is highly variable across NHs and there are substantial disparities in the quality of EOL care associated with race/ethnicity and socioeconomic disadvantage. For example, residents who are racial and ethnic minorities are less likely to complete advance care planning and are more likely to die in a hospital. It is not clear how telehealth may impact these disparities. Additionally, there may be unintended consequences and challenges of telehealth provision for residents with ADRD. Over three years after the start of the PHE, the expansion and phase out of telehealth flexibilities requires a careful evaluation of its capacity to impact the quality, utilization, and cost of care for NH residents. The overall objectives of this study are to leverage the natural experiments surrounding changes in Medicare telehealth benefits to examine changes in access to telehealth for NH residents with ADRD and in the last 90 days of life. We will focus on the following specific aims to achieve these objectives: (1) To characterize patterns of telehealth provision at the EOL for NH residents with ADRD, including the overall and relative rates of telehealth to in-person services; (2) To evaluate the extent to which access to telehealth mediates the relationship between resident race/ethnicity, dual-eligibility, and rurality of the NH, and the use of specialized medical care at the EOL; and (3) To measure the relationship between telehealth provision and the quality and cost of care at the EOL for NH residents with ADRD, overall and by race/ethnicity, dual-eligibility, and rurality. This application is innovative because it leverages a quasi-experimental approach to estimate the effect of telehealth use, with a focus on the extent to which telehealth may impact disparities in EOL care for residents with ADRD. This project it will be the first to measure telehealth use in NHs for both Medicare FFS beneficiaries and residents enrolled in MA, who constitute over 25% of long-stay NH residents. The proposed research is significant because as coverage for many telehealth services are set to expire December 2024, this study will shed light on the potential impacts of reducing access to telehealth for NH residents and individuals with ADRD. This project will also importantly inform NIH goals for expanded research on the use and efficacy of telehealth to improve the delivery of care for people living with ADRD.

NIH Research Projects · FY 2025 · 2024-09

The Meyer Cancer Center (MCC) of Weill Cornell Medicine (WCM), and NewYork Presbyterian Medical Center (NYP) is a matrix cancer center serving a catchment area of approximately 6 million patients in following locations: WCM, located in the Upper East Side of Manhattan, NYP Lower Manhattan (NYP-LM) located in lower Manhattan south of Greenwich Village (with virtually all cancer care occurring at WCM), NYP-Brooklyn Methodist Hospital (NYP-BMH), located in Park Slope, and NYP-Queens Hospital (NYP-Q), located in Flushing. WCM was a long-standing main member of CALGB as well as COG, while also having full member status including leadership within and participating in trials for RTOG, ECOG, and ACRIN. Most recently, within the NCTN, MCC/WCM has predominantly been involved in the Alliance, including affiliate membership at the NYP-BMH site and COG while continuing to have some leadership roles in NRG Oncology (including main membership at the NYP-BMH site and affiliate status at the NYP-Queens site). WCM was a founding member of the N01 funded NYCC, now participating in the ETCTN via Ohio State University. The Research Specialist (Clinician Scientist) applicant Dr. Tagawa has been most intimately involved with the NCTN via CALGBAlliance (serving as institutional PI since 2013). He has personally led and mentored others across multiple disciplines and Departments in leading NCI studies. Within the MCC, the applicant leads NCI clinical trials and has served as primary leader of the GU Disease Management Team across the MCC sphere. He is the top oncology accruer to NCTN studies within the MCC. Since his arrival at WCM and as he took over leadership of the Alliance, NCTN accruals have increased overall, as has accruals from high-risk populations. Most of his direct contributions to NCI clinical trials has come via leadership with the Alliance and specific work within the GU committee. He has held a seat on the Board of Directors since 2013 and continues to serve on various Alliance committees. Within the GU group, he has had several concepts move through the Alliance, Task Force, GU Steering, and CTEP. He is now focused on mentoring others in this process, having brought in investigators from multiple disciplines to the committee; for instance, he has mentored a radiation oncologist who is now leading Alliance and NRG studies. Dr. Tagawa plans to continue to expand the MCC NCI trial portfolio into Brooklyn and Queens. With experience and leadership roles both within the Alliance and the MCC, he will leverage infrastructure that he has built for prostate cancer clinical trials to grow the clinical research portfolio across other Disease Management Teams, initially in Brooklyn, then Queens. The applicant stands poised to significantly increase access to and participation in NCI-sponsored clinical trials across the high-risk population within the MCC catchment area.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY Our goal is to develop and assess the clinical potential of quantitative imaging biomarkers of masticatory myofascial pain syndrome (MMPS). MMPS afflicts nearly 10% of Americans. Many treatments have been proposed. However, the lack of a reliable non-invasive tool for evaluating changes in myofiber microstructure has been a major hindrance in assessing existing treatment methods and developing new therapies for myofascial pain. We have recently developed methods to measure and analyze Diffusion Tensor MR Imaging (DTI) data with varying diffusion times, DTI(t): from the time-dependent diffusion signal transverse to fibers, we extract anatomical maps of myofiber diameter and sarcolemma permeability to water molecules, and from the time- dependent diffusion signal along the myofibers, our preliminary results reveal sensitivity to the sarcomere length. This innovative non-invasive quantitative approach, referred to as the random permeable barrier model (RPBM), is based on effective medium theory, and has been validated using Monte Carlo simulations and animal models, as well as tested in human skeletal muscle studies. The proposed biomarkers are the RPBM parameters for myofiber diameter, sarcolemma permeability and sarcomere length scale. These biomarkers are highly favorable biophysical parameters of interest to study myofiber integrity in myofascial pain syndrome (MPS): Indeed, sarcomeres have been shown to be abnormally contracted/shortened and myofibers enlarged in myofascial trigger points observed in MPS. Treatments of MPS including botulinum toxin A treatment may lead to reduction of myofiber diameter. Furthermore, study of the entire muscle rather than local biopsy is needed to understand the initiation of myofascial trigger points, which may occur when exceeding a given threshold in case of muscle overuse, trauma or psychological stress. In the R61 phase, we will develop and optimize the RPBM method to measure myofiber changes associated with MMPS, with the following three aims: in Aim 1 we will establish an optimal 15-minute long MRI protocol and processing pipeline to robustly estimate RPBM parameters. Aim2 is to establish an optimal MRI protocol that includes the optimized 15-min DTI(t) and a 15-min protocol for conventional quantitative MRI measures including T1, T2, and fat fraction, and evaluate their repeatability and reproducibility. Aim 3 is to assess the diagnostic performance of the RPBM parameters. In the R33 phase with a clinical trial, we will determine the RPBM parameters and their combinations that best assess and predict treatment response in MMPS. Once completed, the same RPBM method can be directly applied to assessing other musculoskeletal areas, such as the shoulder, the upper/lower back and the pelvis.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Cardiovascular disease (CVD) is a leading cause of hospitalization and death in patients with chronic obstructive pulmonary disease (COPD), especially among Black adults with COPD. Black adults with COPD carry a disproportionate CVD risk factor burden compared to White adults, with higher diabetes and hypertension prevalence, lower physical activity levels, greater proportion of actively smoking individuals, and disparities in guideline concordant statin therapy. Black individuals with COPD describe several barriers to engaging in CVD risk reduction. For example, the complexity of COPD care leaves less time in clinic visits to proactively discuss CVD prevention. Breathlessness limits physical activity, a key strategy to improve COPD outcomes and decrease CVD risk. Black adults also face socially determined barriers and distrust in the health system. Prior behavioral interventions have successfully engaged Black adults in CVD risk reduction but are not designed to meet the unique needs of patients with COPD. Interventions to prevent CVD that simultaneously meet the needs of COPD patients and the Black community are urgently needed. The overarching goal of this proposal is for me to become an implementation scientist poised to lead clinical trials improving health equity. To accomplish this, I will conduct mentored research to adapt existing interventions for CVD risk reduction in Black communities into a novel multicomponent behavioral intervention called COPDHeart. COPDHeart will be tailored to the needs of Black patients with COPD to increase the uptake of evidence-based Life's Essential 8 cardiovascular health recommendations put forth in an American Heart Association Presidential Advisory. To accomplish this, I will in Aim 1, identify barriers from patients, providers and interventionists to engaging with a multicomponent CVD prevention intervention for Black adults with COPD; in Aim 2, iteratively refine the COPDHeart intervention with user-centered design; and in Aim 3 determine the feasibility, acceptability, and preliminary effectiveness of COPDHeart in a pilot clinical trial. I will combine didactics with experiential learning and mentorship to develop expertise in stakeholder-engaged research methods, behavioral intervention design, clinical trials, and implementation science. I have engaged an interdisciplinary mentorship team (Drs. Monika Safford, Fernando Martinez, and Neeta Thakur) and focused content advisors (Drs. Riffin, Benzo, Schoenthaler, Peña, and Banerjee). The results of this project will inform a large-scale randomized controlled trial of COPDHeart. This proposal will result in an innovative intervention focused on CVD risk reduction among Black patients with COPD, a population that has disproportionate risk of adverse outcomes. Given that comorbid COPD and CVD contribute to significant morbidity and mortality, especially among Black adults, this proposal has the potential for substantial public health impact. My planned training will allow me to gain expertise in stakeholder engaged research that is crucial for my long-term goals to become a leading clinical researcher and implementation scientist focused on health equity in COPD.