Weill Medical Coll Of Cornell Univ

NIH Research Projects · FY 2026 · 2024-01

Abstract. Genome-wide association studies have identified numerous genetic variants associated with type 1 and type 2 diabetes mellitus (T1DM and T2DM), many of which might affect genes that are involved in pancreatic β cell function and survival. However, the exact biological functions and the mechanistic nature of these genetic variants remain unclear. Human embryonic stem cells (hESCs), provide, in theory, unlimited resources to generate differentiated cells to study the role of genetic factors in human diseases. Of the diabetes-associated genes identified so far, GLIS3 is the only one (other than insulin) associated with both T1DM and T2DM, and neonatal diabetes mellitus (NDM). Recently, we reported an optimized strategy to efficiently derive GLIS3+ pancreatic β-like cells. Using this platform, we found that loss of GLIS3 causes impaired differentiation toward β cells and increases β cell death. Here, we propose to test the hypothesis that genetic and environmental factors caused loss or reduction of GLIS3 impairs human pancreatic β cell generation, survival, and proliferation in both healthy and disease conditions. In preliminary studies, we have created 2 isogenic T2DM-SNP-hESCs, 2 isogenic NDM-M-hESCs, and 2 isogenic KO (knockout)-hESC lines. In addition, we identified a TGFβ inhibitor that rescues the increased death rate in GLIS3-/- β-like cells. In this proposal, we will systematically study the differentiation of isogenic T2DM-SNP-hESCs, NDM-M-hESCs, and GLIS3-KO-hESCs, exploring the generation, function, and survival of the endocrine cells in the disease conditions. Additionally, we will explore the downstream mechanism of GLIS3. Finally, we will develop approaches to improve β cell survival in T2DM conditions by targeting GLIS3 and its downstream pathways. Toward these goals, the following aims are proposed: Aim 1. Evaluate the impact of GLIS3-associated genetic variants in the generation and survival of human pancreatic β cells both in vitro and in vivo. Aim 2. Decode the molecular mechanism of GLIS3 controlling human pancreatic β cell survival. Aim 3. Rescue T2DM islets survival by targeting GLIS3 and its downstream mechanisms. This proposal will systematically analyze the biological function of GLIS3 and associated variants in human β cell's generation, survival, and proliferation. It will significantly enhance our knowledge of β cell biology, which will pave the road for developing novel therapies for T2DM patients.

NIH Research Projects · FY 2026 · 2023-12

People living with HIV (PLHIV) are 18 times more likely to have an active TB infection than people without HIV. Though significant epidemiological evidence highlights the significantly worse outcomes for HIV and tuberculosis (TB) co-infections, the mechanisms underlying this increased risk have not been identified. This is particularly important since all-cause mortality is four times higher for people living with HIV (PLHIV) that also have a history of active TB compared to PLHIV without TB, regardless of TB cure and effective ART. This research team's preliminary data suggest differences in the HIV reservoir, the latent HIV virus integrated into host cell DNA throughout the body, as a potential culprit. Their data show T is mechanisms more intact HIV provirus per million circulating CD4+ cells in people with HIV-TB coinfection compared to those with no history of TB. The objective of this proposal to determine how TB impacts the HIV proviral CD4 reservoir with the long-term goal of identifying actionable that can be targeted to eradicate the HIV reservoir, the primary barrier to curing HIV. The concurrent diagnosis we the to goal of Aim 1 is to determine how HIV infection is distributed in immune cell subtypes in people with active TB-coinfection. At GHESKIO Centers in Port au Prince, Haiti, we will enroll people with a new of HIV (n=75) with or without concurrent diagnosis of TB in a cross-sectional study From this cohort, will compare the diversity of T cell receptors in HIV-infected CD4 cells in people with vs. without TB. From cross-sectional cohort, we will follow people with (n=10) vs without (n=20) TB longitudinally over 18 months document the changes in their peripheral immune cellular profiles with HIV and TB treatment . with hypotheses that i) CD4 of PLHIV with TB coinfection will have more “exhausted” phenotype than in PLHIV and ii) this exhaustion phenotype will not resolve with TB treatment or ART. We will quantitate HIV provirus after 1 year of therapy to associate proviral levels with immune subsets. Phenotypic immune exhaustion may contribute to the etiology of increased all-cause mortality in PLHIV who have had active pulmonary TB. The goal of Aim 2 is to determine HIV proviral burdens in Mycobacterium tuberculosis (Mtb)-specific CD4+ T- cells in comparison to other antigen specificities. We will conduct a case-control study in New York City where people living with HIV with (n=10) vs without (n=10) history of TB will have 5 billion white blood cells collected via leukapheresis. We will stimulate leukapheresis-derived cells with peptide pools and quantitate HIV provirus in CD4 cells responsive to different antigenic stimuli. Digital droplet PCR will be used to measure the percentage of CD4 cells containing HIV. We hypothesize that Mtb peptide-responsive CD4 will be most likely to contain HIV provirus, and thus contribute to the larger HIV reservoir seen in HIV-TB coinfection. Fundamental understanding of TB's impact on HIV reservoir will have significant impact on HIV cure options in areas with high rates of TB.

NIH Research Projects · FY 2026 · 2023-12

Abstract. The goal of our project is to implement a novel scoring system for chronic lung disease of prematurity previously known as bronchopulmonary dysplasia (BPD) in premature infants using structural and functional magnetic resonance imaging (MRI) which identifies the primary cause of the disease subtypes. Currently, there is no means in the clinic to identify the cause of BPD in each infant and whether it has affected the large airways, lung parenchyma or pulmonary perfusion. Clinical care only assesses the degree of respiratory support or oxygen that each infant needs and for what time period without knowledge of the underlying cause of the disease. However, specific treatment would differ knowing that the large airways or tracheal area was decreased in comparison with an infant having pulmonary hypertension and perfusion abnormalities. Our preliminary data in 25 premature infants has shown that novel MRI techniques can be used to non-invasively (without radiation) and without the need for sedation or administration of Gadolinium based contrast agents to quantitate both lung structure and function in this vulnerable population. Our overarching hypothesis is that we can use these sequences that measure both ventilation and perfusion to quantify BPD-specific contributions of Airways, Lung Parenchyma and Perfusion. Specifically, in aim1 we will implement a novel ALP scoring system for BPD phenotypes which identifies the relative contributions of Airways, Lung parenchyma and Perfusion. We will enroll 95 premature infants with all grades of BPD (I, II & III) in the neonatal intensive care unit (NICU). Our center is only one of three in the nation offering high-resolution MRI to infants directly in the NICU. Specific MRI sequences will include anatomic sequences such as BLADE, STARVIBE and PETRA to image the tracheal airway, lung volume and parenchymal structure. We will also use a novel phase-resolved functional lung (PREFUL) sequence to measure both ventilation and perfusion defects as well as pulmonary perfusion. One strength of this proposal is that the PREFUL MRI acquisition uses a routine 2D fast gradient echo (GRE) multi-phase sequence that may be readily implemented using product sequences on most if not all MRI scanners even those outside the NICU. The total scan time will only be approximately 15 minutes. Our aim 2 will then investigate the association between the ALP score and patient specific outcomes including death before discharge, length of time in the NICU, tracheostomy, need for vasodilator or inhaled pulmonary medications. Our study is the first to add real-time function assessment of lung perfusion and ventilation to structural MR markers of BPD in this vulnerable population of premature infants in the NICU.

NIH Research Projects · FY 2025 · 2023-12

ABSTRACT Human cytomegalovirus (HCMV) is the most common in utero infection, causing hearing loss and other neurodevelopmental defects in congenitally infected infants. Despite high prioritization and over 40 years of research in the field, a CMV vaccine has yet to be licensed for clinical use. We are just beginning to understand immune correlates of protection against HCMV, and Fc-mediated antibody effector functions, such as antibody dependent cellular phagocytosis (ADCP) and cytotoxicity (ADCC), have recently been implicated in prevention of placental CMV transmission. CMV is adept at immune evasion, and targeting immune evasion mechanisms that interfere with key immune responses is a promising strategy for producing more effective vaccines, potentially through simple modification to vaccines already in development. HCMV expresses three viral Fcγ receptors (vFcγRs), glycoproteins capable of binding to the Fc portion of immunoglobulin G (IgG), that interfere with antiviral Fc-mediated effector responses. The purpose of this work is to define the humoral immune responses against vFcγRs, both during natural infection and following vaccination with vFcγR protein subunits, to determine if antibodies targeting these proteins can block their Fc-binding ability, thereby improving Fc-mediated effector responses. In Aim 1, we propose to define vFcγR-specific immune responses in chronically HCMV-infected individuals. We will then utilize a rabbit immunogenicity model to define the immunogenicity of vFcγR protein subunit vaccine antigens (gp34, gp68, gp95) in combination with common glycoprotein immunogens, glycoprotein B (gB) and/or the pentameric complex (PC), adjuvanted with squalene emulsion. The primary goal will be to identify the optimal combination of vFcγRs and glycoproteins that elicit the best ADCP and ADCC responses, in terms of both magnitude and breadth. In Aim 2, we will define vaccine-elicited gB-, PC-, and vFcγR-specific B and T cell responses. In Aim 3, we will test our primary hypothesis that co-immunization with glycoprotein(s) and vFcγRs will result in improved glycoprotein-specific Fc-mediated functional antibody responses. Given the importance of Fc mediated effector responses in prevention of congenital CMV, observed improvements in these responses upon co-immunization would suggest that such a vaccine would have greater efficacy in preventing congenital CMV given the demonstrated importance of those responses in preventing vertical CMV transmission. Additionally targeting vFcγRs through active vaccination may be a simple modification to current vaccine strategies to yield stronger responses that have a demonstrated impact on vertical CMV transmission.

NIH Research Projects · FY 2025 · 2023-12

Project Summary: High-risk prostate cancer (PC) is the second most common cause of cancer-related death in men. Improvements in overall survival and long-term morbidity will depend on the ability of the operating surgeon to completely resect regional metastatic lymph nodes (LNs) and obtain negative surgical margins; failure to do so increases the likelihood of local tumor recurrence and added tumor burden. Unfortunately, surgical resection techniques have principally relied upon visual cues and tactile information. While significant advances have been made in real-time intraoperative fluorescence imaging techniques, there are no targeted intraoperative imaging probes that can specifically detect local disease or identify one or more molecular signatures defining the cancer itself. This highlights the importance of developing new and clinically translatable high-resolution intraoperative visualization tools that can specifically localize nodal metastases and residual disease along margins, while permitting accurate molecular characterization or phenotyping of tumor. One such next-generation imaging technology is an ultrabright, sub-8-nm diameter fluorescent core-shell silica nanoparticle, Cornell prime dots (C’ dots), that can be surface-modified with PC-targeting peptides for accurately identifying one or more metastatic markers, including PSMA. Since not all high-risk PCs express PSMA, it is important to assay other targets, such as GRPr, as part of a complementary multiplexing strategy. Therefore, a long-term goal of this proposal is to create PC-targeting fluorescence-based multiplexing tools (Cornell prime dots, C’ dots) for improving the intraoperative detection of cancer targets in high-risk PC patients. Such a precision-based approach can be used to stratify high-risk PC patients potentially curable by surgical resection from those requiring systemic therapy. This strategy also builds upon our prior successful translational and clinical trial efforts. As an extension of our previous R01 application, we completed a Phase 1, first-in-human PET imaging trial in metastatic melanoma patients using a first-generation FDA IND-approved integrin-targeting particle tracer with favorable “target-or-clear” capabilities. Our active intraoperative clinical trials have exploited this highly-fluorescent particle technology for image-guided treatment of nodal metastases in melanoma patients. In this application, we will target two well-characterized PC markers, PSMA and GRPr, using Cy5.5-containing PSMA- and cw800-containing GRPr-targeting C’ dots, according to the following aims: (1) determine tunable surface chemistries for near-infrared dye (NIR)-encapsulated PSMA- and GRPr-targeted C' dots to optimize in vitro biological properties; (2) assess tumor-selective uptake and pharmacokinetic profiles of optimized hybrid C’ dots in PSMA- and GRPr-expressing models; (3) develop spectrally-distinct NIR dye-containing C’ dots from lead candidates to permit accurate and sensitive concurrent detection of multiple markers expressed on nodal and distant metastases; and (4) identify a lead PSMA-targeting C’ dot candidate for IND-enabling studies and an early-phase clinical trial to assess feasibility, particle safety, dosimetry, and cancer-detection capabilities.

NIH Research Projects · FY 2026 · 2023-12

PROJECT SUMMARY Alzheimer’s Disease (AD) is the most prevalent form of late-onset dementia, known for the presence of amyloid plaques and neurofibrillary tangles of hyperphosphorylated tau. There is a portion of patients with AD who develop symptoms before the age of 65, known as early-onset autosomal dominant AD (ADAD), caused by mutations in the presenilin-1 (PSEN1) gene. A specific kindred of these patients was identified for having PSEN1 E280A mutations in Colombia, leading to mild cognitive impairment in their early 40s and dementia by late 40s. One patient from this kindred interestingly did not develop any memory deficits until she was in her 70s. Postmortem analyses showed that in addition to her PSEN1 E280A mutation, she also was homozygous for a mutation in her APOE3 gene, known as the Christchurch mutation (APOE3cc). Apolipoprotein E (APOE) is a lipid transporter that is expressed by astrocytes and microglia in the central nervous system and is the most common risk factor for AD. Ultimately, a better understanding of how this mutation yields resilience against ADAD could be a promising therapeutic target for AD. First, we created a mouse model of human APOE3cc to replicate the patient’s rare homozygous mutation in mice. We leveraged single nuclei RNA sequencing (snRNAseq) to elucidate which cell types could be responsible for APOE3cc’s resilience. The snRNAseq data implicated both microglia and astrocytes as regulators of APOE3cc’s neuroprotection. In microglia, our data showed that ApoEcc/cc+P301S mice significantly downregulated several interferon genes. High levels of type-I interferons in the CNS, present in both aging and neurodegeneration, have been associated with detrimental effects on cognition. In astrocytes, ApoEcc/cc+P301S mice showed reprogramming of mitochondrial and antioxidant genes. Oxidative stress and neurodegeneration are inextricably linked, and having increased antioxidant genes could explain downstream resiliency in the patient. Additionally, previous studies have linked oxidative stress to activation of the interferon pathway. I hypothesize that the combination of microglial interferon suppression and astrocytic antioxidant reprogramming protect against tau-mediated dysfunction in the ApoE3cc/cc mice. To test this hypothesis, we aim to determine the following: 1) determine the relationship of the interferon response in ApoE3cc/cc microglia to neuronal health and neurite outgrowth. 2) analyze the ApoE3cc/cc astrocytic mitochondrial, antioxidant, and metabolic response to tauopathy. Both aims will utilize a combined in vivo and in vitro approach.

NIH Research Projects · FY 2026 · 2023-11

SUMMARY Tuberculosis (TB) is the leading cause of death from a single infection worldwide, with an annual death toll of over 1.6 million lives. TB is curable and drug regimens can be above 90% effective if completed but are long and toxic leading to noncompliance and emergence of resistance. New treatment options relying on novel and unexplored targets are scarce. The BPaL regimen recently approved by the FDA features, for the first time in many decades, drugs against new Mtb targets (ATP synthase) and with novel mode of action (nitroimidazoles). Nevertheless, more inhibitors against previously unexplored targets are urgently needed to sustain the TB drug pipeline, as resistance is already detected to components of BPaL. Both shortages, in effective antibiotics and unexplored targets, are even more glaring in the field of non-tuberculous mycobacterial (NTM) diseases which are on a rise and are recognized now as an emerging global threat in both immunocompromised and immunocompetent individuals. Mycobacterial lipoamide dehydrogenase (Lpd) represents one of the unexplored but Mtb-validated targets and serves in at least 4 enzyme complexes in Mtb: in pyruvate dehydrogenase (PDH), -ketoacid dehydrogenase, branched chain keto-acid dehydrogenase, and peroxynitrite reductase/peroxidase. Lpd is a genetically validated target: Mtb with lpd deleted does not survive in a mouse model of TB infection and a conditionally regulated lpd Mtb strain is cleared in mice, when Lpd expression is suppressed in either the acute or chronic infection. This application leverages the knowledge of the chemical biology of Mtb Lpd to explore our newly identified tight binding inhibitors (TBI) of Mtb Lpd by structure-guided analysis, enzyme kinetics and binding assays to define Lpd binding site features responsible for tight binding interactions and extensions of the on-target residence time (t1/2). We aim to define what drives antibacterial activity of Lpd TBI, how t1/2 contributes to whole cell activity and selectivity, and how we can design/predict better analogs with improved t1/2 to enable further efficacy improvements. We will develop a framework for progression of TBIs from an isolated target to its cellular PDH complex target and its whole cell activity against TB in culture and during host infection. Extension of those studies to NTM pathogens and testing against Mycobacterium avium and M. abscessus Lpd orthologs will lead to scaffold progression and SAR development of a novel whole cell active inhibitor of NTM. Collectively our studies will explore the SAR of Lpd TBI in vitro, define vulnerability of mycobacterial Lpd to chemical inhibition in vivo, advance our understanding of ways to improve inhibitors' efficacy through its target's t1/2, contribute to rational prediction of in vivo efficacy and characterize structural features of mycobacterial PDH that define its distinct macromolecular organization and sustain its functional diversity.

NIH Research Projects · FY 2025 · 2023-11

PROJECT SUMMARY We submit this application in response to RFA-DK-22-506. The North East Consortium for Transplant Outcomes in APOL1 Kidney Recipients (NECTAR), APOLLO Clinical Center 6 (CC6), is a current member of the APOLLO Consortium - a national consortium of transplant programs established in 2017, which collaborates with United Network for Organ Sharing, Association of Organ Procurement Organizations, American Society of Histocompatibility and Immunogenetics and Scientific Registry of Transplant Recipients. The goal of this consortium is to prospectively evaluate the role of APOL1 kidney risk variants on graft outcomes in kidney transplant recipients (KTRs) and kidney function of living donors (LD) with African ancestry. The APOL1 risk variants G1 and G2 have a prevalence of 30% and 8%, respectively, among African Americans (AAs). Presence of homozygous risk variants increases the risk of non-diabetic end-stage kidney disease by 7-10 fold. NECTAR/CC6 oversees 6 Engaged transplant centers, Icahn School of Medicine at Mount Sinai (ISMMS), Weill Medical College-NewYork Presbyterian (WMC-NYP), New York University Medical Center, Northwell Health, SUNY-Upstate Medical University, and 2 Non-Engaged transplant centers, SUNY- Stony Brook University Hospital and Robert Wood Johnson University Hospital. Our 8 centers have enrolled 125 recipients of deceased donor kidneys, 30 living donor recipients, and 35 living donors with African ancestry and have collected >90% the DNA for the total cohort of 190 enrollees. Our site has established regular communication to monitor CC6 enrollment and oversee biospecimen collection and data entry at our own site and that of our network centers to ensure accurate timely completion of forms. The goal of this current proposal is to continue collaboration with the APOLLO Consortium to understand the potential modifiers of graft loss associated with APOL1 kidney risk variants, identify biomarkers predictive of graft loss, and expand the database of LD with African ancestry to better define kidney donor risk. In Phase 2, we will (1) re-engage/reconsent ALL study participants enrolled in Phase 1 to collect long-term data on kidney function outcomes in KTRs and LDs, including measurement of urine albumin to creatinine ratios, (2) obtain comprehensive data on post-transplant clinical course of ALL KTRs to understand potential second hits, (3) collect additional urine and blood biospecimens beyond 1 year post-transplant and kidney biopsy slides associated with diagnostic or surveillance kidney biopsies at the main CC6 sites (ISMMS and WMC-NYP), (4) recruit new LD with African ancestry at ISMMS and WMC-NYP, and (5) collaborate with Scientific Data and Coordinating Center to return genotype results of all interested participants accurately and safely while adhering to rules of privacy of protected health information. NECTAR/CC6 will participate in the Steering Committee and develop the necessary protocols for accurate and complete data capture that will address the goals of this collaboration.

NIH Research Projects · FY 2025 · 2023-09

Project Summary Alzheimer's disease (AD) is the most common cause of dementia. Current clinical standard-of-care for assessing metabolic dysfunction in AD is 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET), based on a temporoparietal pattern of hypometabolism. However, 1) PET is impractical as a longitudinal assessment tool because it requires injection of a radioactive tracer, is expensive, and has poorer spatial resolution and availability compared to MRI; and 2) FDG-PET may not be an accurate measure of neuronal metabolism, because FDG signal can reflect glucose uptake by microglia and astrocytes for glycolysis, as well as glucose uptake for oxidative phosphorylation by neurons. The cerebral metabolic rate of oxygen (CMRO2), reflective of oxidative phosphorylation in neuronal mitochondria, may more directly measure the abnormal metabolism seen in patients with MCI and AD. Moreover, an MRI-based tool for mapping neuronal metabolism would allow for longitudinal monitoring both clinically and in therapeutic trials. Therefore, the objective of this proposal is to develop and optimize an MR-based CMRO2 mapping technique. Aim 1 will be to develop a multi- echo gradient echo acquisition, integrated with arterial spin labeling to construct oxygen extraction fraction, cerebral blood flow, and CMRO2 maps using sparsity fingerprinting. Aim 2 will investigate whether this CMRO2 mapping demonstrates regional correlation with well-established measures of AD pathology, including A, tau, and FDG hypometabolism, the “ATN” stages of AD per the 2018 NIA-Alzheimer's Association research framework. Aim 3 will investigate the value of our CMRO2 mapping in predicting longitudinal gray matter degeneration and cognitive decline. If successful, this proposal will develop and validate a noninvasive, quantitative MR-based tool to diagnose and longitudinally assess cerebral hypometabolism in AD.

NIH Research Projects · FY 2025 · 2023-09

Rising rates of injection drug use in the United States have led to a crisis of serious injection-related infections (SIRI) affecting people who inject drugs (PWID), such as endocarditis, osteomyelitis, and spinal abscess. SIRI are associated with high severity and mortality, often needing long hospitalizations, and need for intensive health services. Addiction treatment interventions, such as addiction specialty consultation or initiation of medications for opioid use disorder, have shown benefit in smaller studies and in commercially insured populations. Evidence generated in Medicaid populations is needed to inform Medicaid program policies. In this proposal, our overall objective is to comprehensively understand addiction treatment delivery for patients with SIRI and the associations of those interventions with clinical and economic outcomes. Specifically, we aim to 1) Use national Medicaid administrative data from 2015-21 to determine if delivery of addiction treatment interventions to PWID hospitalized with SIRI is associated with clinical and economic outcomes, 2) how hospital- and area-level capacity to provide addiction treatment explains the variation in treatment delivery, and 3) use qualitative methods to determine the factors that promote or hinder addiction treatment interventions in hospital settings. To improve outcomes for PWID with SIRI, we first need to understand the current landscape of healthcare delivery, and the motivating factors that will transform healthcare practices to better meet the needs of PWID. Understanding the gaps in evidence-based healthcare delivery for SIRI in the United States are critical first steps for implementing system change to improve care for PWID with SIRI.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT Traumatic Brain Injury (TBI) is a leading cause of death and disability and a risk factor for later development of Alzheimer's Disease (AD.) This project focuses on brain cerebrospinal/interstitial fluid systems essential for clearing the brain of waste and toxins, including the glymphatic system, as important to the pathophysiology of both TBI and AD. We will use neuroimaging to measure brain fluid clearance after TBI. Our preliminary results suggest that TBI causes significant reduction in clearance. In this project, we will confirm these results using additional clearance measurement methods, and determine if lower post-injury clearance is associated with worse cognitive, functional and symptomatic recovery from TBI. We will also use neuroimaging (Positron Emission Tomography - PET) to measure brain amyloid-β (Aβ) – a hallmark pathologic feature of AD – as soon as possible after TBI. Studies in animals and our preliminary data in humans indicate that Aβ is released after TBI and deposits rapidly in the brain, but after a variable period of time, is usually no longer present. We hypothesize that the rate of brain fluid clearance will predict the change in brain Aβ over one year after TBI. Poor clearance and persistent Aβ may explain (in part) why TBI is a risk factor for AD. In addition, monitoring these processes after TBI will provide information relevant to understanding AD in general, since this same pathophysiology – poor clearance leading to Aβ deposition – occurs in AD, but slowly over decades, making it more difficult to study. We will conduct a five year longitudinal study which will recruit subjects within hours after moderate or complex-mild TBI from a network of busy NYC emergency rooms. Neuroimaging, blood draw for TBI biomarkers and detailed cognitive/clinical assessment will be performed as soon as possible (<14 days) after injury and repeated at one year. Because there is no current gold standard for measuring brain fluid clearance in humans, we use a panel of complementary PET and MRI neuroimaging methods to estimate fluid flow, mixing and clearance through interconnected fluid-filled spaces in the brain. This includes a PET method we developed that measures the rate of radiotracer egress from the ventricle. Integrating measures from these multimodal methods will provide greater insight into human fluid clearance than could be achieved with any single modality, and will also provide information about the relative accuracy/predictive ability of each measure that can inform design of future studies. Results from this project will provide novel information about brain fluid clearance after TBI that is also relevant to AD, and that can inform targeted therapies to enhance TBI recovery and reduce future risk of neurodegeneration.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT Diffuse large B-cell lymphomas (DLBCL) arise from B-cells transiting different stages of the germinal center (GC) reaction. It has become clear that these tumors can co-opt regulatory circuits of normal B-cells to drive their own malignant phenotype. Prior studies observe an inverse correlation between the timing of transcriptional activation during reprogramming and the degree of topological reorganization near the gene locus. This suggests that the reorganization of the 3D genome is critical for B-cell development and highlights its importance in DLBCL. Regulatory hubs are highly interactive regions of enhancers that can form interactions with multiple genes within topologically associating domains (TADs) to induce gene activation at a higher probability than pairs of non-interacting genes within the same TAD. Hubs are often rewired during cell fate transitions. Recent work also suggests a new level of organization into broadly interactive networks called chromunities, which putatively allow for transboundary sharing of information and more extensive gene regulatory information critical for cell identity. Critical to understanding the mechanisms driving changes in gene networks is the study of how large-scale chromosomal rearrangements (structural variants, SVs) can co- opt regulatory elements to form aberrant or de novo chromunities, consequently driving aberrant gene expression. While the interpretation of complex structural variants (SVs) has focused primarily on gene dosage and disruption by aberrant TAD structures, little is known regarding the role of SVs in reprogramming regulatory hubs and their target genes. To investigate the role of chromunities and its associated hubs in cell fate transitions and oncogenesis, we will leverage chromatin conformation capture interaction maps (pcHiC, Pore-C) to develop a computational framework to nominate chromunities and map networks of enhancer and promoters driving epigenetic and transcriptional reprogramming. We will also integrate chromatin contact maps with WGS data to investigate the role of complex SVs in reprogramming chromunities in lymphomas. Here, we hypothesize that physiological reprogramming of chromunity regulatory elements creates de novo coordination between sets of genes required to establish specific cell states and phenotypes during the humoral immune response and that SVs occurring in DLBCL alter these hub structures or create new ones leading to selective advantage of malignant clones. In our first aim, we will integrate transcriptional, epigenetic, and chromatin conformation capture assays to identify chromunities and their regulatory elements associated with establishing cell identity in the GC reaction. In our second aim, we will characterize the genomic rearrangement landscapes of B-cell lymphomas and how these directly link to hubs and chromunities using patient-derived xenograft models by generating matched WGS, Pore-C, and RNA-seq data.

NIH Research Projects · FY 2025 · 2023-09

Mammalian sperm are stored in the epididymis in a dormant state; they are immotile and unable to fertilize the egg. Upon ejaculation, sperm begin swimming and initiate a process called capacitation, where they become competent to fertilize. An initial event in capacitation and activation of motility is the HCO3- induced stimulation of soluble adenylyl cyclase (sAC: ADCY10). Men and male mice with the sAC gene knocked out are infertile, and pharmacological inhibitors specific for sAC block in vitro fertilization and temporarily render male mice infertile. Thus, sAC is a genetic and pharmacologically validated, non-hormonal target essential for male fertility. The overall hypothesis tested in this application is that sAC inhibitors can be designed which can be appropriately dosed to block sperm functions while minimizing undesirable side effects. We propose to test a series of potent, selective sAC inhibitors, using in vitro and in vivo studies of efficacy, safety, and pharmacokinetics, to identify the most well-developed, potent, selective, drug-like, non-toxic sAC inhibitors. The goal of this Project is to advance a compound from this series into preclinical development candidates suitable for development partners to apply for an FDA Investigational New Drug (IND) for a novel oral, non-hormonal contraceptive.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ ABSTRACT Every five minutes, a new patient is diagnosed with urothelial carcinoma (UC) in the United States, resulting in the death of 18,000 patients annually. Nearly all patients with advanced UC will develop resistance to systemic treatment. Intratumoral heterogeneity (ITH) is a major contributor to treatment resistance by increasing the chance for resistant subclones to emerge. However, genetic ITH is currently not druggable and not considered in therapeutic decision-making, thus worsening drug-resistant patient phenotypes. The fundamental knowledge gap regarding genetic drivers of ITH impedes the development of effective therapeutic strategies to prevent and eliminate drug resistance. Our long-term goal is to define targetable mechanisms of ITH and treatment resistance to develop an effective precision strategy to achieve cures in patients with advanced UC. The overall objective is to define targetable mechanisms by which APOBEC3A-mediated ITH drives drug resistance and identify strategies to eliminate UC cells with APOBEC3A activity. Our central hypothesis is that APOBEC3A-induced cytidine deamination drives genetic ITH leading to the emergence of therapy-resistant UC clones and, in so doing, simultaneously creating unique targetable vulnerabilities. This hypothesis was formulated based on our published work and strong preliminary data showing that APOBEC3A expression in isogenic UC cell lines and patient-derived organoids drives genetic ITH. We found that APOBEC3A-induced, de novo mutations in the PIKC3A-AKT-MTOR signaling hub drive the resistance to erdafitinib, an FGFR3-inhibitor (FGFR3i) approved for UC treatment. Our preliminary data also revealed that APOBEC3A-induced double-stranded DNA breaks are preferentially repaired by the microhomology-mediated end-joining (MMEJ) pathway and that targeting the critical MMEJ mediator, polymerase theta (Polθ), is synthetically lethal in APOBEC3A-expressing clones. The rationale is that identifying targetable mechanisms by which APOBEC3A-induced ITH drives drug resistance and developing strategies to eliminate APOBEC3A-expressing UC cells will improve cure rates for patients. We will test our hypothesis by pursuing two specific Aims. Aim 1: Identify targetable mechanisms by which APOBEC3A- induced mutational ITH drives treatment resistance in UC. Aim 2: Identify synthetic lethal strategies to target UC tumors with APOBEC3A-induced DNA double-strand breaks. Aim 1 will use longitudinal clonal barcoding and in vitro and in vivo laboratory evolution to identify targetable APOBEC3A-driven kinase hubs that mediate FGFR3i resistance and validate them in patient samples from FGFR3i clinical trials. Aim 2 will use genetic and pharmacologic inhibition of Polθ in APOBEC3A-expressing UC models and a co-clinical trial of patient-derived UC organoids and xenografts to identify clinical biomarkers of response to APOBEC3A-MMEJ synthetic lethality. The approach is conceptually and technically innovative, creating a new paradigm for eliminating treatment- resistant cancers. Impact: Completion of the proposed research will establish APOBEC3A as a genetic driver of treatment resistance and enable synthetic lethal approaches to increase cure rates.

NIH Research Projects · FY 2025 · 2023-09

SUMMARY This proposal seeks Dr. Juan Francisco Linares’s salary as a Research Specialist to support Dr. Maria T. Diaz-Meco’s research program at the Weill Cornell Medicine Department of Pathology and Laboratory Medicine to study the molecular and cellular mechanisms that regulate lineage plasticity in prostate cancer. The elucidation of the molecular mechanisms that castration-resistant prostate cancer cells (CRPC) use to evade therapeutic pressures requires scientists with an in-depth understanding of the molecular biology of this process, 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 perform rigorously epigenetic analysis. Therefore, with this Research Specialist Award, we intend to provide stable research opportunities for the exceptional scientist Juan Francisco Linares to develop impactful research in this area of expertise. He has made seminal contributions in signaling, inflammation, metabolism, and cancer and has solid interdisciplinary training that will be critical for the project’s success. He will contribute to the research program focused on defining the molecular and cellular mechanisms that drive the differentiation of CRPC to more aggressive prostate cancer variants, such as Neuroendocrine and Mesenchymal prostate cancer. With his expertise in cancer biology and cancer metabolism and his capacity to apply novel mouse models and bioinformatics approaches, he is filling a unique niche within the Diaz-Meco lab that will provide continuity, stability, and detailed scientific knowledge to achieve the aims of the NCI-funded grants. Dr. Linares’s long-time expertise and dedication will advance our understanding of the lineage plasticity in CRPC to help design more effective therapies to overcome the acquired resistance in prostate cancer.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY & ABSTRACT By 2045, most of the new cases of diabetes will occur in low- and middle- income countries (LMIC) like India, but 50% of those afflicted will not know. Improving postpartum diabetes screening for women with gestational diabetes (GDM) – a marker of high risk for progression to type 2 diabetes (T2DM) – can help close this diagnostic gap. This is particularly important in India, where few women with GDM receive postpartum T2DM screening, even though 25% of women with GDM develop T2DM within the first year postpartum. Improving T2DM screening during the critical life stages of pregnancy and postpartum will help prevent the sequelae of untreated diabetes, including cardiovascular disease, the leading cause of death among Indian women. In partnership with the Deep Griha Society and King Edward Memorial Hospital Research Center, we propose a hybrid type II effectiveness-implementation cluster randomized trial to evaluate if community health workers (CHW) can improve postpartum T2DM screening in the urban slums of Pune, India. We will screen pregnant women living in slum communities in India for GDM during pregnancy. The slum communities will be randomized in equal number to one of two study arms: (1) the home-based testing arm, where women with GDM will be offered the WHO-recommended oral glucose tolerance test for T2DM screening in their homes; and (2) the referral arm, where women with GDM will be referred for clinic-based postpartum T2DM screening. Through a mixed-methods approach, we will determine the impact of CHW-delivered services on the uptake of postpartum T2DM testing as well as factors pertaining to intervention implementation. Our specific aims are to: 1. Determine the uptake of postpartum T2DM screening in home testing versus referral arms among women with GDM in Pune, India. The primary outcome is uptake of postpartum T2DM screening in women with GDM. We hypothesize that 70% of women in the home testing arm will accept screening for T2DM within one-year postpartum compared to 45% in the referral arm 2. Evaluate implementation of the CHW-delivered programs using a convergent, mixed methods study design and the Consolidated Framework for Implementation Research (CFIR). We will collect qualitative and quantitative data from Aim 1 participants with GDM in both study arms, as well as from CHW, clinical staff, and Ministry of Health Officials to systematically evaluate CFIR Domains. This will be the first study to determine if trained CHW can improve postpartum T2DM screening in urban Indian slums. The results of this study will improve uptake of postpartum T2DM screening, identify low-income women at the highest risk of postpartum T2DM in India, and potentially identify novel approaches for improving postpartum screening for other diseases in low- and middle-income countries, in line with the NIH PAR-22-132.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT Candidate. Dr. Sasha Fahme is an Internal Medicine-trained physician-scientist who has spent the past four years conducting refugee health research in Lebanon. She has first-hand experience treating sexually transmitted infections (STIs) and conducting sexual and reproductive health (SRH) studies of refugee women. She has trained a research team and peer educators to conduct SRH research and has established capacity for STI testing. Her preliminary data suggest that refugee women are eager to learn about SRH from peers and to engage in longitudinal SRH care, with 89% 1-year retention. She seeks to adapt and pilot-test an evidencebased intervention (EBI) to address barriers to SRH care in this population. Career Goals. Dr. Fahme’s goals are: 1. To gain expertise in mixed-methods health sciences research. 2. To strengthen experience in the conduct of humanitarian health research. 3. To foster implementation science skills to develop and evaluate evidence-based interventions. 4. To develop skills in dissemination to translate research findings into practice. 5. To build leadership skills and successfully compete for R01 research grants. Career Development. Dr. Fahme will achieve her goals through workshops, virtual courses, and one-on-one mentored training from Dr. Fitzgerald (career mentorship, humanitarian health, STI epidemiology) Dr. DeJong (mixed-methods, humanitarian health), Dr. Downs (implementation science), and Dr. Abu-Raddad (STI epidemiology, dissemination). She will disseminate contextualized STI guidelines based on her findings, and present her research at international conferences. She will participate in grant-writing workshops and submit an R01 proposal of a hybrid type I cluster-randomized trial to improve refugee women’s SRH in Year 5. Environment. The proposed research and training will take place at Weill Cornell Medical College (New York, USA) and at the American University of Beirut (Beirut, Lebanon), a global leader in refugee health research. Research. Refugee women in Lebanon are among the world’s largest and most vulnerable displaced populations, with a high burden of genital infection symptoms. The etiologies of these symptoms are not known and access to treatment is limited by numerous barriers that are most acute among rural women. Dr. Fahme will recruit 204 symptomatic, rural refugee women to participate in a longitudinal mixed-methods study. She hypothesizes that >30% will experience recurrent genital infections, and that guidelines fail to address drivers of recurrence, which she will explore through in-depth interviews. She will use these data, the ADAPT-ITT model, and the Implementation Outcomes Framework to adapt and evaluate an EBI to address genital infection symptoms in a single-group pilot feasibility study among 30 refugee women

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY Heart failure represents a major cause of illness and mortality in the United States. Preemptive and preventative care are the most effective methods for mitigating the severity of this disease. Thus, the early detection of heart failure is critical to patient prognosis and overall cardiovascular health. The conventional methods for diagnosis are limited to detection of significant cardiac damage and pathological remodeling. We propose using 2- [18F]fluoropropionic acid ([18F]FPA) to image the metabolic alterations in fatty acid metabolism which precede cardiac injury. [18F]FPA-PET is favorably suited for imaging these events and translation to the clinic as: 1) [18F]FPA-PET has been used for imaging tumors in humans and accumulates in the heart, thereby confirming its safety and favorable dosimetry, 2) short chain fatty acids, such as [18F]FPA, are preferentially taken up by the injured heart in response to the impairment in long chain fatty acid oxidation, 3) propionic acid metabolism is restricted to a single mitochondrial pathway which targets [18F]FPA to this organelle and limits its potential for degradation. We predict the metabolic alterations that occur during heart failure effectively increase the uptake and sequestration of [18F]FPA to the myocardium. The metabolic trapping of [18F]FPA is driven by acetyl-CoA synthetase short chain family 1 (ACSS1), which converts these short chain fatty acids to metabolically active and membrane impermeable CoA intermediates. ACSS1 expression and activity are upregulated in patients experiencing heart failure, and many animal models of heart failure. Thus, we hypothesize that [18F]FPA effectively accumulates in the injured heart and can be applied to image the early manifestations of cardiac disease which precede irreversible cardiac injury and remodeling. The goals of this fellowship project are to 1) determine if [18F]FPA can be used to image heart failure, and 2) investigate the role of ACSS1 in accounting for the cardiac accumulation of [18F]FPA. The successful application of most imaging probes depends on a comprehensive understanding of the biochemical pathways that these probes report on. In building our understanding, we can develop precise applications for these tracers to image heart failure, as well as other disease states. The long-term goals of this project will serve as a foundation for the applicant's independent research career. These will be facilitated by the technical, conceptual, and practical knowledge that he will gain over the course of the fellowship training.

NIH Research Projects · FY 2025 · 2023-09

ABSTRACT Diffuse large B-cell lymphoma (DLBCL) is the most frequent B-cell non-Hodgkin lymphoma (B-NHL). The treatment of these diseases remains challenging, with many patients ultimately dying. Despite the clinical success of recent advanced immunotherapies against different tumor types, DLBCLs are largely refractory to these new therapies. The immune resistance mechanisms of these diseases are unclear. The heterogeneity of DLBCLs suggests that their treatment can benefit from precision-medicine approaches. Mutations in the TLR mediator MYD88 and B-cell receptor (BCR) signaling molecules, including CD79B, define the MCD- DLBCL subtype, which displays the greatest aggressiveness and refractoriness to therapies. MYD88 and BCR pro-lymphoma signals are integrated by a downstream molecular complex, whose major functional subunit is MALT1. Targeting MALT1 thus represents an attractive option to specifically interrupt the driver pro-lymphoma signals of these aggressive diseases and block their growth. Our collaborators developed the first selective MALT1 inhibitor (MALT1i) and contributed to the generation of the first MALT1i ever tested in patients (NCT03900598; NCT04876092; NCT04657224). Notably, MALT1 is also active in cells that dampen anti-tumor immunity, specifically immunosuppressive regulatory T cells (Tregs) and exhausted T cells (Tex), which are incapable to react and kill tumor cells. Thanks to our unique access to newly developed MCD- DLBCL mouse models, which harbor an intact immune system, we can now for the first time reliably examine the direct anti-tumor and immune-mediated effects of MALT1is, and their potential for combination with immunotherapy. Our preliminary studies in these models show that MALT1is decrease MCD-DLBCL cells as well as lymphoma-infiltrating Tregs and Tex. Moreover, we find that MALT1is increase MCD-DLBCL antigen presentation and co-stimulatory potential as well as T-cell activation and tumoricidal function, which may overall promote anti-lymphoma T-cell responses. Thus, we hypothesize that pharmacologic MALT1 inhibition in the setting of MCD-DLBCLs will have dual positive anti-tumor effects: (1) limiting tumor proliferation, by interrupting the MYD88 and BCR pro-lymphoma signals and (2) potentiating anti-lymphoma immunity, by counteracting immunosuppressive and dysfunctional T cells and increasing lymphoma cell immunogenicity. Based on this hypothesis, our objective is to establish optimal combinations of MALT1is with immunotherapy able to eradicate otherwise immune evasive aggressive lymphomas. Toward this goal, we will test clinically relevant MALT1is alone and in combination with immunotherapy against MCD-DLBCLs in syngeneic mouse models with normal vs. defective immune system (i.e. lacking specific T-cell subsets/function) to discover the mechanisms by which MALT1 inhibition promotes anti-lymphoma immunity. Moreover, we will perform the first validation that MALT1is can activate T-cell responses in patients enrolled in NCT03900598.

NIH Research Projects · FY 2026 · 2023-09

Attrition along the career development path attenuates the impact of programs designed to attract and support young people entering the biomedical sciences. Reasons for this attrition are many, but include under-preparation, insufficient mentorship, limited networking opportunities, and lack of engagement within the academic community. Weill Cornell Medicine has a longstanding institutional commitment to education, professional development, scientific excellence, and mentoring the next generation of scientists and physician scientists. The proposed program, Advancing Success and Persistence in Research Education, ASPiRE will augment current WCM efforts by focusing on a population not targeted by existing educational programs: postbaccalaureate scholars. ASPiRE will leverage expertise cultivated over many decades, relationships with local and regional partner institutions (Cornell University, Hunter College, Brooklyn College) and WCM presence at national graduate and medical school recruitment meetings to recruit talented scholars who will benefit from support to be competitive for admission in PhD and MD/PhD programs. The selected scholars will be paired with a primary research faculty mentor based on their career interests, collegiate research experiences and the expertise of the faculty members. An additional faculty member, at an academic rank different from the research mentor, will serve as a career mentor. In addition, the scholars will be paired with current 1st or 2nd year graduate students who will serve as near-peer mentors. This tiered mentorship structure will ensure that our scholars have mentors and advisors at multiple levels of the professional development spectrum and thus exposure to the many factors and considerations along the academic scientific career path. The experiential research training will be complemented with professional development advising, coaching and skill building. We will also provide the expertise of an educational psychologist who will meet with students collectively and individually to assess and build personalized academic success strategies relevant to their roles as research trainees, graduate school applicants and future graduate/medical students. We expect that the combination of research education, career development coaching, tiered mentorship and cohort building activities will yield short- and long-term dividends. In the short term, we expect scholars to progress successfully to PhD or MD/PhD programs within two years of program participation. In the long term, we project that program participation will equip scholars with the skills for long and successful careers l as academic research faculty.

NIH Research Projects · FY 2025 · 2023-09

ABSTRACT: UNDERSTANDING GENETIC COMPLEXITY IN SPINA BIFIDA Among neural tube defects (NTDs), myelomeningocele (spina bifida:SB), is a devastating but survivable, human structural malformation. Up to 70% of SB cases are attributed to genetic predisposition, with intrauterine environment precipitating SB manifestation in those at risk. Despite decades of research into genetic factors that underlie NTDs in mouse models, translation to human risk assessment and amelioration of SB cases remain elusive. This is largely attributable to limitations of the typical candidate gene approaches used in genetic studies of human NTDs. Here, our comprehensive systems biology approach to mutation burden in whole genome sequence (WGS) analyses is illuminating molecular pathways to human SB through interrogation of protein coding and non-coding regions, and introduces machine learning to select, in an untargeted fashion, genes with SB discriminatory potential based on gene enrichment by rare, likely deleterious protein coding variants. The project extends our comprehensive genomic effort, generating new WGS on 200 recently collected patient-parent trio (600 genomes) samples. Studies aim to identify specific gene drivers of human SB, illuminate gene-gene interactions leading to SB, and improve mechanistic understanding of this complex birth defect. Aim 1 uses family study and systems biology approaches to seek genes with transmitted or de novo rare variants suggesting SB-association. This begins assessment of parental vs de novo, “second hit”, contributions to SB. Analyses include protein-coding and noncoding sequence single nucleotide variants (SNVs), rare copy number variants (rCNVs), and state-of-the art computational probes leveraging genome 3D structure. Aim 2 tests the functional significance and interactions of these detected genes and variations to: (a) use CRISPR edited isogenic, double heterozygous human stem cells in a novel SOSRS, 3-D in vitro method to evaluate proliferation, self-organization, and differentiation, (b) test the transcriptional impact of these mutations using bulk and single cell RNAseq in mutagenized cells. Aim 3 examines double/multiple-heterozygous protein coding mutations using existing and CRISPR- edited mice to test the histological and gene expression impact of gene interactions on NT closure. Our computational approaches are highly innovative in the field, using machine learning to build network models of human SB risk. We then apply advanced technology for the functional testing of these genetic risk models, including gene editing of human stem cells, compared to isogenic controls, and mice for cellular and systems based hypothesis testing in vitro and in vivo, along with evaluation of the cell-type gene expression changes induced by these variants. Insights from our studies will pave the way for a precision medicine capability to individualize NTD prevention and care for families and the hundreds of thousands of patients living with SB.

NIH Research Projects · FY 2025 · 2023-09

Abstract Despite intensive treatments that often combine surgery, chemotherapy, and radiation, patients with head and neck squamous cell carcinomas (HNSCCs), including oral cavity and esophageal squamous cell carcinomas (OCSCCs & ESCCs), have a long-term survival rate of only 15-40%. Among the reasons for the poor prognoses are that many of these cancers are diagnosed at late stages. Furthermore, “field cancerization” leads to high rates of primary site recurrences. Even after initial surgery/radiotherapy for treatment, patients are at a very high risk for recurrence. Metastases to regional lymph nodes also occur with high frequency. Thus, there is a great need for improvements in both cancer prevention and treatment regimens for head and neck squamous cell carcinomas (HNSCCs). The retinoic acid receptor γ (RARγ) acts as a tumor suppressor in stratified squamous epithelial cells of the skin, a very similar type of stratified squamous epithelium to the oral cavity. Moreover, we have shown that a retinoic acid receptor γ (RARγ) selective agonist, CD1530, can substantively reduce the numbers of carcinomas that develop in a murine model of oral cavity carcinogenesis. Thus, CD1530 acts as a cancer chemopreventive drug in this model. Our hypothesis, which is based on both our published work and new, preliminary data, is that this selective, retinoic acid receptor γ (RARγ) agonist is effective in oral cancer prevention because by changing the transcriptional profile of the oral cavity stem/progenitor cells, CD1530 enhances the ability of stem cells to generate daughter cells destined to differentiate rather than to proliferate. To test this hypothesis we will carry out the following aims: Specific Aim (1): To determine how this RARγ selective agonist, CD1530, affects the proliferation and differentiation properties of the stem/progenitor cells in the pre- malignant state in the carcinogen treated mice: a) we will perform advanced lineage tracing on transgenic mice to delineate the pharmacological actions of CD1530 on the stem/progenitor cells of the oral epithelium; and b) we will define how CD1530 acts on human oral epithelial stem/progenitor cells using a 3D air:liquid culture system. Specific Aim (2): We will perform similar experiments on mice with RARγ specifically knocked out in the stem/progenitor cells of the oral cavity epithelium to assess the function of RARγ as a tumor suppressor and the selectivity of the CD1530 ligand for RARγ. Our goal is to improve cancer prevention approaches for human OCSCCs and to reduce the high frequency of relapse, reducing both mortality and morbidity. Here we will identify the pharmacological mechanism(s) of our novel cancer prevention therapy. We will additionally be able to test critically the idea that RARγ in vivo is indeed the pharmacological target for therapy with CD1530.

NIH Research Projects · FY 2025 · 2023-09

ABSTRACT. Heart failure (HF) affects 6.2 million people in the US, costs $30 billion dollars per year, and results in 1 million hospitalizations per year. Readmission within 30 days occurs in 25% of Medicare beneficiaries hospitalized for HF, and previous interventions to reduce readmissions have had limited success. One of the most promising strategies to reduce readmissions and improve outcomes in HF is through home health care (HHC), which is delivered by Medicare certified HHC agencies, and provides skilled nurse home visits to monitor and manage patients during the post-acute period. Annually, 34% of Medicare beneficiaries hospitalized for HF receive HHC. Our prior AHRQ-funded national, observational, comparative effectiveness study (R01HS020257) found that HF patients had an 8% lower 30-day readmission rate (40% relative reduction) when they received two evidence-based practices: a) early and intensive HHC nurse visits (defined as a first HHC nursing visit within 2 days of hospital discharge with a total of three or more nursing visits within the first week) and b) an outpatient medical visit within the first week of discharge, compared to those who did not receive this timely follow-up. However, nationwide, only 12% of Medicare beneficiaries receive this early visit protocol, representing a major implementation gap. To advance the science and improve outcomes in HF, we will test an intervention called Improving TRansitions ANd OutcomeS for Heart FailurE Patients in Home Health CaRe (I-TRANSFER-HF), comprised of early and intensive HHC nurse visits and an outpatient visit within 7 days of discharge. Using a Hybrid Type 1, stepped wedge randomized trial design, we will test the effectiveness and implementation of I-TRANSFER-HF in partnership with 4 geographically diverse dyads of hospitals and HHC agencies (“hospital-HHC agency” dyads) across the US. Aim 1 will test the effectiveness of I-TRANSFER-HF to reduce 30-day readmissions (primary outcome) and ED visits (secondary outcome) and increase days at home (secondary outcome) among HF patients who receive timely follow-up compared to usual care. Hospital-HHC agency dyads will be randomized to cross over from a baseline period of no intervention to the intervention at different points in time. Medicare claims data from each dyad will be used to ascertain outcomes; these data will be supplemented with national claims data for external controls not in the trial, weighted to produce covariate balance. Hypotheses will be tested with generalized mixed models. Aim 2 will assess the determinants of I-TRANSFER-HF’s implementation using a multi-method approach and guided by the Consolidated Framework for Implementation Research (CFIR). Qualitative interviews will be conducted with key stakeholders across the hospital-HHC agency dyads to assess acceptability, barriers, and facilitators of implementation; feasibility and process measures will be assessed with Medicare claims data. As the first pragmatic trial of HHC in HF, this study has the potential to dramatically improve care and outcomes for HF patients and produce novel insights for the dissemination and implementation of HHC nationally.

NIH Research Projects · FY 2025 · 2023-09

Revised Abstract Recent evidence shows that creating new fat cells (adipogenesis) can counteract the harmful metabolic effects of obesity, which have been shown to originate primarily from abnormal enlargement (hypertrophy) and resulting dysfunction of existing fat cells. Thus, how to increase adipogenesis over hypertrophy is of great interest. Previous work showed that preadipocytes in vivo and in vitro must complete one or more cell cycles, a process referred to as clonal expansion, before they can differentiate into adipocytes. One of the most striking genetic examples of increased adipogenesis was demonstrated by manipulating this clonal expansion period by knocking out the cell cycle inhibitors p21 and p27. Knockout of either p21 or p27 in mice results in a 2-fold increase in adipogenesis and fat mass, but knockout of both results in a dramatic 6-fold increase. Previous work suggests that p21 and p27 are regulated by very different mechanisms and are active at different times during adipogenesis. In recent published work, we identified the molecular mechanisms that could explain the increased adipogenesis observed in the p21- knockout mouse. However, how p27 regulates adipogenesis and tissue mass and how p21 and p27 synergize are poorly understood. We hypothesize that the synergistic expression of p21 and p27 during adipogenesis is the primary mechanism that controls the number of cell divisions before differentiation, and thus controls the number the adipocytes produced per preadipocyte. We will test this hypothesis by using live-cell imaging approaches, together with a fat-pad injection mouse model. We will first use methods to inducibly express and rapidly degrade p27 to determine when and how p27 regulates cell cycle progression during adipogenesis. We will then use live cell reporters for CDK4/6 and CDK2 activity to understand when and how p27 and p21 synergize to regulate CDK4/6 and CDK2 activity and control the number of adipocytes produced. The outcome of this work will be a framework how the clonal expansion period can be controlled to significantly increase adipogenesis over hypertrophy while also ensuring that the progenitor pool is maintained. Our results will likely have broad applicability not only to the maintenance of adipose tissue, but also more generally for the maintenance and regeneration of neuronal, muscle, and other terminally differentiated tissues.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY The NIH All of Us (AoU) Research Program is a national research initiative launched by the National Institutes of Health (NIH) in May 2018 with the goal of advancing precision medicine, which aims to provide personalized medical treatment and prevention strategies based on an individual's unique genetic, environmental, and lifestyle factors. Analysis of real world data like AoU typically requires creation of cohorts that are clinically similar with the exception of the characteristic(s) being evaluated. If the creation of compared cohorts is not conducted with care, results may be confounded by systematic difference in the characteristics of patients assigned to the compared cohorts. This proposal, Similarity Matching In Longitudinal Electronic Patient Data (SMILE PD), will apply a sophisticated patient matching algorithm within an easy- to-use interface to help Investigators to create suitable analytical cohorts to enable generation of accurate, reproducible real world evidence from the rich content of the All of Us data. The project has 4 Aims : • Aim 1. Develop algorithms that learn patient similarities from AoU data in a comprehensive manner. • Aim 2: Develop approaches that can integrate drug and disease information from publicly available data sources to improve the quality of learned patient similarities. • Aim 3: Implement an interactive user interface to specify similarity matching criteria and demonstrate the learned patient similarities • Aim 4 : Apply the patient similarity matching algorithm and interface to conduct an initial assessment of the impact of mental illness and its treatment on chronic disease outcomes The patient similarity matching interface created through this proposal will enable investigators to conduct predictive analytics, risk assessments and comparative effectiveness research in a more robust and reproducible fashion.