Columbia University Health Sciences

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Since 2021, TB incidence in New York City (NYC) has surged partly due to decreased attenƟon during the COVID-19 pandemic and in part due to increased migraƟon across the southern US border. Approximately 205,000 migrants from TB-endemic regions arrived in NYC since April 2022. In 2023, TB incidence in NYC rose by 28%, the highest rates in over a decade, with 89% of cases among individuals born outside the US. Our proposal aims to evaluate innovaƟve methods to improve TB detecƟon, prevenƟon, and treatment among migrants in NYC. IniƟal work by our team in NYC migrant shelters has demonstrated high numbers of persons with of latent TB infecƟon (LTBI) and acƟve TB. Current clinic-based approaches to TB surveillance are ineffecƟve since few high-risk persons complete TB screening and fewer are retained in the TB cascade of care. The proposed intervenƟon, SPOT-TB (Screening with Portable X-rays for rapid recOgniTion of TB), evaluates the use of mobile diagnosƟc teams integraƟng ultraportable digital chest radiography paired with arƟficial intelligence-assisted interpretaƟon, upfront tesƟng for TB (interferon gamma release assay) and HIV, and community engagement to improve iniƟaƟon and retenƟon in the TB cascade of care compared to convenƟonal, clinic- based approaches to TB surveillance. Aim 1 is to idenƟfy acƟve and latent TB in migrant communiƟes using this mobile detecƟon platiorm, hypothesizing that it will increase the proporƟon of migrants compleƟng diagnosƟc evaluaƟon compared to convenƟonal approaches. Aim 2 is to determine the feasibility and acceptability of the SPOT-TB strategy using mixed methods, hypothesizing that it will be highly feasible and acceptable to both care workers and parƟcipants. Aim 3 is to evaluate structural and behavioral barriers to TB care in NYC migrant communiƟes, hypothesizing that unstable housing will be a fundamental barrier and that perceived TB sƟgma will predict subsequent loss to retenƟon in the care cascade. This project employs mixed methods to evaluate the intervenƟon’s feasibility, acceptability, and effecƟveness, uƟlizing advanced staƟsƟcal techniques to understand complex relaƟonships. The scalable SPOT-TB model aims to provide a robust framework for improving TB care in urban settings, with data supporƟng future NIH R01 submissions for larger trials. By enhancing TB detecƟon and care retenƟon, the project seeks to reduce TB transmission and improve health outcomes for NYC's migrant populaƟon.

NIH Research Projects · FY 2025 · 2025-09

Individuals with spinocerebellar ataxia (SCA) suffer from incapacitating symptoms, including imbalance, frequent falls, and loss of movement control. No therapies currently exist to treat cerebellar ataxia symptoms in SCA patients because the intricate cerebellar circuit dysfunction across different SCA types poses a significant challenge for pharmacological therapeutic development. Despite the complexity of the cerebellar circuit, it is uniquely organized, with all the circuit computation ultimately going through a single output- the deep cerebellar nuclei (DCN), representing a pivotal target for neuromodulation. Over the past 5 years, studies in animal models showed promising results that cerebellar deep brain stimulation (DBS) targeting DCN could alleviate ataxia-like motor deficits, paving the way for the initiation of clinical trials in patients. Importantly, a preliminary case series conducted in Brazil supported the early efficacy of cerebellar DCN DBS in improving cerebellar ataxia symptoms in human patients, especially two individuals with SCA3. However, in order to realize the ultimate goal of utilizing cerebellar DBS as a clinical treatment to improve lives of SCA patients, it is imperative to conduct a rigorous Phase 1 clinical trial in the United States, which will inform the design of subsequent, larger trials. In addition, we will need to know if cerebellar DBS can be effective across different SCA types with different cerebellar circuit involvement to determine the patient selection criteria in the future. To this end, we propose to initiate a Phase 1 study of bilateral cerebellar DBS for individuals with SCA1 and SCA3 to assess its safety and preliminary efficacy (Aim 1). Moreover, we will use temporary lead externalization and a DBS system that is capable of recording neural activity to gain an understanding of human DCN physiology. Those data will be synchronized to cerebello-cortical electroencephalogram to gain insights into network effects of cerebellar DBS (Aim 2). The knowledge of human neural activity linked to cerebellar ataxia severity and the circuit responses to cerebellar DBS holds the promise to refine DBS parameters based on neural activity in the future. Our research will offer valuable insights for making decisions regarding the further development of cerebellar DBS for SCA patients and will advance the knowledge of human cerebellar physiology.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY The overall goal of the current project is to determine the functional significance of microglial FOXO3 in Alzheimer’s disease (AD). AD is the leading cause of dementia in the elderly. In addition to the hallmark pathological features, such as β-amyloid peptide (Aβ) plaques, tangles and widespread neuronal loss, there are profound inflammatory changes in the AD brain. Microglia, the brain's immune cell, links closely to all pathological cascades including amyloid, tau and neuroinflammatory changes. Genome-wide association studies (GWAS) have revealed that the known AD risk genes are predominantly expressed in microglia, including the genes encoding the triggering receptor expressed on myeloid cells-2 (TREM2). Aberrant elevation of type-I interferon (IFN-I) signaling, typically associated with an antiviral immune response, has been observed in AD. Recent studies have identified a microglial IFN-I signature in the aging brain as well as in AD, suggesting a role for IFN-I signaling in AD pathobiology. We recently demonstrated that the FOXO3 gene, encoding the transcription factor forkhead box O-3, is a key mediator of cellular stress-induced IFN-I response. FOXO3 is one of the strongest genetic modifiers that determines the longevity of humans as well as a critical regulator of aging process. It is highly expressed in the brain with its abundance in microglia. Our preliminary data shows that FOXO3 signaling is critical for the regulation of lipid droplet accumulation as well as IFN-I pathway activation in microglial cells. Furthermore, FOXO3 directly mediates the signal from TREM2, a prime regulator of microglial activities, making it an attractive molecular target for therapeutic intervention in AD. Despite its critical role in IFN-I response and aging, the role of microglial FOXO3 in AD pathobiology remains elusive. Our central hypothesis is that aberrantly activated FOXO3 critically contributed to microglial activation states, including disease-associated microglia (DAM). To this end, our Specific Aims are: To determine the role for microglial FOXO3 in AD-associated phenotypes in a transgenic mouse model of AD; To investigate the role for FOXO3 in microglial functions in human iPSC-derived microglia (iMGL) model. The proposed study will demonstrate the role of microglial FOXO3 in AD pathogenesis and lay the foundation for therapeutic strategies to restore normal microglia function.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Statin therapy is widely prescribed for the management of cardiovascular diseases, yet statin-associated muscle symptoms (SAMSs) frequently lead to therapy discontinuation. Our study aims to elucidate the underlying mechanisms of SAMSs and explore potential therapeutic interventions. We hypothesize that statin-induced muscle weakness is mediated through ryanodine receptor 1 (RyR1) calcium leakage, exacerbated by the RyR1- T4706M mutation. We have access to muscle tissue and other samples from a patient who carries this RyR1- T4706M mutation and is profoundly intolerant of all statins. We further have a mouse model based on this patient’s genotype. Using cryo-electron microscopy, electrophysiological recordings, in vitro assays, and genetic mouse models, we will identify the binding sites of commonly used statins on RyR1, evaluate their effects on muscle function, and assess the potential benefits of RyR1 stabilization with ARM210 in preventing statin- induced muscle weakness. This research holds promise for identifying novel therapeutic strategies to mitigate SAMSs and improve patient tolerance of statin therapy.

NIH Research Projects · FY 2024 · 2025-09

The Primary Immune Regulatory Disorders (PIRDs) are a group of inborn errors of immunity (IEI) that result from constitutive activation and/or dysregulation of specific immune pathways. There are 130 genes identified to date that are associated with PIRDs. Each PIRD is extremely rare and the PIRDs in general comprise approximately 5% of IEI. Patients with PIRDs often have multiple life-threatening opportunistic infections, autoinflammatory conditions and autoimmune sequelae related to the constant activation of their immune system. Given the rarity of each PIRD, and of PIRDs in general, there are few if any therapeutic interventions for these patients. Hematopoietic Stem Cell Transplant (HCT) offers a curative option for many patients with PIRDs. The high levels of inflammatory mediators in patients with PIRDs however has made it extremely difficult to have successful outcomes due mostly to graft failure/rejection as well as post-transplant immune complications. Patients with PIRDs therefore have limited therapeutic options and only those that are most severely affected are considered for cures with HCT. The BRIDGE Trial is a Phase 2 clinical trial to improve outcomes of curative therapy with HCT for patients with a PIRD diagnosis. The protocol utilizes a biomarker-guided immune suppression prophase to dampen the inflammatory milieu prior to and during a myeloablative conditioning regimen for HCT. Patients may also receive targeted inflammatory suppression regimens to balanced milieu while they are receiving conditioning and to enable more efficient engraftment, balanced immune reconstitution, and improved outcomes:  Patients with PIRDs that result in perturbations of their IFNγ pathway will receive a prophase of an IFNγ neutralizing monoclonal antibody called emapulamab prior to and during the conditioning regimen. Emapalumab is an orphan drug approved for primary hemophagocytic lymphohistiocytosis (pHLH).  Patients with PIRDs that result in dysregulation of other inflammatory pathways will receive a generalized inflammatory suppression prophase with fludarabine and dexamethasone, similar to what is currently being used for patients with hemoglobinopathies undergoing HCT. The dataset produced by this trial will be pivotal to expand indications for emaplaumab. The trial will provide critical data for continued future clinical trials to provide durable cures to patients with PIRD diagnoses. We take advantage of our expertise in immune reconstitution and biomarker discovery studies to provide in- depth correlative biology. Our focus centers on deep immunophenotyping of reconstituting subsets, identification of soluble biomarkers for immune mediated complications, and on identifying mechanisms of how a targeted immune suppression prophase helps provide an appropriate immune milieu during conditioning and as the hematopoietic system regenerates after HCT.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Background. Global tuberculosis (TB) incidence has only decreased incrementally – despite concerted efforts to understand TB transmission patterns in high-prevalence settings. As TB exhibits pronounced spatial heterogeneity in high-incidence settings like South Africa, spatially targeted case-finding approaches may be effective. Although the underlying processes giving rise to spatial heterogeneity remain unclear, individual mobility and assortative patterns likely underlie areas of heightened TB transmission. Understanding spatial mobility patterns may provide insights into the mechanisms that generate and interconnect hotspots within a community, guiding future active case-finding approaches. Aims. In line with NIAID Strategic Priorities for Tuberculosis Research, this study will 1) characterize forms of spatial mobility and their association with recent transmission and 2) examine the relationship between spatial mobility subclasses and community-based TB transmission hotspots. Elucidating these gaps will advance our understanding of local transmission and inform the development of targeted case-finding interventions to curb ongoing TB transmission in endemic settings. Approach. Since there is a limited understanding of the mobility patterns of TB patients, this research will use detailed mobility data (i.e., the frequency, duration, and spatial dimensions) from TARGET-TB, an ongoing population-based epidemiologic study that enrolls all incident TB cases identified in a peri-urban community in KwaZulu-Natal, South Africa, to identify individuals, groups, and places where control efforts may be targeted. Furthermore, advances in genomic statistical modeling have greatly enhanced our understanding of transmission linkages at various spatial scales. This contextual setting presents a unique opportunity to combine detailed spatial mobility data with bacterial whole genome sequencing data to understand the relationship between spatial mobility and recent transmission and identify transmission hotspots. The overarching goal is to provide insights into local transmission mechanisms to inform targeted case-finding strategies. Training. Ms. Bezuidenhout’s training plan leverages her quantitative abilities and TB research experience to advance her skills and launch her career as an independent investigator focused on spatial mobility and TB transmission. Her training goals are to develop in-depth knowledge of spatial mobility, advance her expertise in molecular epidemiology and TB transmission inference, learn advanced epidemiologic techniques for missing data, and build capacity for effective research dissemination. Under the guidance of her Primary Sponsor, Ms. Bezuidenhout will receive tailored mentorship from a team of experienced TB researchers who work with the parent study, conduct spatial- and molecular-focused research, and have tremendous expertise in the requisite quantitative methods. Training will take place at Columbia University, a high-caliber institution with specialized research programs in population health, infectious disease, and spatial and social epidemiology.

NIH Research Projects · FY 2025 · 2025-09

SUMMARY Lung regeneration involves the reuse of signaling pathways that are important for organ development. Previous studies have shown that these pathways converge to regulate the transcription of downstream targets. In contrast, little is known about the modifications of the resulting transcripts. In this proposal we will fill the knowledge gap and provide initial insights into the mechanism by which posttranscriptional regulation controls lung development and regeneration. We will study how Mettl3/14 complex-mediated RNA modifications are involved in lung epithelial differentiation. Our central hypothesis is that Mettl3/14-mediated m6A deposition on transcripts including Sox9 is critical for lung development and regeneration. We will test the hypothesis with three specific aims. Aim 1 will address the mechanism by which Mettl3/14-mediated RNA modification regulates lung development. We will use a combination of mouse genetics, Nanopore, m6a-SAC-sequencing and proteomics to identify and functionally test mRNA substrates that are modified by the Mettl3/14 complex. We will also study whether Sox9 transcripts are modified by the methylation complex. Aim 2 will focus on the Mettl3/14 complex-mediated RNA modification in alveolar regeneration. We will also investigate the role of Sox9 in alveolar regeneration through Sox9 loss- and gain-of-function studies. Aim 3 will examine whether the function of posttranscriptional regulation is conserved during the differentiation of human pluripotent stem cells-derived lung progenitor cells. Combined with the findings obtained from Aim 1, Aim 3 is expected to offer candidate transcripts that are regulated by the Mettl3/14 complex across species. Together these studies will help us gain a better understanding of the normal mechanism regulating lung development, meanwhile enabling insights into alveolar regeneration following injury.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT To ensure accurate perception of the world, nervous systems must distinguish between sensory inputs caused by external stimuli and those generated by the body’s own movements. During rapid eye movements, or saccades, the brain suppresses sensory signals from self-generated motion through a process known as saccadic suppression. However, little is known about how this suppression affects the feature encoding capabilities of specific cell types within a visual network and the impact on broader visual processing. This project aims to elucidate the neural mechanisms of saccadic suppression using the Drosophila melanogaster model, which offers unparalleled genetic access and a tractable nervous system with a fully mapped connectome. The research will focus on the Lobula Columnar (LC) cell network, which encodes specific visual features and is known to exhibit suppression during body saccades. The project has three specific aims: (1) to characterize the neural inputs contributing to saccadic suppression in LC neurons through electrophysiological recordings and connectomic analysis, (2) to evaluate how saccadic suppression affects feature encoding across the LC network using population-level two-photon calcium imaging and advanced analytical techniques, and (3) to develop a computational model predicting how suppression impacts distinct LC subpopulations and their contributions to visual perception. This research will provide fundamental insights into how self-generated motion is processed and suppressed across visual systems. As part of the fellowship, I will receive training in electrophysiology, calcium imaging, and computational modeling under the mentorship of Drs. Gwyneth Card, Rudy Behnia, and Larry Abbott at Columbia University’s Zuckerman Institute. This world-class environment will provide me with the necessary skills and resources to achieve my long-term goal of establishing an independent research program focused on sensorimotor integration and neural circuit function.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY In this project, we propose to investigate the role of RNA modifications in Alzheimer's disease (AD) through an innovative integration of genetics, multi-omics analysis, and functional validation. Recognizing that the molecular mechanisms underlying AD onset and progression remain incompletely understood, our study aims to examine how genetic variants influence N6-methyladenosine (m6A) and pseudouridine (Ψ) modifications in aging brains and their contributions to AD pathogenesis. Our overarching goal is to map RNA modifications in human brain cells, identify their genetic regulators, and understand their causal roles in AD through three integrated aims: (1) Creating a comprehensive atlas of m6A and Ψ modifications in human brain cells from multiple ancestries and mapping their quantitative trait loci (RNAmQTL); (2) Integrating RNAmQTL with other molecular QTL and AD genome-wide association study (GWAS) data to elucidate the molecular functions of RNA modifications and their impact on AD; and (3) Characterizing molecular and cellular phenotypes of candidate m6A sites and AD risk genes using human iPSC models. The impact of this work extends beyond providing the first genetic study of RNA modifications in human brain. By leveraging genetic variation as natural perturbations, we can distinguish causal factors in AD pathogenesis from reactive changes that merely respond to disease progression. Our approach combines novel experimental technologies (CAM-seq, BID-seq) with advanced statistical methods for multi-context QTL integration (ColocBoost, multi-cTWAS) to reveal new mechanisms underlying AD. This project promises to identify novel therapeutic targets with clear genetic underpinnings, potentially leading to the discovery of new AD biomarkers and treatment strategies.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Stillbirth is far too common in the U.S. with 20,000 stillborn babies every year with large racial and ethnic disparities. Black birthing individuals have twice the risk of stillbirth compared to White individuals. The Collaborative Action for Research to End Stillbirth Research Center (CARES) will conduct innovative, integrated, multilayered research - with and for people with lived experience of stillbirth squarely at the center- to develop and implement actionable strategies to improve the prediction of stillbirth early in pregnancy and to understand reasons for the excess risk for Black birthing individuals. We propose to address a critical area in stillbirth care – early identification of patients at highest risk for stillbirth to facilitate prevention. Screening patients early in pregnancy is important as 63% of stillbirths occur before 32 weeks of gestation. Joining efforts from researchers across essential disciplines, people with lived experience of stillbirth, and community, public health, and health care stakeholders, CARES will address the following Specific Aims: Aim 1. Establish a strong infrastructure to support stillbirth research and collaboration across the consortium. With input from the CARES Stakeholder Advisory Board and the CARES Parent Advisory Board, we will develop and maintain a core team of investigators, collaborators and staff with expertise essential for a broad range of stillbirth-related research. We will also build shared resources to promote interdisciplinary team science and ensure access to a diverse patient population to facilitate stillbirth research. Aim 2. Develop a scalable, electronic health record (EHR)-based, dynamic risk prediction model for stillbirth. Inadequate data sources have been identified as a major barrier to advancing knowledge on stillbirth and its prevention. We will (2a) Ascertain patients’ and health care professionals’ perspectives on risk factors for stillbirth (overall and for Black birthing individuals specifically), data needs for stillbirth research, and the acceptability and design of a mobile app-based patient data reporting tool to support pregnancy monitoring and stillbirth prediction; (2b) Develop and validate EHR-based and artificial intelligence-powered algorithms for automated identification and characterization of stillbirth, measurement of stillbirth risk factors, and prediction of stillbirth risk scalable across institutions; (2c) Develop and test a mobile app for patient-reporting of pregnancy information to augment EHR data and support pregnancy care. Aim 3. Develop novel markers of underlying incipient placental dysfunction early in pregnancy for predicting stillbirth. Fetal growth restriction (FGR) is a major antecedent to stillbirth with the most common underlying pathogenesis being placental dysfunction. Accurate identification early in pregnancy and management of FGR could potentially make an impact on stillbirth prevention. We will conduct a prospective cohort study to investigate innovative (3a) placental imaging before 14 weeks’ gestation, (3b) placental biomarkers, and (3c) fetal genetic markers for predicting fetuses at greatest risk for stillbirth. CARES will use multifaceted approaches applicable to the entire population of birthing people to prevent stillbirth.

NIH Research Projects · FY 2025 · 2025-09

Atherosclerotic cardiovascular disease (CVD) is the leading cause of death worldwide. While many athero- sclerotic plaques remain clinically silent, a subset of high-risk plaques with thin fibrous caps and necrosis can rupture or erode, leading to acute CVD events such as myocardial infarction. There is abundant evidence in humans and experimental models that one major cause of thin-capped, necrotic plaques is defective clear- ance of apoptotic cells (ACs) by macrophages (Ms), a process known as efferocytosis. Efferocytosis pre- vents dead cells from becoming necrotic and also activates pathways that promote both additional dead cell clearance (continuing efferocytosis) and tissue resolution. For these reasons, the impairment of efferocy- tosis that occurs in atherosclerosis promotes thin-capped, necrotic lesions. However, when plasma LDL is markedly lowered, the effero-resolution cycle is "re-awakened," leading to cap thickening and lower necrosis (regression) and, in humans, lower risk for CVD. Accordingly, understanding the mechanisms linking ef- ferocytosis to resolution and cap thickening, which represents a major gap in CVD research, could suggest novel treatments. I have begun to address this gap through my recent discovery of a novel pathway in effero- Mϕs: tryptophan (Trp) from the phagolysosomal degradation of AC proteins is metabolized by IDO1 to kynurenine, which activates the aryl hydrocarbon receptor (AhR) to promote tissue resolution. Most im- portantly, I have strong preliminary evidence that this pathway is crucial for enhancing plaque stability during athero-regression. In this context, the goal of my proposal is to elucidate the molecular-cellular mechanisms that link the Trp-AhR pathway to cap thickening; test causation in mouse models of athero-regression; and show relevance to human atherosclerosis. I hypothesize: (1) AhR activation in effero-Ms enhances cap formation by promoting crosstalk with smooth muscle cell (SMC)-derived cap forming cells; and (2) the pathway relies on two essential processes: upregulation of the lysosomal Trp transporter SLC36A4 by pro- teasomal regulation; and enhancement of continuing efferocytosis by two complementary pathways that ac- tivate the actin-remodeling GTPase Rac1. For hypothesis #1 (Aim1, K99 phase), I will use inducible knockout models of AhR and IDO1 in Ms and SMCs and single-cell RNA sequencing in SMC-tracer mice to explore how the Trp-AhR pathway in effero-Ms communicates with cap-forming cells in athero-regression to pro- mote cap thickening. For hypothesis #2 (Aim2, R00 phase), I will examine how efferocytosis enhances SLC36A4 stability by regulating the ubiquitin-proteasome system; and explore both genomic and non-ge- nomic mechanisms linking the Trp-AhR pathway to Rac1 activation and continuing efferocytosis. This re- search will provide new insights into the mechanisms of plaque stabilization and thereby suggest novel ther- apeutic ideas to promote stable plaques. Importantly, the program will provide me with outstanding mentor- ship and career guidance to enable my transition to an independent career in cardiovascular research.

NIH Research Projects · FY 2025 · 2025-09

Project Summary The rapid increase in the incidence of Barrett’s esophagus (BE), its malignant form esophageal adenocarcinoma (EAC), and junctional gastric cancer has produced serious health and financial burdens in the U.S. Thus far, effective treatment options for these diseases are limited in part due to an incomplete understanding of the molecular mechanisms driving the initial metaplasia and subsequent neoplastic progression. This application, by two PIs with complementary expertise, seeks to address the issue through combining scRNA-sequencing analysis, innovative BE mouse models and organoid modeling. We previously demonstrated that gastric cardia progenitor cells and transitional basal cell (TBCs) contribute to BE in the transitional zone of the gastro-esophageal junction (GEJ). However, how these progenitor cells behave in BE-dysplasia-EAC progression remains unclear. Additionally, the molecular mechanism driving the disease progression is also unknown. Our preliminary data suggest GEJ metaplasia and its progression towards EAC involves progenitor plasticity facilitated by p53 loss, an early genetic lesion in BE. Furthermore, we found that Barrett’s metaplasia and EAC is associated with the enrichment of tuft cells. Therefore we hypothesize that Barrett’s metaplasia and dysplasia originate from GEJ progenitor cells, modulated by the presence of p53 mutation and tuft cell expansion. Three specific aims are formulated to test the hypothesis: Aim 1 is to determine the origins and evolution of BE metaplasia from progenitor cells at the EGJ. Aim 2 is to elucidate the mechanisms by which p53 mutation promotes BE progression, and Aim 3 is to clarify the role of tuft cells in BE pathogenesis and progression. Combining our joint expertise on mouse genetics, cell biology, chromatin biology and epigenomics, this work will provide novel mechanistic insights into the mechanisms underlying Barrett’s metaplasia and its malignant progression, offering new approaches to treat these diseases.

NIH Research Projects · FY 2025 · 2025-09

Project Summary The majority of synthesized proteins undergo glycosylation, a process by which a carbohydrate, or glycan, is attached onto the protein surface serving both structural and functional roles. Proper glycosylation in the lumen of the endoplasmic reticulum requires membrane accessible sugars, primarily mannose, in order to synthesize complex, branched oligosaccharides for transfer onto nascent peptides. To traffic sugars along the membrane, they must be transferred onto lipid polyprenyl carriers, namely dolichol phosphate. The synthesis of these mannose glycosyl carriers by the Dolichol Phosphate Mannose 1 (DPM1) represents the primarily mechanism of glycosyl donor biosynthesis, a pathway that is subsequently disrupted in severe types of Continental Disorders of Glycosylation (CDGs). Since sugars play a critical role in folding, stability, and affect the function of numerous proteins across several organ systems, DPM1 causing CDGs result in severe development delays, seizures, liver disease, and neuromuscular impairment. The molecule mechanism of DPM1 remains unsolved, largely due to a lack of structural information about its interaction with both the sugar and polyprenyl substrate which need to be mediated towards an active site that lies just outside the membrane. Existing structural studies have focused on a bacterial enzyme homolog, GtrB, which provides a model for understanding DPM1 and CDG. Although GtrB has been structurally characterized, significant questions remain about the binding sites and conformational changes required for its enzymatic activity. Specifically, we lack a model by which a hydrophobic polyprenyl carrier is brought into proximity to the cytosolic sugar substrate and if a conformational change is needed within the membrane region of GtrB. Here, we propose a time-resolved cryo-EM approach to study the enzymatic states of GtrB catalysis. The approach involves a 'flash and freeze' system using chemically-caged substrates to rapidly initiate enzyme activity during sample preparation with UV light. This method is designed to overcome the limitations of traditional cryo-EM in capturing transient and high-energy states. By applying this technique, the project will identify and analyze various structural states of GtrB, including its holo, intermediate, and product-bound forms, thereby providing a detailed model of glycolipid biosynthesis. The collected model will be integrated with molecular dynamics to provide a holistic model of catalysis that is experimentally and computationally validated. We observe that to mediate polyprenyl coordination, there is a major shift in two peripheral membrane helices in order to lower the lipid carrier into the cytosolic active site. Several mutations in DPM1 that cause CDG can be mapped to this region, indicating a conserved mechanism critical for product formation. We will investigate the kinetic effects of these mutations by monitoring the rate of product formation in a native-liposome environment. Through these investigations, the project aims to enhance our understanding of glycosylation and its disruption in genetic disorders.

NIH Research Projects · FY 2024 · 2025-09

Project Summary/Abstract In the U.S, preterm birth affects 1 in 10 pregnancies, and about half of preterm births are spontaneous as opposed to clinically-indicated inductions or cesarean sections. Despite the grave and widespread threat posed by spontaneous preterm birth (sPTB), its etiology is not fully understood, and diagnostic and therapeutic tools remain limited. Research has independently linked human genetics and vaginal microbes to preterm birth, but no study has explored links between all three entities. Furthermore, research on the associations between genetics and the vaginal microbiome has been constrained by small sample sizes, heterogeneous sample populations, and the use of 16S rRNA sequencing, which cannot classify bacterial taxa at the subspecies level. To define sPTB risk factors and develop effective diagnostics and therapeutics, we must gain a high-resolution understanding of microbial and genetic contributions to prematurity, including causal effects. The objective of this proposal is to investigate associations between host genetics, the vaginal microbiome, and sPTB in a large, diverse cohort with metagenomic sequencing. The nuMoM2b study collected genotyping, vaginal swabs, and extensive clinical data on >10,000 women from eight sites across the U.S. I will detect sample processing errors in this cohort by comparing genotypes inferred from metagenomic sequencing of vaginal swabs to those independently obtained in chip genotyping. I will generalize this method such that it may be applied to any study with both genotyping and metagenomic sequencing. After using my method for quality control in the nuMoM2b cohort, I will conduct Genome Wide Association Studies to detect genetic variants associated with the microbiome. I will investigate variants associated with microbiome characteristics imperceptible by 16S sequencing, such as the relative abundances of bacterial strains or their genomic profiles. I will then utilize microbiome-associated genetic variants in Mendelian Randomization analysis to probe causation of the microbiome on sPTB. Finally, I will train a predictive model on both genetics and microbiome data and benchmark it against models trained on either data source alone. This project will investigate causal effects of microbiome characteristics on sPTB, thus elucidating sPTB’s etiology and providing targets for novel interventions. The machine learning model will demonstrate the potential of diagnostic tools that predict sPTB risk from vaginal microbiota and genetics, which can be easily collected via vaginal swabs and blood testing, respectively. At Columbia, I have access to the facilities, equipment, and mentorship necessary to complete the proposed work. The F31 Ruth L. Kirschstein NRSA will support completion of this specific project while broadly encouraging my academic and professional development, including my progress towards a career as an independent investigator using computational tools for the study of reproductive biology.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract This proposal outlines a five-year research career development program aimed at prioritizing genes that are potentially causal to the development of systemic sclerosis (SSc) using multi- omics analyses. The candidate is currently an Instructor in Medicine at the Columbia University Irving Medical Center and a rheumatologist at the New York-Presbyterian Hospital. The proposal leverages the candidate's established research background in genetic epidemiology and computational biology and broadens his expertise to encompass multi-omics analysis across the realms of both population genetics and single-cell sequencing. The proposed research and training will equip the candidate with a distinctive set of cross-disciplinary skills, fostering his transition to an independent physician-scientist in -omics science and precision medicine in SSc. SSc is a systemic autoimmune rheumatic disease with a 10-year survival rate of 71.7%, a statistic that has unfortunately remained stagnant over the past two decades. There is an unmet need to understand the causal biological signals that drive organ-specific disease activity. With the advent of multiple population quantitative trait loci (QTL) datasets, which concurrently measure genomic variation and other -omics data, innovative methodologies have been developed to predict the causal genes which mediate the genomic loci discovered in the genome-wide association studies (GWAS). The understanding derived from population-level post-GWAS analyses can generate pivotal hypotheses that guide the analyses of single-cell sequencing data. The specific aims of this proposal are: 1. Prioritize putative causal genes associated with SSc using population-level post-GWAS analyses, including the transcriptome- wide association study (TWAS), proteome-wide association study (PWAS), and multi-omics Mendelian randomization. 2. Discover key pathological B cell states using simultaneous scRNA- seq with scCITE-seq and scBCR-seq, with data-driven and hypothesis-driven analyses. The proposed research could enhance our understanding of SSc mechanisms and generate hypotheses for the discovery of novel therapeutic targets and biomarkers.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Dysfunction in insulin receptor (IR) signaling is implicated in various metabolic disorders, including diabetes and cancer. Since the discovery of insulin more than a century ago, considerable effort has been made to elucidate its metabolic function. Given the high incidence of patients with both diabetes and cancer and the links between tumorigenesis and hyperinsulinemia (or elevated insulin level in the blood), there is a pressing need to reassess insulin’s “mitotic” function via activation of the MAPK signaling pathway. The primary objective of my research is to understand the molecular mechanism and biological function of biased agonism of IR activation by designer ligands. Additionally, I aim to use these designer ligands as tools to elucidate the regulatory mechanism of IR trafficking system. Recently, we functionally characterized and determined the cryo-EM structures of insulin-bound and designer ligand-bound IR. Notably, we observed that designer ligand induces a distinct active conformation of IR compared to insulin and exhibits biased agonism against the MAPK signaling pathway through the same IR. Furthermore, my preliminary data demonstrates that the designer ligand reduces IR levels in vivo and in cultured cells by promoting the degradation of internalized IR, rather than recycling it back to the cell surface. These results raise immediate questions: (i) how do different IR active conformations induce biased agonism and modulate downstream signaling pathways, (ii) what are the biological outcomes of the biased agonism against the MAPK signaling pathway, and (iii) which regulators sort IR for recycling or degradation? To address these questions, in Aim 1, I will elucidate the mechanism and biological function of biased agonism of designer ligands in cultured cells and mice. In Aim2, I will use designer ligands as tools to identify regulators of IR trafficking by proximity-dependent biotinylation proteomics. By combining cell biology, biochemistry, proteomics, and mouse physiology, I aim to establish structure- to-function relationship between IR, its downstream signaling pathways, and physiological processes. This research project will be conducted at Columbia University under the co-mentorship from Dr. Eunhee Choi and Dr. Domenico Accili. The collaborative environment at Columbia, coupled with distinct yet complimenting expertise of my sponsors in structural biology, cell signaling, and physiology, provides me with unparalleled access to a wealth of resources, both intellectual and technical. These resources are crucial for the successful execution and accomplishment of my proposed multidisciplinary research project and training.

NIH Research Projects · FY 2025 · 2025-09

Every year, more than 1.6 million U.S. adults experience an acute cardiovascular disease (CVD) event (i.e., acute coronary syndrome, stroke/transient ischemic attack). Over 200,000 of these adults will develop clinically significant posttraumatic stress symptoms (PTSS) that undermine health behaviors (e.g., poor sleep, physical inactivity) and increase secondary risk. Critically, acute CVD is not experienced in isolation. Partners also experience significant distress, further endangering patients’ health—and their own. Aging partners are more likely to also be patients with chronic health conditions of their own, which underscores the necessity of examining acute CVD as a dyadic experience. The proposed study will be the first to empirically evaluate the impact of couples’ distress early after evaluation for acute CVD on dyadic health and estimate dyadic influences in the progression of patient and partner distress during the first month post-event. Relationships are among the strongest predictors of mental, physical, and behavioral health. Dyadic interventions could be leveraged to improve patient outcomes. Current recommendations to bring a close other to the ED as a source of support reflect our belief in the health-promoting potential of relationships. However, our research suggests that dyadic processes differ substantially early after an acute event v. during the well- studied chronic disease phase. In this early phase, partners can increase CVD patients’ psychological distress in the ED and, subsequently, worsen their PTSS. We will leverage our ED-based research infrastructure to recruit a diverse sample of patients evaluated for acute CVD and their partners (N = 160 dyads). Data collection will include surveys at baseline enrollment and 1- and 6-months post-hospital discharge, weekly assessments of distress during the first month post-discharge, and 28 days of continuous accelerometer- derived sleep and physical activity assessment. Guided by Cornelius’ (PI) dyadic disruption theory (DDT), we hypothesize that couples’ greater distress at ED evaluation will be associated with greater PTSS, poor sleep, and physical inactivity at 1- and 6-months post- hospital discharge. We expect to reveal dyadic influences in distress progression over the first month after acute CVD and will test theory-based mechanisms of patient and partner influence. We will use qualitative inquiry to elaborate, clarify, and enhance the validity of dyadic mechanisms of health and distress progression. We will query suggestions, preferences, and barriers regarding in-hospital dyadic interventions to address key gaps limiting clinical care, including the current lack of effective interventions to prevent medically induced PTSS and the unfortunately typical neglect of partners’ needs during the sensitive window early after acute CVD. Researchers and couples facing medical stressors report high enthusiasm for dyadic interventions. If successful, results will inform the generation of implementable, mechanistic interventions that can be delivered to couples in the hospital to promote dyadic mental, physical, and behavioral health and optimal aging.

NIH Research Projects · FY 2025 · 2025-09

Project Summary The primate visual system must balance competing demands, including representing objects and places in a format that is both abstract enough to be recognizable under novel conditions, but also specifically bound to other objects and places via contextual associations. How the visual system achieves this balance remains to be understood, as current artificial neural network (ANN) models fail to exhibit this same robustness and flexibility. One notable difference between ANNs and the brain is that the former preponderantly model the visual system as a single feedforward hierarchy, while ample evidence suggests that the latter in reality includes numerous parallel hierarchies with possibly complementary propensities for abstraction versus granularity. Aim 1 addresses such variations in representational geometry over cortical space by contrasting joint encoding of multiple objects in inferotemporal cortex (IT) and parahippocampal cortex (PHC) of common marmoset monkeys. I hypothesize that representations of different objects in IT will be comparatively independent of each other, while PHC will more nonlinearly encode groups of objects. Artificial neural networks trained on various loss functions, architectures, and training diets will then be used to attempt to model these phenomena. Aim 2 will investigate variation in representational geometry over the course of familiarization with a novel virtual environment over several days. I hypothesize that neural representations of different views of the learned environment will acquire the same correlation structure as the images themselves in the underlying latent factor space. This research will suggest new, non-standard neural network architectures for modeling vision, help us make more precise predictions about the effects of stroke or lesion on different parts of the brain, and better understand the underpinnings of disorders like attention deficit hyperactivity disorder, autism, frontotemporal dementia, and face and object agnosias. The training plan described in this proposal will afford me proficiency in new experimental and theoretical methodologies, including large-scale, multi-area electrophysiological recording, the use of common marmosets as a model organism for visual neuroscience, deep neural network modeling, and advanced data analysis techniques for understanding the structure of neural representations. I will receive expert training in electrophysiology and machine learning from my sponsor Dr. Elias Issa, as well as in theoretical neuroscience and advanced neural data analysis methods from my co-sponsor Dr. Stefano Fusi. This work will be conducted at Columbia University’s Zuckerman Institute, a world-class neuroscience research and training institution whose faculty specialize in approaches ranging from molecular to systems to theoretical.

NIH Research Projects · FY 2025 · 2025-09

The International Workshop on Pediatrics & HIV is organized on an annual basis prior to the biennially organized IAS or AIDS Conference. This workshop is the only meeting entirely devoted to research in prevention and treatment of HIV infections in infants, children, adolescents and pregnant and breastfeeding women, making it the primary forum for the world’s leading researchers. By bringing together experts from different disciplines with presentations in a variety of formats, the meeting offers a collaborative setting where the latest developments are presented, discussed, interrogated, and evaluated. The 17th Workshop is scheduled to be held in Kigali, Rwanda and virtually on 11-12 July 2025, prior to the 13th IAS Conference on HIV Science (IAS 2025). The program will include topics from among the following: Antiretroviral Treatment in Infants, Children, and Adolescents; Clinical Management of Infants, Children, and Pregnant/Breastfeeding Women; Coinfections/Complications in Infants, Children, Adolescents, and Pregnant/Breastfeeding Women with HIV; Clinical Issues in HIV Negative Infants Exposed to HIV; Prevention of Vertical HIV Transmission – Interventions and Implementation; HIV Prevention & Treatment in Pregnant and Breastfeeding Women; Clinical Management Issues Specific to Adolescents; HIV (and STI) Prevention in Adolescents; and Pediatric HIV Case Finding Including Early Infant Diagnosis. Given previous success with this format, we expect the 18th and 19th editions to follow this same pattern, including a similar program and schedule. The meeting format is also highly innovative. Moving from a more traditional format of plenaries and oral abstract sessions, the organizers have introduced unique approaches including structured debates, oral poster presentations, poster walks, clinical-case presentations, curated panel discussions, video presentations and a social program including a networking dinner where early career investigators meet with senior researchers. Attendance has increased substantially in the last several years with 292 delegates in 2024; highly favorable annual evaluations underscore the Workshop’s importance. The aims of the workshop are to 1) provide a platform for presentation and discussion of the latest developments in the field; 2) gather leading researchers involved in pediatric and perinatal HIV in a stimulating, interactive forum; and 3) promote the next generation of researchers. The objective of this proposal is to provide support for three annual workshops including participation of plenary speakers as well as members from the community of adolescents with HIV infection, and to increase the number of scholarships for early career investigators.

NIH Research Projects · FY 2025 · 2025-09

Project summary/abstract This application presents a five year research career development plan focused on the study of neonatal respiratory progenitor cell function in response to hyperoxic conditions. The candidate is currently an Assistant Professor in Pediatrics in the division of Pediatric Pulmonology at Columbia University Medical Center. The current proposal outlines a plan to build on the candidate’s prior research and clinical experience with lung disease by merging two fields of interest, each represented by her mentor and co-mentor #1: mechanisms of lung injury and repair, and early lung development and progenitor cell function. Under the guidance of Drs. Jeanine D’Armiento and Wellington Cardoso, both well-established researchers and experienced mentors in their respective fields, the candidate plans to develop interdisciplinary and translational skills that will enable her to transition towards independent health-oriented research in mechanisms of injury and repair in the premature respiratory system. As obstetric and neonatal care advances, children born at earlier gestational ages are surviving longer. Bronchopulmonary dysplasia (BPD), a chronic lung disease that affects roughly 35% of extremely prematurely born children in the United States, is the most common complication of prematurity, and will likely remain so without significant biomedical advances in its management. Children with BPD are often oxygen dependent for long periods of time, and as respiratory care is largely supportive at this point, some require tracheostomy and prolonged mechanical ventilation. The developing lung and its progenitor cells are remarkably plastic, and a better understanding of the mechanisms by which post-natal lung development occurs in the face of injurious agents such as oxygen and mechanical ventilation can inform future therapies to promote healthy and functional lung growth. This research proposal aims to address these questions by studying the differentiation capacity and transcriptional profile of neonatal respiratory progenitor cells after hyperoxic exposure. The candidate and her mentoring and advisory team hypothesize that secreted frizzled-related protein 1 (SFRP1), a member of the Wnt signaling pathway, is central to regenerative capacity. More specifically, the aims of this proposal are 1) To determine the effect of hyperoxia on neonatal airway basal cell differentiation and Wnt signal gene expression, and 2) To determine the role of Sfrp1 in type 2 alveolar epithelial cell signaling during epithelial regeneration in a mouse model of neonatal hyperoxic lung injury. Through these scientific aims and training plan, the candidate intends to generate further hypotheses that will inform the future management of infants and children with BPD.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Combination chemotherapy is the standard of care in treatment-naïve metastatic pancreatic adenocarcinoma (mPDA), and the addition of immune checkpoint blockade has failed to improve outcomes. The C-X-C motif chemokine receptor 4 (CXCR4)/C-X-C motif chemokine ligand 12 (CXCL12) axis contributes to the exclusion of anti-tumor immune cells from the tumor microenvironment (TME) in mPDA. We recently conducted a phase I study of motixafortide (CXCR4 inhibitor), cemiplimab (anti-PD1), gemcitabine and nab-paclitaxel (MCGN) in 11 patients with treatment-naïve mPDA, demonstrating promising, durable clinical efficacy with an objective response rate of 64% (7/11). Using single nucleus RNA sequencing (snRNAseq) analyses of pre-treatment biopsy samples, we demonstrated that CXCL12-producing cancer associated fibroblasts (CAFs) were more abundant in patients with a better response to therapy. These CXCL12-producing CAFs belonged to a CAF subtype displaying a ‘pro-axonogenic’ gene expression signature, enriched in axon guidance and axonogenic programs. We are now conducting a phase II, investigator-initiated, multicenter, randomized controlled trial (RCT) to evaluate this novel immunotherapeutic approach. This trial compares MCGN (N=72) with gemcitabine and nab-paclitaxel (GN, N=36) in treatment-naïve mPDA. The primary endpoint of the trial is progression free survival and secondary endpoints include response rate, disease control rate, duration of clinical benefit and overall survival. We also seek mechanistic insight into response and resistance to these novel therapies. All patients will undergo pre-treatment biopsies which will be analyzed using quantitative multiplex immunofluorescence (qmIF) to categorize the abundance and spatial relationships of CAF, tumor and immune cell populations. This panel will categorize CXCL12-producing pro-axonogenic CAF populations, the drivers of CXCR4/CXCL12 pathway- mediated immunosuppression, to validate their abundance as a potential marker of preferential benefit from MCGN. A subset of patients in each arm of this trial will undergo on-treatment biopsies which will be used to characterize the impact of MCGN (N=21) and GN (N=10) on the TME. qmIF and snRNAseq will be performed on paired pre- and on-treatment biopsy specimens. The goal of this investigation is to evaluate for mechanisms of response and resistance. GN is one of the most commonly used regimens in mPDA, but its impact on the TME has not been evaluated prospectively. This study could lead to a better understanding of response and resistance mechanisms to GN and lead to promising therapeutic combinations. We hope to elucidate why immunotherapy has so far been ineffective in mPDA and whether there are patients for whom adding PD1 and CXCR4 inhibition to chemotherapy can improve outcomes.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Significance. Recent national drug-involved overdose death data has shown that the current opioid epidemic is characterized by four salient waves that claimed over 106,000 lives in 2021 alone. The current fourth wave of the epidemic is characterized as an opioid-stimulant polysubstance use. However, it is still unclear how individuals transition through different substance use profiles, the individual and structural determinants that are associated with these transitions, and polysubstance use profiles that are at increased risk of overdose. Additionally, no study to date has used a multilevel approach to develop a machine learning risk prediction model to predict overdose risk. Career Development Plan. Dr. Cadet’s training program will include seminars, workshops, coursework, and conferences to develop her skills and expertise in Multilevel Latent Markov Modeling, Bayesian Inference, longitudinal causal modeling, and in machine learning risk prediction modeling, which are necessary for conducting her proposed research plan and achieving her career goals of becoming an independent substance use epidemiology scientist who conducts large observational studies that will inform the targeted public health intervention and polysubstance use related overdose prevention. Mentorship. A highly accomplished team of mentors (Drs. Martins, Musci, Stingone, Tabb, Aiello) who are experts in substance use epidemiology, Bayesian Inference, longitudinal structural equation modeling, biostatistics, and machine learning, will support Dr. Cadet’s research and training goals. Research Plan. Dr. Cadet will conduct a multilevel epidemiological study informed by the Risk Environment Model that leverages the size and scope of the National Longitudinal Study of Adolescent to Adult Health (Add Health) from 1994-2026 (N> 20,000 participants) to answer the following aims: 1) Examine the dynamic transitions across substance use patterns using Multilevel Latent Markov Models (Latent Transition Analysis) among people who used drugs enrolled in the Add Health study; 2) Examine whether polysubstance use typologies have poorer survival risk of fatal overdose by using latent class modeling with a time-to-event distal outcome joint-model approach to explore latent polysubstance use classes with higher risk of fatal overdose and all-cause mortality in the Add Health study; 3) Develop a multilevel machine learning algorithms using a train-test split procedure to predict people who use drugs (PWUD) who are at increased risk of overdose episode by using micro-level (e.g., behavioral, psychosocial) and macro-level (e.g., area deprivation) factors in the Add Health study. Findings from this study will inform an R01 to lead a mixed-methods approach to better understand the nuances between intentional polysubstance use and treatment implications. Public Health Impact. The cross-disciplinary methodologies such as combining structural equation modeling, Bayesian modeling, and data science is crucial for addressing the multifaceted challenges of polysubstance use effectively.

NIH Research Projects · FY 2025 · 2025-09

This research proposal is in response to the NOT-OD-24-079 “Notice of Special Interest: Women’s Health Research” focused on health conditions that are female-specific. The ovary is the first organ to age in the human body. Ovarian aging negatively influences lifespan and a broad range of health outcomes in cardiovascular, skeletal, metabolic, immune, and neurocognitive systems in women. However, as with so many aspects of women’s health, ovarian aging has received limited scientific attention, even in large genomic survey projects, and the biological mechanisms underlying human ovarian aging and that may have broad implications for women’s healthspan remain poorly understood. The objective of this proposal is to investigate the molecular mechanisms that control the remarkably complex processes of ovarian aging and that are causally linked to human genetic factors influencing ovarian aging. In our preliminary studies, by performing a coupled single nucleus (sn)RNA-seq and snATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) analysis of flash-frozen ovary tissues from young (age 20s) and reproductively old (age ~50s) women, we made an interesting discovery that aging in the ovary proceeds through the conserved hallmark pathways of aging in each cell type, such as activation of mTOR signaling, but in an accelerated manner compared to other human tissue types, and there is a remarkable coordination of transcriptome and regulatory changes across all cell types in the ovary. These findings raise the hope that known geroprotectors that target the hallmarks of aging can be used to delay aging in the ovary in women. However, they also raise important new questions: how early aging starts in the ovary which is important to understand if we want to delay ovarian aging and its negative health outcomes; and what mechanisms underlie the dynamic and coordinated transcriptional and regulatory changes in the ovary and how they influence interactions between oocytes and their surrounding somatic cells during ovarian aging. Furthermore, we found that the great majority (94%) of the genetic variants associated with age at natural menopause (ANM), a proxy for female reproductive aging, as well as a trustworthy indicator of postmenopausal health, reside in non-coding regions of the genome, indicating that regulatory changes contribute to ovarian aging. However, elucidating the functional role of these non-coding regulatory variants and identification of their target genes is challenging and difficulties in GWAS interpretation has been the major barrier to understanding the genetic basis of ovarian aging in women and translation of human genetic discovery. By addressing the new questions and filling the knowledge gaps in the molecular mechanisms and genetic basis of human ovarian aging through integrated in silico analysis and unbiased genomic profiling at single cell level, and CRISPR-mediated genome editing and data-driven functional assays, our long-term goal is to define and validate regulatory drivers of the “premature” aging in the ovary and identify potential targets for therapeutic interventions in women.

NIH Research Projects · FY 2025 · 2025-09

Abstract: Polygenic scores combine small effects of GWAS risk variants across the genome to improve personalized risk prediction. The first-generation polygenic scores consisted of simple sums of risk alleles at significant GWAS loci and showed only modest associations with disease risk. The second-generation scores used genome-wide approaches to improve risk prediction by harnessing extra information from non-significant GWAS loci. Genome-wide polygenic scores (GPS) for several complex traits have now been shown to exhibit clinically actionable effects motivating similar approaches for CKD. Recently, we developed and validated a GPS for CKD optimized for cross-ancestry performance. The top 2% of the GPS was associated with >3-fold increased risk of CKD across ancestries, the degree of risk equivalent to a family history of kidney disease. Although these results are promising, several critical gaps remain. First, there is a need to further improve the predictive properties of the GPS, and this can be achieved with more powerful GWAS and more sophisticated statistical methods. Second, the clinical utility of the GPS continues to be limited by partial cross-ancestry transferability. This problem can be addressed by incorporating larger and more diverse GWAS, enhanced models of ancestry-specific loci (e.g. accounting for pN264K in APOL1), and novel statistical methods aimed at improving portability. Third, polygenic effects are context-dependent, thus there is a recognized need to evaluate GPS performance across diverse clinical contexts. Forth, there are no validated integrated models for CKD that combine polygenic, monogenic, family history, and clinical risk factors into a unified CKD risk stratification framework. In this proposal, we aim to formulate a third-generation GPS for CKD and address the above gaps in order to accelerate clinical implementation of polygenic prediction in nephrology. We propose to model polygenic risk with the latest multi-ancestry GWAS for renal function involving 3.4 million individuals, and externally validate the new GPS in large ancestrally diverse testing cohorts. We will test the GPS across heterogenous clinical contexts, including in the setting of monogenic kidney disease, glomerular disease, and kidney transplant. Lastly, we will develop and validate an integrated genomic risk score for CKD using a population-based cohort of 20,000 eMERGE-IV participants and the Columbia CKD Biobank cohort of 10,000 CKD patients. Our team benefits from the existing infrastructure for efficient genetic analyses, access to all relevant datasets, and first-rate local genotyping, bioinformatic, statistical and computing resources, thus we are ideally positioned to make this project successful.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT In the last few decades, novel pathogens have emerged at an unprecedented rate, causing significant health and economic burdens in our society. However, our ability to detect and quantify key epidemiological features of these pathogens has been limited during the early phase of outbreaks – a critical but short time window to understand new diseases. This gap arises primarily due to a lack of observational data and incomplete detection of transmission events, constrained by the resources invested in traditional surveillance systems. Our research group has been at the forefront of developing mathematical models and computational tools to advance the methodology for surveillance, inference, and forecasting of emerging infectious agents, including SARS-CoV-2, pandemic influenza, and antimicrobial-resistant organisms (AMROs). Our goals for the next five years are to develop novel computational tools to detect early signals of cryptic transmission and infer critical epidemiological features in data-sparse settings. Leveraging theories in complex systems and advanced techniques in machine learning and deep learning (ML/DL), we propose to synergistically use traditional (e.g., syndromic surveillance, PCR tests, sequencing, human mobility, and contact tracing) and non-traditional (e.g., wastewater, social media, and search queries) data sources to conduct a series of studies centering on three key questions. 1). How can we detect early transmission of emerging infectious diseases? We will take a biomimicry approach, inspired by the mechanism of the human physical sensation system to detect external stimuli (e.g., light, sound, and pressure) spanning several orders of magnitude in intensity. We will develop and optimize excitable sensor networks that collectively assimilate a multitude of data sources in different locations to assess the transmission potential for novel pathogens. 2). How can we infer key epidemiological features of novel pathogens using limited data? We will combine process-based models (e.g., metapopulation and agent- based models) and ML/DL techniques (e.g., Graphical Neural Networks and Transformers) to identify signatures of disease characteristics, such as asymptomatic shedding and superspreading, using early-stage data. 3). How can we validate model-derived hypotheses to reduce uncertainty? Determining characteristics of novel pathogens is a high-stakes task. We will develop strategies (e.g., sampling in specific locations at certain times) to cost-effectively validate hypotheses on spatial spread of new viruses and gather new evidence in real time to reduce uncertainty. For all three projects, the developed methods will be applied to a range of infectious agents with disparate epidemiology, including SARS-CoV-2, influenza, AMROs, and zoonotic viruses. We will apply new methods to retrospectively acquired data and quantify their advantage over classical approaches (e.g., how much data is needed with classical versus new methods). Our vision of the research program is that the synergistic use of computational tools and diverse data sources can enhance our ability to perform timely and impactful research to understand novel pathogens using sparse and imperfect data.