Columbia University Health Sciences

NIH Research Projects · FY 2026 · 2026-03

SUMMARY Incurable neurodegenerative diseases are a growing public health crisis. The ability to generate substantial quantities of disease-pertinent neuron types, with and without predisposing mutations, holds great promise for probing disease mechanisms and developing therapies. However, current protocols yield neurons that fail to mature in vitro and stall at an embryonic identity. This reflects a fundamental gap in knowledge concerning regulatory programs that drive neuronal maturation and limits the potential of stem-cell-based interrogations of age-related neurodegenerative disease. The nervous system employs alternative splicing (AS) to massively expand transcriptomic diversity and protein function. In particular, conserved AS programs consisting hundreds of exons are coactivated at distinct stages during neurodevelopment, including postnatal neurons. In my postdoctoral work, I have found that differentiated neurons, fail to activate the postnatal AS program, and I hypothesize that this postnatal AS program is a conserved, pan-neuronal mechanism driving neuronal maturation. My preliminary data includes contracted and accelerated physiological maturation of mouse embryonic stem cell-derived motor neurons upon global activation of postnatal splicing, suggesting feasibility of my hypothesis. This proposed study aims to expand and generalize the notion that RNA biogenesis strategies such as AS, drive neuronal maturation in human reprogrammed neurons: Aims 1 and 2 ask if activation of the adult alternative splicing program will advance the maturation of human motor and cortical neurons. This will be achieved through overexpression of master splicing factors in postmitotic neurons, evaluation of transcriptomic changes using bulk and single cell approaches, and assessment of physiological maturation. Thereafter, I utilize my approach to build a novel model to study age-related 4R tauopathies: Aim 3 takes advantage of my unique strategy to yield mature tau isoforms and elevated 4R tau in cortical neurons carrying MAPT variants, and to identify mechanisms to reduce tau pathology. Using this unprecedented stem cell-based model, I will assay tau burden, understand gene expression driving disease onset, and target cis-regulators in the MAPT that will decrease tau pathology. Existing reprogramming strategies are incomplete and do not overcome the barrier of the intrinsic aging clock in differentiated human neurons. Thus, it remains vital to continue investigating additional pathways to understand and modify maturation timescales. My undertaking has critical importance in this context: I will explore a novel function for alternative splicing during neurodevelopment, improve understanding of mechanisms that control maturation of human neurons, and demonstrate that my approach is a major advancement for studying age-related neurodegeneration. The insights and technology generated here will have important applications for the exploration of neurodegeneration and will be broadly useful to the scientific community for modeling neurons in health and disease.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT Background. In Eswatini, adult HIV prevalence is over 31%, and national adult HIV incidence is the highest in the world at 7.77 new infections per 1,000 persons annually. While the country has almost met UNAIDS’ 95-95- 95 goals for epidemic control, HIV incidence is declining at a glacial pace, pointing to the need for comprehensive HIV prevention programs. Eswatini’s scale-up of HIV pre-exposure prophylaxis (PrEP) began in 2018, with nearly 100,000 individuals initiating PrEP in-country since. The proposed study will develop better methods to determine who could most benefit from PrEP (i.e., PrEP need) in Eswatini, and whether that need is being met at programmatic and individual levels, to inform future implementation of HIV prevention programs. Aims. In line with the NIMH Division of AIDS Research’s strategic priorities, this study will 1) compare models for predicting who could most benefit from PrEP in Eswatini; 2) compare novel PrEP-to-Need Ratios (PnRs) to original PnRs at the facility level; and 3) examine individual-level prevention-effective persistence and trajectories over time. Approach. This research will use data from the 2021 Eswatini Population-based HIV Impact Assessment (N=11,199) and Eswatini’s HIV-1 Recent Infection Surveillance (N~32,780) to build machine learning models to predict both recent and long-term but newly diagnosed HIV infections, providing insight into vulnerable subpopulations most in need of PrEP. Using routinely collected health facility data (N=150 facilities), PnRs will be created that account for heterogeneity in infection timing (i.e., recent vs. long-term), as well as subpopulation variability. Facilities will be compared over time. Lastly, using data from the DYnamics of Contraception in Eswatini (DYCE) Study (N=321), changes in PrEP need over time, relative to changes in use of PrEP and other prevention methods, will be assessed using an operationalization of prevention-effective persistence. Latent class analysis will be used to detect actionable differences between classes of prevention-effective persistence trajectories. Each aim is designed to identify gaps in HIV prevention efforts and guide the continued scale-up of PrEP in Eswatini to ultimately reduce HIV incidence. Training. Ms. Wallach’s training plan leverages her quantitative analysis and HIV research experience to advance her skills and launch her career as an independent HIV investigator. Her training goals are to develop a deep, nuanced understanding of PrEP need, gain experience working with and triangulating various data sources, gain skills in machine learning methods and latent class analysis, gain experience with longitudinal data analysis, and build capacity for effective research communication and dissemination. Under the guidance of her Primary Sponsor, Ms. Wallach will receive tailored mentorship from a team of experienced HIV researchers who work with the included data sources, conduct PrEP-related research, and have expertise in the advanced epidemiologic methods herein. Training will occur at Columbia University, a high-caliber institution with specialized research programs, including in infectious disease epidemiology, and that houses ICAP, a global health and HIV implementation and research organization.

NIH Research Projects · FY 2026 · 2026-03

Summary The inability to maintain epithelial integrity or recover from prolonged injury is closely linked to the development of end-stage lung diseases such as idiopathic pulmonary fibrosis (IPF), which currently lacks effective treatments. The long-term objective of the Que laboratory is to restore epithelial integrity by gaining a comprehensive understanding of how the epithelium develops in embryos and regenerates in adults. We have employed a combination of genetic manipulation, lineage tracing, 3D organoid models, and single-cell RNA sequencing, along with advanced bioinformatics analyses, to demonstrate that developmental signaling pathways and downstream factors, including transcription factors, are re-used during regeneration. For example, we have shown that Wnt signaling molecules (such as Wntless/Gpr177) and transcription factors like Isl1 and Sox9 are critical in both lung development and injury repair. While our lab has highlighted the importance of genetic regulation in epithelial generation and regeneration, recent work has shifted focus to the role of posttranscriptional regulation. Preliminary data suggest that the deletion of posttranscriptional regulators disrupts epithelial progenitor specification and lung development. Further studies indicate that these regulators are also crucial for epithelial regeneration following injury. Additionally, we are exploring the interaction of posttranscriptional regulators with transcription factors in the reprogramming of fibroblasts into alveolar progenitor cells. Our research has led to numerous collaborations, and we will expand these efforts to broaden the impact, particularly in the areas of posttranscriptional regulation in lung generation, regeneration, and reprogramming. The goal of our proposed studies is to deepen our understanding of how the lung epithelium is generated and restored, with the aim of identifying new targets and developing more effective, targeted therapies to reverse end-stage lung diseases such as IPF.

NIH Research Projects · FY 2026 · 2026-03

Mild Cognitive Impairment (MCI) and early-stage dementia (ED) affect one in five adults over 60. Despite nationwide efforts, over 50% of these cases remain undiagnosed—63% within home healthcare (HHC). Black older adults are at higher risk due to limited healthcare access, biases in medical examinations, and lower health literacy, leading to increased misdiagnosis rates. The lack of culturally and linguistically appropriate diagnostic tools exacerbates these disparities. Language impairment is an early sign of cognitive decline, making verbal communication a critical biomarker for MCI-ED diagnosis. However, existing speech processing algorithms are generally not trained on Black Verbal Language (BVL)—a collective term encompassing diverse Black dialects like African American English, Caribbean English, and Nigerian English. This oversight can lead to misinterpretation, delay essential care, and deepen health disparities. To address these challenges, we propose to create the largest corpus of Black patient-nurse communications from VNS Health in New York City, capturing the city's rich sociolinguistic diversity. Our multidisciplinary team—comprising experts in HHC nursing, automated speech processing, speech pathology, BVL linguistics, cognitive impairment, and Clinical Decision Support (CDS)—aims to: 1) refine speech-processing algorithms to enhance early detection of MCI- ED in older Black patients by analyzing audio-recorded patient-nurse communications from 500 Black patients (250 with MCI-ED and 250 cognitively normal); 2) develop a multimodal screening algorithm, SpeechCARE, by integrating Electronic Health Record (EHR) data and MCI-ED risk factors extracted from clinical notes with verbal communication features; and 3) assess the feasibility of implementing SpeechCARE as a CDS tool within HHC EHR systems. This study introduces several innovative features. By creating the largest BVL speech corpus, we advance speech processing algorithms that account for often-overlooked linguistic diversity. Our design goal for SpeechCARE, a multimodal screening algorithm built on routinely generated HHC data, is to create a sensitive, inexpensive, non-invasive, easily accessible, and linguistically appropriate diagnostic tool to address critical gaps in MCI-ED detection among Black patients. Assessing the practical implementation of SpeechCARE within clinical workflows ensures its adaptability and real-world applicability. The outcome will lay the foundation for an efficacy trial of SpeechCARE in HHC, ultimately improving timely diagnosis and tailored interventions for Black patients, enhancing outcomes, and reducing disparities in care.

NIH Research Projects · FY 2026 · 2026-03

Background. Neurodevelopmental disorders (NDDs) present a major global health challenge, particularly in low-resource settings like South Africa, where traditional diagnostic frameworks and access to comprehensive evaluations are limited. This research shifts the focus from formal NDD diagnoses to neurodevelopmental difficulties—measurable impairments in cognitive, social, emotional, and behavioral functioning—offering a more adaptable, resource-efficient approach grounded in the WHO’s International Classification of Functioning, Disability and Health (ICF). Given the rising prevalence of neurodevelopmental difficulties in South Africa and the critical role of caregivers, data-driven approaches are urgently needed to identify and support affected children. This study, which will utilize data from the Asenze Cohort Study (ACS), is the first to use adapted, non- specialist-administered measures alongside data-driven methods for a comprehensive assessment of neurodevelopmental difficulties in an LMIC context. Aims. Aim 1 will cross-sectionally identify neurodevelopmental profiles of children in Asenze at ages 5, 7, and 16 using latent profile analysis to identify distinct strata of children based on patterns of neurodevelopmental difficulties at each timepoint. Aim 2 will longitudinally characterize neurodevelopmental trajectories based on latent profile changes and examine the association between trajectories and cognitive and functional impairments in adolescence. Aim 3 will evaluate caregiver mental health, alcohol and other drug use as predictors of adolescents’ cognitive and functional impairments at age 16. Approach. This study leverages data from Waves 1-3 of the ACS, a longitudinal study conducted in KwaZulu-Natal, South Africa, which followed 1,581 children and caregivers from ages 5 to 16 between 2008 and 2021. Employing Latent Profile Analysis (LPA), we will identify distinct neurodevelopmental profiles at each wave, capturing the dynamic nature and heterogeneity of child development. Subsequently, these profiles will be used to track neurodevelopmental trajectories into adolescence, enabling us to assess the associations between trajectories and cognitive and functional impairments in adolescents. Finally, we will use Marginal Structural Models to evaluate the effects of caregiver mental and behavioral health on impairments in adolescents. Training. In this F31, the PI will establish expertise in the epidemiology of child and adolescent mental, neurological, and substance use disorders in low-resource settings, while developing a deeper understanding of neurodevelopmental difficulties and their assessment within LMIC contexts. Additionally, the PI will enhance professional development through manuscript and grant preparation, conference presentations, and engagement within scientific communities. This research will inform the development of focused interventions, applicable to resource-limited US populations, aiming to improve neurodevelopmental outcomes in vulnerable children and adolescents. This F31 will equip the PI with the expertise to become an independent researcher, driving advancements in global child neurodevelopment.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY The kinase Akt is a central mediator of insulin signaling. Its activation by insulin occurs when Akt is phosphorylated at two canonical sites, T308 and S473. Other covalent posttranslational modifications also contribute to Akt regulation, such as phosphorylation at alternative residues, acetylation, and ubiquitination. In this grant, we investigate a distinct mechanism of Akt activation: controlled access to a manganese (Mn2+) ion. Mn is an essential trace element that is acquired through the diet and excreted primarily via efflux from hepatocytes into bile. The efflux of Mn is mediated by the canalicular transporter Slc30a10. We have found in mice, cells, and in vitro that increased Mn availability directly promotes Akt activity in hepatocytes, in a manner that does not require upstream insulin signaling. The Mn-induced activation of Akt is sufficient to suppress glucose production, which provides a biochemical explanation for longstanding observations that Mn has glucose-lowering effects in humans and mice. Moreover, we have found that Mn availability is regulated nutritionally, via carbohydrate signaling. In this grant, we will use classic and state-of-the-art biochemical tools to investigate the cellular and biophysical features of the interaction between Akt and Mn. We will furthermore use genetic and dietary interventions in mice to investigate how control over Mn availability contributes to normal physiology and states of overnutrition. Success of this work will reveal a novel mechanism of regulating Akt activity and hepatic glucose production and generate new avenues for research in metabolism and cell signaling.

NIH Research Projects · FY 2026 · 2026-03

Project Summary Natural behaviors, such as exploration, are composed of distinct, highly stereotyped motor syllables—like locomoting, climbing, and rearing—that are seamlessly sequenced and executed by a network of brain regions. Understanding natural behaviors first requires an understanding of how these motor syllables are represented, transformed, sequenced, and executed through cross-region interactions. However, due to technological limitations, previous studies of motor control have largely examined individual brain regions in isolation and relied on highly constrained behavioral paradigms, leaving open the question of how regions like the motor cortex (M1) and dorsolateral striatum (DLS), two key nodes of the cortico-striatal network, interact to generate spontaneous, natural behaviors. By combining newly available simultaneous multi-region recordings and motor-syllable- segmented behavioral data from mice with theoretical neuroscience tools, this project will develop a theory for how M1 and DLS work together to orchestrate movement sequences. In close collaboration with experimentalists, I will use computational modeling and theoretical analysis to: (1) characterize and compare neural representations of motor actions across M1 and DLS, (2) disentangle their inter-regional interactions, and (3) construct a multi-compartment model explaining how these regions work together to generate and sequence natural behaviors. By explicitly modeling the division of labor between M1 and DLS, this framework will allow me to elucidate why modularity is critical for flexible motor control. Additionally, by aligning the model with the brain’s structure, it will provide a powerful tool for guiding future experiments. This project will advance our understanding of the neural computations underlying natural movement, bridging the gap between theoretical models and biological reality. By capturing how brain areas interact when planning and execution unfold simultaneously in a neurally constrained model, this work will generate experimentally testable predictions. In doing so, it will not only refine our models of motor control but also provide insights that could inform new therapeutic strategies for movement disorders such as Parkinson’s and Huntington’s disease. Ultimately, this work will provide a powerful framework for understanding the distributed computations that underlie flexible, spontaneous behavior.

NIH Research Projects · FY 2025 · 2026-02

Frontotemporal dementia caused by mutations in microtubule-associated protein tau (MAPT), including the N279K mutation, is a common cause of early-onset dementia. It is neuropathologically characterized by toxic aggregation of hyperphosphorylated tau, glial activation, and neurodegeneration. The factors contributing to the disease are likely numerous and poorly understood, and no disease-modifying therapies exist for FTD. Oxidative stress (OS) occurs when a cell’s innate antioxidant system is overwhelmed by reactive oxygen species, and oxidative modifications of biological molecules have important consequences on protein, DNA, and lipid function. In particular, uncontrolled lipid peroxidation can lead to ferroptosis, a specific cell death pathway which we found to be enriched in FTD postmortem brain and may contribute to neurodegeneration. We also identified an OS and neuroinflammatory phenotype in postmortem brain from FTD patients and induced pluripotent stem cell (iPSC)-derived neurons from FTD patients. Specifically, FTD iPSC-derived neurons show upregulation of the gene secreted phoshoprotein-1 (SPP1) and its protein product osteopontin (OPN), which can activate iPSC-derived microglia in vitro. Given the centrality of OS in our FTD models and the apparent association with SPP1, this proposal seeks to investigate mechanisms of OS generation and downstream sequelae in FTD. In aim 1, I will interrogate the effects of different classes of oxidative and ferroptotic stressors on FTD MAPT N279K iPSC-derived neurons. In aim 1a I will assess cell viability and lipid peroxidation. In aim 1b I will assess tau pathology and neurite outgrowth. In aim 1c I will attempt to rescue any effects seen in aims 1a and 1b by co-treating with antioxidant and ferroptosis inhibiting compounds. In aim 2 I will characterize astrocyte-neuron crosstalk in the FTD context. First, in aim 2a I will generate iPSC-derived astrocytes from FTD MAPT N279K patients or healthy control patients and treat with OPN and assess for astrocyte reactivity. In aim 2b I will generate antioxidant response gene reporter astrocytes and treat with Ctrl or FTD neuron conditioned medium to determine the role of neuron-secreted factors in astrocyte response. Finally, in aim 3 I will explore the potential of targeting OS in FTD. I will xenotransplant FTD or Ctrl neural progenitor cells into mice forebrains and treat systemically with liproxstatin, an antioxidant and ferroptosis inhibiting compound. In aim 3a I will characterize proteins involved in these pathways as well as glial reactivity and graft survival by histology. In aim 3b I will perform snRNA-seq on micro dissected grafts to map changes in gene expression profiles in response to OS targeting.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Eosinophilic esophagitis (EoE) is a newly described immune-mediated disease and a leading cause of esophageal morbidity in children and young adults. Histologically, pediatric EoE is characterized by esophageal basal cell hyperplasia (BCH) and extensive Th2-associated inflammation. Despite many advances in our understanding of the pathophysiology of EoE, the molecular mechanisms leading to the development of BCH and subsequent epithelial barrier dysfunction in pediatric EoE remain to be elucidated. We previously demonstrated that yes-associated protein 1 (YAP), a key transcriptional regulator in the Hippo signaling pathway, is required for the proliferation and differentiation of basal cells in the developing murine and human esophagus. Using novel pre-weaning mouse models of early-onset EoE and 3D organoid culture systems we have been able to study Th2-driven BCH. Our preliminary data demonstrate nuclear enrichment of YAP in the hyperplastic basal cells of a pre-weaning transgenic mouse model of EoE and esophageal biopsy samples from a pilot study of an EoE patient cohort. In parallel an exploratory untargeted proteomics approach, using human esophageal basal cells (EPC2) cells treated with IL-13 demonstrated that Tenascin-C (TNC), a matrix protein enriched in the basement membrane underlying the hyperplastic basal cells, was among the top-enriched proteins in EPC2 cells upon IL-13 treatment. Moreover, we demonstrated TNC/YAP double-positive cells in our preclinical EoE mouse models as well as increased expression of CD74 in a subpopulation of hyperplastic esophageal basal cells of EoE patients. Based on these findings, the overarching hypothesis is that YAP mediates IL-13-induced CD74 expression, which promotes chronic inflammation characterized by BCH and epithelial barrier dysfunction in pediatric EoE. In Aim 1, we will use YAP loss-of-function mouse models and CD74 inhibitors to test the hypothesis that CD74 activation promotes BCH. In Aim 2, using in vivo and in vitro assays, we will elucidate how CD74 affects the epithelial barrier integrity in the pathogenesis of pediatric EoE. Overall, findings from the proposed studies will significantly advance our understanding of the pathophysiology of pediatric EoE and provide new insights into potential biomarkers and novel therapeutic targets for pediatric EoE.

NIH Research Projects · FY 2026 · 2026-02

Specialized home-based palliative care offers cost-effective, patient-centered care, enhancing satisfaction and quality of life for individuals with serious illnesses. Home healthcare (HHC) patients, predominantly seriously ill older individuals with multiple chronic conditions, could greatly benefit from such care. However, only 7% of home-based palliative care programs are operated by HHC agencies. Addressing this gap, the National Association of Home Care and Hospice (NAHC) has advocated for Medicare payment model revisions. The “Expanding Access to Palliative Care Act” bill proposes a broader HHC palliative care approach. Nevertheless, a wider integration of palliative care into HHC depends on clinician readiness, patient and caregiver receptivity, and a robust screening tool for the timely identification of palliative care beneficiaries. Currently, no HHC-specific screening tool exists. The 2018 National Consensus Project (NCP) Clinical Practice Guidelines for Quality Palliative Care outlines eight domains for comprehensive palliative care. However, existing assessments often overlook crucial contextual or social factors, important for patients with complex care needs. Variations in palliative care access and utilization exist, and factors affecting public perception of palliative care are multifaceted. Our team, guided by the 2018 NCP guidelines, developed two HHC-specific questionnaires to measure Palliative Care-related Knowledge, Attitudes, and Confidence: one for HHC clinicians (PC-KAC- Clinician), and another for HHC patients and caregivers (PC-KAC-Patient/Caregiver). Using the unique HHC setting-specific PC-KAC questionnaires, this project seeks to assess readiness for palliative care integration in HHC, explore variation in readiness and receptivity, and devise a screening tool for identifying HHC patients benefiting from palliative care. We will 1) develop a consensus and evidence-based screening tool to identify HHC patients who can most benefit from palliative care and assess the feasibility and acceptability of the screener; 2) assess the preparedness of HHC clinicians to deliver palliative care; 3) evaluate the knowledge and receptiveness of palliative care among HHC patients and caregivers and identify differences in knowledge and receptivity; and 4) explore the barriers and facilitators related to the integration of palliative care services into HHC practice. Screening tool development will be through systematic review, expert input, validation and pilot testing with HHC clinicians. Questionnaires will be conducted among HHC clinicians (n=480), and patients/caregivers (total n=480) to understand their palliative care-related knowledge, attitudes, and confidence. Qualitative interviews will be conducted with key stakeholders to explore how best to incorporate palliative care into HHC practice. Alignment with PAR-22-092, this project aims to advance a new care model, integrating palliative care within HHC, catering to patients with multiple chronic conditions, especially those with multiple chronic conditions and complex social and care needs.

NIH Research Projects · FY 2026 · 2026-02

Project Summary The entorhinal cortex (EC) is ground zero for Alzheimer’s disease (AD), showing early signs of tauopathy and neuroinflammation, which then spread through the entorhinal-hippocampal (EC-HPC) circuit. There are major gaps in knowledge regarding why the EC is vulnerable early in AD, and what drives disease progression from the EC to the HPC. We developed an approach to image EC layer 2 projection neuron activity in vivo with 2-photon microscopy in models of tauopathy. We discovered EC layer 2 projections are profoundly hyperactive. This is important because neural activity causes the release of toxic forms of tau and other disease associated proteins. Thus, hyperactivity in EC projection neurons may accelerate disease. In support of this, we found that directly inducing hyperactivity in EC projections (using chemogenetics) accelerates tauopathy spread to the HPC. It is essential to determine why EC layer 2 projections are hyperactive in tauopathy. It is well established that there is early neuroinflammation in the EC driven by microglial activation. In diseases such as epilepsy, activated microglia releases cytokines that cause neuronal hyperactivity. Thus, microglial activation may drive the hyperactivity we found in tauopathy. Our central hypotheses are 1) EC layer 2 hyperactivity drives disease progression through the EC-HPC circuit, and 2) Neuroinflammation within the EC drives neuronal hyperactivity in tauopathy. These hypotheses form the core of our model that three factors in the EC – tauopathy, neuroinflammation, and neuronal hyperactivity – form a vicious cycle that drives disease progression in the EC-HPC circuit. We will test this model in three synergistic, but independent, aims utilizing innovative in vivo 2-photon microscopy and targeted neuronal manipulation. In Aim 1, we will determine the longitudinal progression of neuronal hyperactivity and neuroinflammation in the EC-HPC circuit in two models of tauopathy. In Aim 2, we will test the causal role of EC layer 2 projection hyperactivity in disease progression in tauopathy. To do so, we will selectivity suppress activity in EC layer 2 projection neurons using chemogenetics. In Aim 3, we will test the causal role of neuroinflammation in EC-HPC circuit hyperactivity in tauopathy. Altogether, our innovative aims will fill major gaps in knowledge regarding the roles of EC layer 2 projection neurons, neuronal hyperactivity, and neuroinflammation in the progression of tauopathy in the EC-HPC circuit.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY We intend to improve brain health in elderly patients undergoing surgery by EEG-guided optimization of pharmacologic decision-making during anesthesia. Alzheimer's disease (AD), the most common form of dementia, frequently co-occurs with surgery in this population. A significant concern is post-operative delirium (POD), a state of confusion and agitation that can worsen cognitive decline. Roughly 65% of elderly surgical patients experience POD, leading to increased hospital readmissions and mortality. Notably, medications used during surgery, particularly sedatives and analgesics, can influence POD risk. Our research explores the potential of brainwave activity, specifically alpha waves measured by electroencephalogram (EEG), to predict intraoperative nociception and guide medication administration. We hypothesize that maintaining alpha waves during general anesthesia reduces the risk of POD. To test this hypothesis, we will conduct a clinical trial involving elderly surgical patients undergoing surgery under general anesthesia with frontal EEG recording. Participants will be stratified by confirmed diagnosis (AD, mild cognitive impairment (MCI), or no cognitive impairment), age, sex, surgery type, and pre-operative cognitive status. Following stratification, they will be randomized to receive either usual care anesthesia or anesthesia protocols incorporating intraoperative analysis of alpha power in the frontal EEG. This study has three main aims: (1) Investigate the influence of EEG-based protocols on alpha waves and POD prevention: We will assess if anesthesia protocols guided by real-time analysis of EEG data can enhance frontal alpha wave activity and consequently decrease the incidence of POD. (2) Evaluate the effects of dexmedetomidine on alpha waves and POD: Dexmedetomidine is a medication with both analgesic and sedative properties. We will determine if its use during anesthesia promotes alpha waves and reduces the occurrence of POD. (3) Examine the association between improved post-operative pain management and alpha power or drug administration: We will investigate whether better post-operative pain control is more closely linked to maintaining alpha waves intraoperatively or to the specific medications administered during surgery. Plasma biomarkers associated with AD will also be obtained from participants pre- and postoperatively. Furthermore, we will assess the effects of anesthesia intervention on long-term cognitive outcomes at 12 months post-surgery. This project combines real-time quantitative analysis of neurophysiological data (EEG), evidence-based pharmacological interventions (specifically targeting medication use based on alpha wave activity), and comprehensive neurocognitive assessments (performed preoperatively, postoperatively, and at a 12-month follow-up). By exploring the use of EEG-guidance for intraoperative pharmacological decisions, we aim to not only develop strategies for reducing POD risk but also gain a deeper understanding of the potential mechanistic link between POD and AD. This knowledge could ultimately lead to the development of strategies to reduce the risk of dementia in elderly surgical patients.

NIH Research Projects · FY 2026 · 2026-02

PROJECT ABSTRACT OsteoarthriƟs (OA) is the most prevalent joint disease. Once viewed as an irreversible, age-related degeneraƟve change to carƟlage, OA is now recognized as a systemic disorder featuring a prominent inflammatory aspect in which T cells appear to play a role. However, the impact of OA on the development of untoward responses to various immune-modifying therapies is largely unexplored. T cell immune checkpoint inhibitors (ICIs) have revoluƟonized cancer treatment, with approximately one million cases qualifying each year. ICI anƟbodies (Abs) have demonstrated clinical effecƟveness, as shown by tumor regression and improved survival rates. However, two major drawbacks limit their applicaƟon. Firstly, tumor control is not uniform and unpredictable. Secondly, the emergence of inflammatory autoimmune toxiciƟes, referred to as immune-related adverse events (irAEs), poses substanƟal challenges. Over half of paƟents treated with ICIs experience irAE syndromes, which are marked by various paƩerns of organ inflammaƟon. We have focused on one chronic irAE, arthriƟs, which affects 37,742 Americans annually. This condiƟon can lead to the terminaƟon of essenƟal cancer therapies and results in lasƟng morbidity. The mechanisms driving irAE-arthriƟs are primarily unknown, creaƟng an urgent need for specific treatments to inhibit joint inflammaƟon while boosƟng the inflammatory tumor response. To address this, we established an irAE-arthriƟs clinic, where we found that paƟents with OA are significantly more prone to develop irAE-arthriƟs when undergoing ICI treatment than matched individuals without OA. Our research into the immunophenotype of OA synovial fluid showed most CD8 and CD4 T cells displayed a Ɵssue-resident memory (TRM) phenotype and, unexpectedly, had elevated levels of the immune checkpoint PD-1. This led us to our central hypothesis that immunoreacƟve proteins produced by mechanically stressed OA carƟlage insƟgate a localized, self-limiƟng autoreacƟve T cell response. PD-1 and the ensuing PD-1 negaƟve signaling curb this T cell-mediated Ɵssue damage, resulƟng in synovial tolerized TRM. However, ICI therapy interrupts PD-1 mediated inhibiƟon, prompƟng TRM cells to convert into effector T cells (TEFF), which drive irAE-arthriƟs. We will test this hypothesis and elucidate the mechanism through which TRM cells facilitate the transiƟon from OA to irAE-arthriƟs aŌer ICI treatment. Aim 1: To invesƟgate the hypothesis that ICIs convert OA PD-1+ TRM cells into TEFF cells, contribuƟng to Ɵssue inflammaƟon and irAE arthriƟs. We will conduct a longitudinal validaƟon study to idenƟfy phenotypes and specific lineages of T cell subsets emerging in OA and irAE joints. By tracing clonotypic TCR profiles, we will assess the extent to which TEFF in irAE joints arise directly from OA PD-1+ TRM cells or from infiltraƟng T cells. Aim 2: To characterize dendriƟc cell (DC) populaƟons in OA and irAE arthriƟs using single-cell RNA sequencing and predict cell interacƟon pathways. To explore the disƟnct funcƟons of DC in OA compared to irAE joints, we will uƟlize transcriptomic data to analyze DC populaƟons in both OA and irAE fluid. Aim 3: To employ spaƟal biology and transcriptomics to confirm the hypothesis that TEFF cells engage with immunogenic DC in irAE arthriƟs. ExtracƟng single cells from Ɵssue results in the loss of spaƟal context. To overcome this and integrate the findings from aims 1 and 2, we will apply spaƟal transcriptomics to represent the components in inflamed joints visually.

NIH Research Projects · FY 2026 · 2026-02

Project Abstract Here we propose to build upon compelling evidence we have uncovered suggesting that RNA-binding proteins (RBPs) regulate their targets in a sex-specific manner. This discovery indicates the presence of unique regulatory mechanisms governing gene expression and cellular function in the male and female brain that are as of yet unexplored. To elucidate these mechanisms, our study employs a multifaceted approach. We will investigate behavioral and molecular changes in both mouse models and human neurons in order to reveal the intricate network of interactions underlying sex-specific vulnerability to neurological disorders. By dissecting the molecular pathways involved, we aim to better understand the differences between male and female brain physiology and to gain valuable insights into sex-specific vulnerabilities in neurological disorders. Furthermore, our findings hold the potential to inform the development of targeted therapeutic interventions tailored to address the distinct needs of male and female patients.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY T cell memory is stored across heterogeneous subsets with diverse functions in both tissues and circulation. While most studies have focused on the pro-inflammatory and cytotoxic functions of memory T cells, regulatory T cells (Tregs) serve an equally important immunomodulatory role in memory responses, particularly in tissues. While specific roles for Tregs in establishing tolerance and promoting tissue homeostasis have been elucidated in mouse models, the role of human Tregs in healthy immune responses and protective immunity in vivo has been difficult to assess. Moreover, the identity and function of human Tregs in diverse tissues remains unknown. We have established an organ donor tissue resource for human immunology that has allowed us to profile antigen-specific T cells across human tissues. Through these efforts, we found that antigen-specific Tregs are substantially enriched among memory T cells that respond to antigens from multiple viruses, including SARS-CoV-2, influenza, and EBV, and are particularly enriched in lymph nodes, spleen and lungs compared to blood, bone marrow and other sites. In addition, we found that memory Tregs induce an activation program that is distinct from effector memory T cells (TEM) involving CCL17 as a novel Treg-derived cytokine not produced by TEM cells or any other T cell subset. Moreover, tissue memory Tregs exhibit clonal overlap with TEM cells within and between sites. These findings raise the possibility that memory Tregs are generated along with TEM during priming and that they share a common pre-cursor with TEM. In the proposed studies, we will pursue three aims: 1) Determine the role of antigen and tissue in memory Treg induction; 2) Define the clonal and migratory relationships (i.e. tissue distributions) between memory Treg and other memory subsets; 3) Elucidate the functional and spatial interactions of tissue Tregs with immune and structural cells in the lymph node. We will combine state-of-the-art technologies for single-cell and spatial profiling with our unique human tissue resource to elucidate mechanisms for the generation, function, and maintenance of memory Tregs in human tissues. The results from this study will be important for designing strategies to promote immunoregulation and tissue repair for protective immunity and can inform Treg-directed therapies for autoimmunity and transplantation.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY In multicellular organisms, development and homeostasis require exquisitely precise, dynamic, and coordinated deployment of complex regulatory programs. As many genes are under the control of vast regulatory regions – with some enhancers located over a million base pairs away from target genes – we and others have explored to what extent the 3D organization of the genome facilitates the establishment of specific regulatory interactions. Additionally, regulatory regions are pervasively transcribed to generate a striking diversity of long noncoding (lnc)RNAs, which are emerging as important chromatin and transcriptional regulators. However, the molecular determinants and regulatory roles of genome organization remain unclear, and only a minute fraction of known lncRNAs have been ascribed any function. My recent work used innovative single-cell live imaging approaches to show that genome organization and cis-regulatory lncRNAs both play a key role in regulating the temporal dynamics of gene expression. My findings also suggest that lncRNAs may exploit – or even regulate – genome organization to exert long-range transcriptional control. The goal of my research is to understand how genome organization and lncRNAs regulate gene expression, and to investigate their mutual interplay. My lab will use our cutting-edge approaches to measure transcriptional dynamics in Drosophila embryos to investigate how long-range interactions are established; how lncRNAs operate in the context of long-range regulation and utilize genome organization; and how in turn lncRNAs can control genome organization. In my prior work, I identified novel “tethering elements” that foster specific long-range interactions to enable fast gene activation during development. In Project I, I will investigate the role of a well-known epigenetic repressor, Polycomb Repressive Complex 1, in facilitating transcriptional activation by mediating long-range interactions between tethering elements. Through a combination of genomics and live imaging, I will identify the molecular mechanisms establishing long-range interactions and determine their impact on gene expression. My recent work also showed that both long-range enhancers and tethering elements are pervasively transcribed genome- wide. In Project II, using methods I developed to visualize the transcription of endogenous lncRNAs in living embryos in combination with complex genetic perturbations, I will begin to determine the regulatory functions of select lncRNAs associated with important developmental genes and dissect their interplay with genome organization. In particular, I will investigate how lncRNAs regulate the recruitment of architectural factors and the establishment of long-range interactions. Finally, in Project III, I will use novel single-cell live imaging approaches that I developed to investigate how lncRNAs dynamically control local regulatory microenvironments to regulate genome organization and gene expression in vivo. Collectively, these three synergistic projects will enable my future research program by identifying guiding principles that will inform our understanding of the dynamics of gene regulation and be examined in future studies in other model systems and cellular and temporal contexts.

NIH Research Projects · FY 2026 · 2026-02

Project summary: Our laboratory invented a novel precision medicine approach for autoimmune disease treatment known as chimeric autoantibody receptor T cell (CAART) therapy, which aims to eliminate only the disease-causing autoimmune B cells while sparing healthy B cells, thus avoiding the risks of general immune suppression. We established initial efficacy of the approach in experimental autoimmune disease models and subsequently initiated a first-in-human clinical trial of DSG3-CAART in mucosal-dominant pemphigus vulgaris, a potentially fatal blistering disease caused by autoantibodies to the epithelial adhesion protein desmoglein 3 (DSG3), and more recently, MuSK-CAART in muscle-specific tyrosine kinase (MuSK) myasthenia gravis, in which autoantibodies to MuSK cause muscle weakness and potentially life-threatening respiratory crisis. DSG3- CAART was generally well-tolerated, although no consistent pattern of clinical or serologic improvement was observed. In contrast, 4 of the first 6 MuSK-CAART-treated patients experienced improvement in clinical disease activity scores, associated with MuSK-CAART expansion and persistence, and 2 of 4 subjects in the higher dose cohort experienced serious adverse events related to therapy. DSG3-CAART and MuSK-CAART are the first precision cellular immunotherapies for autoimmunity to enter clinical trials, which presents a unique opportunity to define the effects of these living drugs in human patients. In a separate line of studies we are investigating DSG3-CAART immune profiles; in this proposal, we will define immune profiles before and after infusion to evaluate pathways activated in MuSK-CAART and host immune cells that may identify biomarkers of safety and efficacy. Our studies will elucidate the cellular mechanisms of MuSK-CAART in vivo and may lead to new strategies for engineering the next generation of precision immunotherapies to achieve safe and durable autoimmune disease remission.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY CaV2.1/2.2 channels are physiologically consequential as they convey Ca2+ influx that initiates vesicular release of neurotransmitters at chemical synapses of both central and peripheral neurons. Not surprisingly, dysfunction of these channels is linked to various human diseases. First, loss-of-function missense mutations in CACNA1A gene that encodes the CaV2.1 channel are linked to severe neurological diseases including ataxia, epilepsy, and neurodevelopmental delay. Second, as CaV2.2 channels serve as key mediators of nociceptive signaling, pharmacological inhibition of CaV2.2 has emerged as a promising non-opioid approach for the treatment of chronic pain, although current FDA approved blockers (gabapentin, pregabalin, and ziconotide) have severe side-effects. New strategies to precisely tune the function of these channels in neurons are therefore highly desired. In this regard, in depth physiological studies have revealed that the localization and activity of CaV2 channels is tightly regulated by a bevy of molecular and cellular factors including alternative-splicing, phosphorylation, and the binding of auxiliary subunits and regulatory proteins. Here, our preliminary data uncovers S-palmitoylation of the pore-forming subunits of both CaV2.1 and CaV2.2 channels as a powerful and largely unexplored modulatory scheme. Unlike other lipid modifications, S-palmitoylation is reversible and dynamic, orchestrated by zDHHC1-23 enzymes that attach lipid groups to proteins and thioesterases that excise lipid modifications. We find that depalmitoylation of CaV2.2 channels potently inhibits Ca2+ currents, while the same maneuver upregulates CaV2.1. The overall goal of this proposal is to: (1) elucidate the physiological relevance of S-palmitoylation of CaV2 channels in both peripheral and central neurons and (2) to devise engineered depalmitoylases to selectively tune CaV2.1/2.2 function in pathophysiological settings. Our central hypothesis is that CaV2 channels are endogenously palmitoylated in neurons and targeted recruitment of a depalmitoylase to the channel complex can reverse pathophysiological changes in channel function. While this proposal focuses on CaV2 channels, the ultimate impact of the methods developed here extends to nearly a wide range of proteins that are S-palmitoylated, and potentially forms the basis for developing new therapeutics.

NIH Research Projects · FY 2026 · 2026-02

Human induced pluripotent stem cell (hiPSC) differentiation offers a unique perspective on species- specific aspects of neuronal development. We employed high-temporal resolution single-cell expression analysis to investigate the mechanisms underlying prolonged and enhanced neurogenesis in the human spinal cord compared to mice. Canonical correlation analysis revealed "human-specific" progenitor clusters marked by early co-expression of NKX2-2 and OLIG2. Lineage tracing revealed that these cells are bone fide motor neuron progenitors. Unlike classical motor neuron progenitors (pMNs), these more ventral motor neuron progenitors (vpMNs) exhibit increased NOTCH and WNT activity, generating motor neurons in a delayed and protracted manner. Furthermore, vpMNs undergo more rounds of cell division, yielding approximately five times more motor neurons that are enriched in motor neuron subtype innervating limbs. Evolution of a new progenitor domain is a novel mechanism through which human CNS increases its size and complexity, distinct from transit amplifying progenitors described in the developing human neocortex. Our proposed research aims to answer four outstanding questions: 1) Is NKX2-2 expression both necessary and sufficient to activate the vpMN program, leading to extended motor neuron genesis? 2) What evolutionary changes in the OLIG2 regulatory system allow human-specific co-expression of OLIG2 and NKX2-2? 3) Does increased NOTCH signaling observed in vpMNs contribute to their specification and delayed neurogenesis? 4) Do vpMNs and pMNs generate different subtypes of motor neurons during human neurogenesis? Addressing these questions will provide valuable insights into the molecular and cellular mechanisms that contribute to the increased number and complexity of motor neurons produced during the human spinal cord development. These insights might lead to improved motor neuron disease models that recapitulate more faithfully human pathology.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY: The mechanisms by which stem cells orchestrate their program to become functional differentiated cells require accurate temporal regulation of specific gene expression programs. This complex network requires precise temporal regulation of transcription and degradation processes to activate specific programs in a coordinated manner. So far, most of the studies have explored the regulation of transcriptional pathways and chromatin remodeling events during the differentiation process. mRNA degradation processes may present an attractive and still poorly explored opportunity for enhancing our understanding of the differentiation process. However, the lack of technologies that can capture rapid mRNA degradation events over highly dynamic processes, such as differentiation, and the heterogeneity of the mRNA degradation machinery in composition and expression patterns during differentiation have presented major technical limitations to further exploring the role of mRNA degradation across the continuum of the differentiation program. Here I propose to explore the existence of specialized RNA degradation complexes that control the decay of specific mRNA subclasses at precise timeframes of the differentiation process. To test this, we will introduce a new platform that uses cutting-edge technologies integrated in an innovative way to interrogate the continuum of the differentiation process at an unprecedented resolution. Our programmable depletion and rescue strategy will allow us to control the expression level of each subunit of complex mRNA degradation machinery robustly and with a precise time resolution of hours. By combining this technology with a high-content imaging system, we can record phenotype changes and accurately determine the specific impact of any perturbed protein on differentiation. Additionally, the use of this platform will guide us to understand the exact gene regulatory network controlled by the machinery at the transcriptional and stability level. The conceptualization and development of this workflow have the potential to impact a broader scientific audience; due to its extremely high flexibility, it could be applied to the study of unlimited biological processes or proteins. In this essay, the application of our proposed platform has the potential to fundamentally overturn the current view of how mRNA decay is dynamically regulated, providing a definite understanding of the function of the degradation machinery on mRNAs and, at the same time, revealing the broader impact of the degradation process on differentiation.

NIH Research Projects · FY 2026 · 2026-02

SUMMARY Metals are neurotoxic at high doses yet can contribute to motor and cognitive deficits even at environmentally relevant doses. Metals contribute to amyloid β misfolding and tau hyperphosphorylation, which are pathological hallmarks of Alzheimer’s disease (AD) and AD-related dementia (ADRD) risk as well as cognitive decline. Metals also interact with the APOE4 allele to influence AD risk, advance neurodegeneration, and have vascular effects that may further contribute to dementia risk. Metals may thus represent multiple hits for risk of cognitive impairment and dementia. Yet, few cohort studies have comprehensively evaluated the association of metal exposures with mild cognitive impairment (MCI) and AD/ADRD. To fill this knowledge gap, we propose to leverage the NIH-funded Atherosclerosis Risk in Communities (ARIC) and Multi-Ethnic Study of Atherosclerosis (MESA) cohorts of diverse US adults to test the hypothesis that widespread exposure to metals—determined by established and novel biomarkers—is associated with MCI and AD/ADRD risk and with key pathophysiological processes that explain this risk. ARIC and MESA have rich biorepositories, as well as examination, laboratory, omics and clinical data. In these unique and diverse cohorts, we propose to add a metallome profile to quantify metal exposure and internal dose for each participant by measuring metals in urine, blood, and serum at repeated visits in all participants, as well as in brain-derived extracellular vesicles in a subset of participants. Priority metals include lead, cadmium, copper, mercury, manganese and zinc, although other metals will also be measured. We will connect these metallome profiles with rich brain health and multi-omics data (whole genome sequencing, epigenomic/methylomic, transcriptomic, proteomics, targeted and untargeted metabolomics). We will use powerful, state-of-the-art analyses to determine the prospective associations of long-term metal exposures with risk of cognitive decline, MCI and AD/ADRD risk (Aim 1), and with the trajectory of plasma AD and brain imaging biomarkers (Aim 2) in diverse US adults overall and by sex, race/ethnicity, and APOE4 genotype. We will then develop a predictive multi-omics fingerprint that quantifies risk of MCI, AD/ADRD, and cognitive decline due to metal exposures (Aim 3). Because metal exposures are preventable and treatable, adding high-quality measures of the metallome profile to diverse cohorts with longitudinal brain health and extensive omics data will enable this project to contribute key knowledge of the molecular/biological pathways involved in development of cognitive decline as well as identify new targets for the prevention and treatment of AD/ADRD. This work will generate critical knowledge and serve as a robust model for generating highly valuable data that can be leveraged to prevent/mitigate harmful metal exposures and protect cognitive health.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Up to 3.1% of women in the United States experience premature menopause (menopause before age 40) and another 6.2% experience early menopause (menopause between age 40-45) due to a spectrum of surgical and non-surgical conditions. Premature/early menopause results in estrogen deprivation which has significant health consequences and adversely affects quality of life. Compared to natural menopause, women who undergo premature/early menopause have an increased risk for cardiovascular disease, osteoporosis, and neurological/psychological conditions, leading to a higher mortality risk. Systemic hormone therapy (HT) is highly effective in mitigating the short- and long-term consequences of estrogen deprivation and is recommended by guidelines from national and international professional organizations. However, research on HT use in women with premature/early menopause is sparse and the limited data available suggest severe underuse. Because women at younger ages are less prepared of menopausal transition and may face greater challenges in work, life, and health care, there is a critical need for research on premature/early menopause. The overarching goal of this project is to improve the long-term health of women with premature/early menopause by understanding factors influencing their HT use and developing a preliminary tool for identifying women at high risk for underuse. We will focus on women without malignancy or hereditary predisposition for cancer – a homogeneous population to better isolate influencing factors. Within this population, we propose the following specific aims: 1) to characterize the overall trajectory and heterogeneity in HT use and identify patient and physician factors associated with HT initiation and continuation; 2) to ascertain patients' and physicians' perceived barriers and facilitators to HT use; and 3) to develop a dynamic risk prediction model for HT underuse and explore the feasibility of a patient prioritization tool for HT counseling. We will achieve these aims by analyzing a unique dataset that integrates insurance claims data with electronic health record data and applying novel analytical approaches to characterize patients’ longitudinal trajectory of HT use (both the overall pattern and heterogeneity among patients), examine physician peer influence in HT practice, and develop artificial intelligence/machine learning-based risk prediction models. This will be supplemented by primary data collection using a mixed methods approach – combining qualitative interviews and focus groups with quantitative surveys of patients and physicians – to uncover individual, structural, and system-level factors influencing HT initiation and continuation and inform proactive interventions for improving HT use. By understanding care patterns related to HT use in women with premature/early menopause, its influencing factors, and characteristics of patients at particularly high risk for HT underuse, this project addresses an important but understudied clinical question. The findings can facilitate targeted interventions and better equip us with the knowledge and tools to improve care for this large population of women.

NIH Research Projects · FY 2026 · 2026-01

Measles (MeV) causes disease worldwide despite efforts towards eradication by vaccine, primarily because it is readily spread between people. Acute MeV infection causes immune amnesia, increasing susceptibility to other infectious diseases. In addition, rare but severe neurological complications can develop several years after measles due to persistent MeV infection of the central nervous system. People with impaired cellular immunity are at increased risk of developing severe measles but often cannot be vaccinated since the vaccine virus itself can lead to fatal illness. There is no specific therapy for acute or persistent MeV manifestations. A successful vaccination campaign could have eradicated MeV more than 20 years ago. As of today, eradication is not in sight, and the resurgence of measles highlights the need for a vaccination strategy that is safe for immune-compromised people and easy to be delivered around the world without the need for a cold chain. The current vaccine elicits antibodies directed against the two envelope glycoproteins, the receptor-binding hemagglutinin and the fusion protein. The antibodies against the hemagglutinin are strongly neutralizing, while current- vaccine-elicited antibodies against the fusion protein are not. This is in contrast to wild type induced immunity that elicits effective anti-F neutralizing antibodies. We have designed ectodomains and full-length MeV fusion protein (FECTO and FFL) stable to high-temperature, confirmed their pre-fusion conformation by cryo-EM, and found that immunization with either of these stabilized, recombinant FECTO and FFL induce in vivo protection. The recent approval of a stabilized respiratory syncytial virus fusion protein as a subunit vaccine highlights the clinical validity of our strategy. This application will test whether we can design a thermostable measles F that elicits protection in immune-compromised individuals and can be delivered worldwide. We propose to capitalize on our structural and functional knowledge of the MeV F to optimize and assess the efficacy of thermostable forms of the F to elicit neutralizing antibodies and induce a protective immune response in vivo. The proposed work will address two Specific Aims: 1. Stability and immunogenicity of thermostable MeV F proteins. 2. Evaluate the protection afforded by anti-F protein immune responses. Our application will significantly impact the growing number of severely immune- compromised individuals who cannot be vaccinated with the current live MeV vaccine and may contribute to the worldwide eradication of MeV.

NIH Research Projects · FY 2026 · 2026-01

ABSTRACT Children from adverse developmental environments demonstrate varied reading achievement. The overarching hypothesis of the proposed research is that genetic and neural canalization provide a buffer against the negative impacts of developmental risks to ensure normative reading and language achievement. Specific Aim 1 tests the hypothesis that genetic canalization protects against the well-established negative effects of low socioeconomic status on written and oral language development. We focus on the polygenic and environmental interactions to characterize canalization, including the extent to which the prevalence of low written and oral language achievement decreases with (better) polygenic scores for children from environments with high developmental risk. Here, we will examine: 1) specific social determinants of health where genetic canalization may be critically important for ensuring normal development; 2) the specificity of canalization to reading and language relative to executive functions; 3) and the degree to which there are brain structure endophenotypes for genetic canalization. Specific Aim 1 examines population-level effects, whereas Specific Aim 2 examines the instantiation of canalization within individuals and tests the hypothesis that a cortical network shown to optimize task performance can explain reading performance in children with risks for adverse development. For both aims, large datasets and novel topological analyses are used to provide optimal rigor for these experiments that will be pre-registered. Specific Aim 3 is to grow an existing data repository of data from neuroimaging studies on reading disability and development, as well as enhance the functions and our data delivery and sharing resource. This resource includes the integration of methods to generate data that can be used to replicate previous reading disability findings. This will include deep learning approaches for identifying neural predictors of reading disability, with a focus on features that canalize reading development. Together, the theoretically motivated study of large datasets will generate results to advance our understanding about the development of reading disability, particularly for children from adverse developmental environments, and further an open science initiative that is expected to advance reading disability research through data access, replication, and new discovery.

NIH Research Projects · FY 2026 · 2026-01

ABSTRACT Heterozygous microdeletions at chromosome 22q11.2, causing DiGeorge syndrome (DGS), with prevalence of 1 in 2,000-4,000 live births, constitute the most common yet understudied microdeletion disorder in humans. Hallmark features include cardiac, palate, immune, neurologic and kidney disease. The resultant DiGeorge- associated kidney diseases (DGS-KD) are heterogenous and suggest the activity of a dosage-sensitive molecular signaling mechanism. We showed that haploinsufficiency of the adaptor protein CRKL, located within this locus, is the main genetic kidney driver (NEJM 2017, NG 2019). We recently contributed to a manuscript reporting that 22q11.2 deletion and CRKL haploinsufficiency result in neural tube defects, broadening the relevance of our work (Science 2024). Via alternative splicing, CRKL encodes two distinct transcript isoforms that serve to link tyrosine kinase signaling to downstream pathways. We hypothesize that proper isoform expression regulates Crkl engagement of receptor tyrosine kinases, guanine exchange factors and GTP-ases. These assemblies, in turn, regulate downstream cellular processes such as growth, cell division and migration. To unravel the pathobiology induced by aberrant CRKL signaling, and aid discovery of new diagnostics and therapeutics, we will combine genetics, transcriptomics and proteomics, and correlate patient cell lines with analogous mouse models. This will help identify the mechanisms underlying DGS-KD biology and define the role of alternative gene splicing that tightly controls morphogenetic events. Matched human and animal genetic models will provide translational relevance and potentially create new personalized tools for study of disease and screening of therapeutics. We will analyze a panel of genetic variants that affect Crkl expression with spatiotemporal specificity. Using high-resolution structural analyses, we will quantify the structural consequences of aberrant Crkl signaling. Using phosphoproteomic approaches, we will study CRKL interacting partners and the resulting signaling pathways. We also will create a panel of mouse- and patient-derived iPSCs to generate in vitro assays that model DGS-KD to help develop a new disease-modeling and screening platform for bench- to-bedside functional genomics. These will serve as translational tools to model kidney disease, which can be utilized to devise drug therapies and intervention strategies. Finally, we will use a multiomic approach to analyze, at the single nuclear level, comprehensive gene expression, gene regulation, cell trajectory and epigenomics in human and mouse models to define the pathobiology of CRKL-mediated kidney disease.