University Of Rochester

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Endothelial cells are vital for maintaining homeostasis and facilitating repair following vascular injury or disease. Vascular regeneration is increasingly recognized as critical for treating vascular diseases, with recent evidence highlighting the role of resident angioblasts. Despite their importance, the cellular characteristics and regulatory mechanisms governing angioblasts remain poorly understood. This project seeks to bridge this gap by leveraging existing scRNA-seq data to explore the trajectory of pulmonary angioblasts (PACs), their derived cells, and the molecular markers and signaling pathways that drive their differentiation and function. As such, this proposal aligns perfectly with the NIH PAR-23-036 funding opportunity, which supports the reanalysis of existing data to address critical gaps in knowledge. By reanalyzing these datasets, we will uncover novel insights into PAC identity, fate, and the regulatory mechanisms driving their function. This approach allows us to address important questions in pulmonary vascular biology with minimal experimental burden, maximizing the utility of existing data while advancing our understanding of vascular development. Our preliminary analyses of available scRNA-seq datasets have identified PACs with significant self-renewal capacity in mouse lungs, peaking between embryonic day 12.5 (E12.5) and postnatal day 7 (P7). Intriguingly, trajectory analysis reveals that PACs do not directly differentiate into mature endothelial cells (ECs) such as arterial ECs (aECs), venous ECs (vECs), or capillary ECs (C2-ECs). Instead, PACs differentiate into an intermediary population of CD34high cells (C1-ECs), subsequently generating other EC subtypes. Underscoring their importance, PACs and their progeny were significantly reduced in hyperoxia-induced bronchopulmonary dysplasia (BPD) mice, which have arrested pulmonary vascular development and alveolarization. We have identified several major knowledge gaps in our understanding of pulmonary vascular development. a) How vasculogenesis, intussusceptive and sprouting angiogenesis are coordinated with lung development remains unclear. b) The spatial-temporal lineages of EC- related cells during lung development and regeneration are unexplored. c) The functional roles of different lineages in lung development and homeostasis are not well defined. d) The specificity of the PACs vs angioblasts from blood island during the embryo stage in mice. e) The regulatory mechanisms guiding PAC cell fate and localization are largely unknown. The previous findings about pulmonary vascular development and our preliminary data lead us to hypothesize that PACs are crucial for pulmonary vasculature development by residing in specific niches that facilitate lung development. PACs have the most robust self-renew ability. In proximal regions, PACs localize along arterial and venous vessel walls to contribute to intussusceptive angiogenesis. In distal regions, PACs differentiate into CD34high cells and lead the protruding into secondary septa, which form neovasculature and promote the alveolar-capillary structure. (Fig. 1). To test this hypothesis, we propose two specific aims. Aim 1: Define PAC cell identity, cell fates, and regulatory mechanisms in mice and humans. Aim 2: Visualize PAC and PAC-derived cell lineages during development and vessel injury.

NSF Awards · FY 2025 · 2025-09

This project aims to improve the understanding of atmospheric methane oxidation by hydroxyl and chlorine radicals. A new, state-of-the-art laboratory setup will provide high accuracy measurements. A wide range of experimental conditions will be employed, including using different radical precursors and varying temperature, pressure, and reactant concentrations in ways not previously studied. This work is motivated by the fact that methane is highly important in global atmospheric chemistry, and the uncertainties associated with atmospheric methane oxidation currently limit the capability to use methane isotopic measurements to study the global methane budget. The new measurements from this study are expected to contribute to the understanding of societally important issues of air pollution and radiative forcing. Training and supporting early career scientists are significant components of this project, and outreach activities are planned. The project will involve fabricating a laboratory photochemical reactor that uses a laser source for radical generation. Tunable Infrared Laser Direct Absorption Spectroscopy (TILDAS) is the primary analytical technique to be used for high-precision measurements of methane mole fraction and isotopic composition, while FTIR and UV Absorption Spectroscopy will be used for measurements of methane and other key chemical species inside the reactor. The photochemical reactor system will enable studying the reactions of OH and Cl with 12CH4, 13CH4, and 12CH3D to improve understanding of the Kinetic Isotope Effects. This will be the first study to cover the full range of temperatures and pressures relevant to the troposphere. The results of the study are expected to substantially reduce current uncertainties for annual average global methane emissions from fossil fuel and microbial sources. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-09

Attention is critical for filtering incoming sensory information; however, attentional function is often impaired in common neuropsychiatric disorders including ADHD or schizophrenia. Visuospatial attention in particular involves both the enhancement of attended information and the suppression of ignored information at locations across the visual field. Major theories of visuospatial attention propose an interdependent relationship between enhancement and suppression, arising from competitive interactions between neural populations representing different visual field locations. Furthermore, recent research demonstrates that visuospatial attention involves ‘rhythmic sampling’ of the environment, with periodic alternation (~4-6 Hz) between two functional states: one that promotes selective processing at an attended location and another in which attentional selection is relatively diminished and attentional shifts are more likely. To investigate the neural basis of rhythmic sampling during visuospatial attention, the proposed research will test the temporal dynamics of enhancement and suppression-related competitive interactions between neural populations in extrastriate visual cortex (i.e., V4) representing different visual field locations (Aim 1). The processing of sensory information in visual cortex can be modulated by top-down control from the frontal eye fields (FEF) and lateral intraparietal area (LIP), two cortical nodes of large-scale ‘attention network’ that have previously been linked with attention-related enhancement and suppression. Recently, rhythmic sampling during visuospatial attention has been shown to involve rhythmic changes in neural activity within FEF and LIP. Emerging evidence points to functional specialization between FEF and LIP with respect to enhancement and suppression. The proposed research will further test the temporal dynamics of enhancement and suppression-related functional interactions between these higher-order cortical areas and visual cortex during the deployment of visuospatial attention (Aim 2). Multisite laminar probes will be used to simultaneously record neural activity from FEF, LIP, and V4 in two to three monkeys. In a visuospatial detection task, cues will indicate the locations of upcoming targets and/or distractors which will be presented within the receptive fields of recorded neural populations. This approach will reveal the temporal dynamics of network-level interactions supporting enhancement and suppression across the visual field, including (i) functional interactions between V4 neural populations representing distinct visual field locations (Aim 1) and (ii) functional interactions between higher-order cortical areas (i.e., FEF and LIP) and V4 during the voluntary deployment of enhancement and/or suppression (Aim 2). Results from these complementary, yet independent aims will provide key insights into how visuospatial attention shapes perception via the enhancement and suppression of sensory processing. The proposed project could therefore uncover new pathways for therapeutic intervention that could ultimately increase quality of life for individuals experiencing attentional deficits.

NIH Research Projects · FY 2025 · 2025-09

Eukaryotic cells can rapidly adjust the abundance, size, and shape of their membrane-bound organelles in response to physiological needs. We recently found that fission yeast cells employ different mechanisms to counteract various types of stress: nutritional deprivation sequentially activates organelle degradation, while ER stress, caused by the accumulation of misfolded proteins, induces morphological changes in multiple organelles, such as the ER, Golgi, and mitochondria, without triggering their degradation. Our current research aims to understand the molecular framework underlying these differential adaptive responses in fission yeast and to investigate their conservation in mammalian systems. We propose that organelles communicate and coordinate sequential degradation through selective autophagy. To explore this, we will integrate structural prediction with genetic and cellular assays to systematically identify selective autophagy receptors and use multi-omics approaches to investigate potential crosstalk between organelles during starvation. Given that ER stress is increasingly recognized as a contributing factor in a number of human diseases including neurodegenerative disorders and cancer, we will also use fission yeast and human cell cultures to examine how these cells reorganize multiple organelles to mitigate ER stress. These insights could advance our understanding of disease pathology and suggest new diagnostic and therapeutic strategies.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Deaf individuals are one of the most understudied and underserved cultural populations in the field of mental health. While limited, data suggests significant mental health disparities among Deaf adults including higher rates of suicidal thoughts and behaviors; yet, they have low rates of mental health treatment engagement. The Candidate’s long-term goal is to develop and test evidence-based interventions for Deaf adults to promote mental health and reduce suicide risk. Reaching that goal requires mentored training in three domains of clinical research, and completion of a research project to produce foundational results (described below). First, the candidate needs to gain expertise in the design, execution, and analysis of randomized controlled trials (RCT) with Deaf individuals (Objective 1) to successfully conduct RCTs in a reliable, valid, and ethical manner, and test target engagement with an experimental therapeutics approach. Second, the candidate needs to gain knowledge and skills related to research with subjects at elevated risk for suicide (Objective 2) to safely and effectively conduct suicide prevention and treatment research. Third, the candidate needs to gain knowledge and skills to support ease of implementation of her interventions in varied contexts including deployment-ready and principle-driven intervention development, and implementation science (Objective 3). The principal objectives of the proposed research study are to use deployment-ready intervention development and implementation science methods to develop an interventionist training and monitoring program for Cognitive Behavioral Therapy for Treatment-Seeking for Deaf individuals (Deaf CBT-TS; Aim 1), and conduct an RCT using an experimental therapeutics approach to examine whether the intervention can modify beliefs about treatment (intervention principles) and increase treatment-seeking behaviors (target mechanism; Aim 2). Secondary objectives include exploring the intervention’s potential to increase hope and reduce indicators of suicide risk (mental health symptoms, alcohol use, suicide ideation; Aim 3), and identifying factors that may impact the efficacy of Deaf CBT-TS including acculturative stress and the availability of Deaf-accessible treatment resources to understand factors that may impact the implementation of the intervention in varied health service settings (Aim 4). One hundred Deaf sign language using adults with clinically significant symptoms of depression, anxiety, PTSD, insomnia, alcohol use disorder, and/or suicide ideation (oversample 50%), who are not engaged in treatment will be randomized to Deaf CBT-TS (2 sessions) or a waitlist control group. Half of the subjects will be from Rochester (Deaf-specialty treatment resources) and half will be from across the U.S. Subjects will complete baseline, 2- and 4-month follow-up assessments. Results of this K23 project will function as a basis for a larger R01 of a fully powered RCT examining clinical outcomes (i.e., reductions in indicators of suicide risk) and the mediation effect of treatment engagement.

NSF Awards · FY 2025 · 2025-09

Aluminum metal is manufactured by passing a large electrical current downward through a layer of molten salt, where aluminum ore has been dissolved, and a layer of molten aluminum beneath. The process uses tremendous amounts of energy -- 3 percent of all the world's electricity. Improving its efficiency would reduce costs, save energy, and reduce emissions. However, the efficiency is limited by a fluid dynamics disruption, the metal pad instability, which can drive an aluminum smelter out of control. In today's smelters, the instability is prevented by thickening the salt layer, but because salt is a poor electrical conductor, thickening it sacrifices efficiency and turns nearly 40% of the electrical energy into waste heat. However, simulations predict that adding an alternating component to the current or to nearby magnetic fields could prevent the instability even with a thin salt layer, thereby increasing efficiency and reducing cost. In this project, researchers will perform experiments to reproduce the instability in the laboratory, measure its growth rate, and seek to prevent it by adding an alternating current component and/or magnetic field, and subsequently determine optimal parameters for preventing it. Small, inexpensive laboratory experiments could pave the way for implementation in full-size smelters (involving about 50 tons of aluminum). If the efficiency of aluminum manufacture can be increased by even 10%, worldwide savings would be about $1 billion per year. Meanwhile, increased efficiency would promote aluminum manufacture within the United States. In the planned experiments, ~300-A currents will be run downward through a layer of nitric acid dissolved in amyl alcohol atop a layer of nitric acid dissolved in water, in the presence of magnetic fields up to 150 mT. Prior experiments showed that such a device produces the instability, but stabilizing it in the lab has not been tried. A camera will image the interface between the two layers, which suffers growing oscillations when the instability occurs. Growth rates will be measured for experiments with varying layer thickness, steady current amplitude, alternating current frequency, alternating current amplitude, alternating magnetic field frequency, and alternating magnetic field amplitude. These experiments look to characterize the instability much more easily than simulations, which are slow and expensive. The results will be used to estimate parameters for stabilizing full-size aluminum smelters. Additionally, the project will support a hands-on engineering course for high school students and graduate-level lectures about the metal pad instability. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-09

Electrocardiographic Detection of Non-ST Elevation Myocardial Events for Accelerated Classification of Chest Pain Encounters (ECG-SMART-2) ABSTRACT There is a clear need to develop improved tools to stratify risk in patients who seek emergency care for chest pain, one of the most common and potentially deadly conditions encountered in acute care settings. The 12- lead ECG has been the mainstay of initial evaluation of chest pain yet is currently only diagnostic for a small subset of patients with ST-elevation myocardial infarction. Over the past funding period, we have built the largest database of multi-hospital, outcome-linked, prehospital 12-lead ECG repository known to us (n=4,132). Using this multi-expert, multi-tier ground truth annotated database, we have developed and validated novel, machine learning-based, ECG interpretation algorithms that could identify non-ST elevation acute coronary events. Using state-of-the-art interpretability toolkits, we identified ECG signatures that are mechanistically linked to ischemia and can serve as plausible markers of acute coronary syndrome. We now aim to move these extensive efforts to clinical use by expanding and building these models at the bedside for prospective validation and real-time clinical deployment. The specific aims of this renewal application are: 1) to build and externally validate a multi-task, ECG-based intelligent decision support system; 2) to build and deploy a real- time architecture for this intelligent system along with a clinician-facing graphical user interface platform; and 3) to perform a prospective clinical validation of this intelligent ECG system, including silent deployment and evaluation at two clinical sites. The final deliverable is an intelligent ECG interpretation system for detecting and stratifying patients with suspected acute coronary syndrome of sufficient readiness to be deployed in clinical trials aimed at improving outcomes in non-ST elevation coronary syndromes. Such intelligent system, when combined with the judgment of trained emergency personnel (physicians, nurses, and paramedics), would more accurately identify patients with acute coronary occlusions for ultra-early intervention. This system will streamline the care provided to non-specific chest pain beyond the costly and time-consuming overnight observations for serial cardiac enzymes and provocative testing.

NSF Awards · FY 2025 · 2025-09

With support from the Chemical Structure and Dynamics (CSD) program in the Division of Chemistry, Professor Daniel Mittleman of Brown University and Professor Michael Ruggiero of the University of Rochester are investigating guest-host molecule interactions in porous materials using a combination of vibrational spectroscopies and computational methods. This project aims to uncover the atomic-level mechanisms that drive the adsorption of gases in porous materials such as metal-organic frameworks (MOFs) and clathrates. A key challenge is that the intermolecular forces are often weak, requiring probes in the terahertz range. The team will apply low-frequency infrared and Raman spectroscopies, exploiting a unique capability to obtain such measurements in a custom-designed pressure cell, to reveal how gas loading alters the vibrational dynamics in real time. Quantum mechanical simulations will help to interpret these spectral changes, linking them to structural information. The combination of computational and experimental results will clarify important open questions in the field, such as the impact of structural disorder on adsorption dynamics. These new insights will inform the rational design of materials optimized for particular applications such as hydrogen storage or toxic chemical remediation. These efforts are linked to a hands-on week-long summer course developed for high school students in Rochester and Providence, which will further the pedagogical training of the graduate students participating in the project. This project integrates state-of-the-art experimental and theoretical techniques to study the vibrational dynamics of porous media under gas-loading conditions. Vibrational spectroscopy, including terahertz time-domain and Raman measurements, will be used to monitor subtle structural changes, through changes in the low-frequency modes, which reflect shifts in the intermolecular forces during gas adsorption. A gas-dosing manifold with stoichiometric control will enable precise quantification of guest molecule uptake and its impact on vibrational spectra. These data will be compared to solid-state density functional theory (DFT) and ab initio molecular dynamics (AIMD) simulations to interpret experimental results and uncover structure–dynamics relationships. The results will reveal the role of host framework flexibility, host/guest molecule disorder, and cooperative phase transformations on the gas loading mechanisms and associated kinetics. The ultimate goal of this project is the development of predictive models that link spectroscopic signatures to molecular-scale mechanisms. This project will establish a new paradigm for characterizing and designing functional porous materials using laboratory-based spectroscopic methods. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-09

With the support of the Chemical Synthesis Program of the Chemistry Division, Professor Tom G. Driver of the University of Illinois Chicago (UIC) is studying the development of new reactions to synthesize medium-ring molecules. Despite their established important bioactivity, this scaffold is underrepresented in pharmaceutical compound libraries because of the lack of synthetic methods for their construction. The goal of this project is to develop new metal-catalyzed processes that leverage and tame the reactivity of highly reactive metal carbenes to trigger new bond formation to create these important molecules. UIC is a designated Minority- and Hispanic Serving institution, and the hypothesis-driven nature of this project is well suited for the education of scientists at all levels. Professor Driver has tailored his research program to provide opportunities for students to advance in their professional development. The funded project also includes research experiences for high school students to inspire their pursuit of careers in STEM fields, and Chemistry Career Fair professional development activities to show the types of jobs and careers undergraduate- and graduate students can aspire to. Medium-sized carbocycles and heterocycles are critical structural motifs in pharmaceuticals and natural products. Despite their established use as scaffolds in drugs, medium-ring molecules remain underrepresented in pharmaceutical compound libraries, which is attributed to the shortage of synthetic methods to construct them. The experiments proposed with this proposal address gaps in state-of-the-art methods by exploiting the novel reactivity embedded in non-carbonyl stabilized metal carbene catalytic intermediates to develop new reactions that form seven- and eight-membered rings through the construction of C–C, C–S, C–O, and C–N bonds. Towards that end, our goals are: (1) to develop new metal-catalyzed cyclization-migration reactions of metal carbenes to construct medium-ring heterocycles by exploiting their unique reactivity with esters; (2) to develop new ring-expansion reactions of metal carbenes to construct all carbon medium-sized rings through a unique C–C bond activation mechanism; and (3) to leverage the reactivity of non-carbonyl-stabilized metal carbenes to participate in [2,3] rearrangements via ylides to enable synthesis of medium-sized heterocycles. The resulting medium-ring compounds are being added to UICentre for Drug Discovery’s novel small molecule library and submitted to our HTS facility for screening to initiate future collaborations. This project serves as a fertile ground for the training of students to advance in their scientific careers and hosting professional career development activities to meet the goals outlined by PCAST to transform and charge the STEM-student pipeline. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-09

Nursing homes are cornerstones of the US post-acute and long-term care systems, serving over 4 million older adults, more than half of whom have Alzheimer’s Disease or Alzheimer’s Related Dementias (AD/ADRD). Despite their importance, older adults’ access to these facilities may be approaching a state of crisis. Recent market conditions disrupted the nursing home industry and resulted in historic and persistent staffing shortages, raising concerns that many facilities may be forced to reduce capacity or close entirely. Our preliminary data analyses indicate these concerns are well-founded. We estimate that functional nursing home capacity has declined by nearly 10% since 2019, with nearly 40% of US counties experiencing a decline of 15% or more. The implications of these capacity declines are not well understood but have the potential to be catastrophic. For example, inadequate nursing home capacity may result in disrupted care transitions and slowed recovery following hospitalization, patients languishing in hospitals while awaiting a nursing home bed, increased risk of injuries from inadequate personal care, and increased strain on family caregivers who often fill in the gaps when care is provided at home. There are several tools available to stabilize or expand the nursing home market, including increasing payment rates, removing barriers to new market entrants, and increasing financial incentives to provide care in shortage areas and/or to patients with reduced access. However, there is a glaring evidence gap regarding the need to intervene, the types of interventions needed, and where these interventions should be targeted. Our proposal will close this knowledge gap with rigorous quantitative analyses that will determine the effects of reduced nursing home capacity on three populations. In Aim 1, we will use Centers for Medicare and Medicaid Services (CMS) administrative data and hospital-level variation in the extent of nursing home capacity declines to estimate effects on the care transitions and recovery of hospitalized patients, with and without AD/ADRD, with intensive post-acute care needs. In Aim 2, we will use similar data and county-level variation in capacity declines to estimate effects on care access and injury risk for community-dwelling older adults with increasing long-term care needs, as signified by a new AD/ADRD diagnosis. Aim 3 will estimate spillover effects on spousal caregivers of older adults with post-acute or long-term care needs. It will use household-level survey data linked with CMS data to identify couples and track spousal care delivery and health outcomes following a partner’s hospitalization or diagnosis of a chronic condition, including AD/ADRD. Geographic information will be used to identify exposure to post-2019 nursing home capacity loss. Results from this proposal will provide a comprehensive portrait of current US nursing home capacity and the ability of this market to meet the institutional care needs of an aging population. Results will also support efforts to ensure access to nursing home care, regardless of geography or patient type.

NSF Awards · FY 2025 · 2025-09

This project examines the generation of potential energy at ocean gyre-scales (>1000 km) and its subsequent release to kinetic energy by mesoscale eddies. The investigators hypothesize that eddies of size 200-500 km are significant net generators of potential energy via eddy-induced upwelling and downwelling, which penetrate deep into the ocean water column. This process is an overlooked sink for mesoscale kinetic energy, implies a downward heat flux, and supports mixing in the ocean interior. The project will utilize novel and mathematically rigorous scale-analysis techniques, state-of-the-art idealized and realistic simulations, and exciting recent advances in in-situ observations of the ocean interior using Argo floats. A graduate student will participate in the project and the team will engage with the public through a collaboration with the Rochester Museum and Science Center. The investigator hypothesizes that eddies of 200-500km size generate potential energy via eddy-induced upwelling and downwelling. This process, which penetrates deep into the ocean, could also be responsible for mixing in the ocean interior. The project will combine a suite of multiscale models and observations. Realistic regional and global eddy-resolving models will be used to estimate potential energy across different scales. Idealized models on the mesoscale and submesoscale will be employed to determine if larger scale eddies are formed through an upward cascade of energy. Observations from ARGO floats will be used to examine the three-dimensional structure of eddy velocities. Finally, coarse-graining will be applied to analyze the models and data to determine the flow of energy between eddy scales. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Gestational diabetes mellitus (GDM) is a form of diabetes that manifests during pregnancy and is characterized by hyperglycemia and glucose intolerance due to pregnancy-driven insulin resistance and inadequate pancreatic beta cell adaptation. GDM has a worldwide prevalence of 1.1-31.5 % and is influenced by race, ethnicity, age, body composition, and screening and diagnostic criteria. The rate of GDM in the US has increased by 30% from 2016 to 2020 and is expected to continue to increase in subsequent years. Women with GDM have an increased risk for pregnancy complications and adverse health conditions following pregnancy, while their fetuses face risks such as premature birth and developing metabolic disease later in life. Published studies have demonstrated that pancreatic beta cell proliferation is critical for maintaining healthy maternal glucose levels during pregnancy. One mechanism regulating beta cell proliferation is serotonin- dependent activation of the G1 cyclins for the cell cycle by the binding of serotonin to the HTR2B receptor. This mechanism is driven by pregnancy-induced activation of the tryptophan hydroxylase 1 gene (Tph1) and local islet serotonin production, a vitamin B6-dependent process. Previous work from our lab has shown that nutritional and genetic factors influencing maternal vitamin B6 levels can alter islet serotonin levels and beta cell proliferation, inducing hyperglycemia and glucose intolerance in pregnant mice deficient in vitamin B6. The proposed research aims to identify environmental and genetic modulators of maternal vitamin B6 to help identify risk factors associated with the development of GDM. Specifically, the proposed studies will investigate the effects of perfluorooctanoic acid (PFOA) on maternal pancreatic beta cell proliferation. PFOA is a synthetic and ubiquitous endocrine disrupting chemical (EDC) that has been detected in blood of humans and wildlife, soil, water, and household products across the globe. Preliminary findings from our lab indicate that gestational exposure to PFOA reduces levels of islet vitamin B6 and serotonin. The proposed studies will test the overarching hypothesis that PFOA exposure at an environmentally relevant dose alters glucose homeostasis regulation and GDM susceptibility in pregnant mice through mechanisms that are dependent on serotonin-driven beta cell proliferation. Elucidating the mechanisms by which gene- environment interactions alter maternal vitamin B6 levels is pertinent to understanding the disparate risks for GDM among individuals and populations. These studies will provide new insights that will benefit maternal and child health outcomes.

NIH Research Projects · FY 2025 · 2025-09

Tubular aggregate myopathy (TAM) is an inherited muscle disease associated with progressive weakness, cramps, myalgia, and exercise intolerance that primarily affects proximal muscles of the lower limbs. The extensive presence of tubular aggregates (TAs), arrays of ordered and densely packed sarcoplasmic reticulum (SR) tubes, in muscle biopsies from TAM patients represents a key histopathological hallmark of this disease. Recent studies have linked TAM to gain-of-function mutations in the Stim1, Orai1, and Casq1 genes. The proteins encoded by these genes coordinate store operated Ca2+ entry (SOCE), a mechanism that enables muscle to replenish SR Ca2+ stores needed to maintain force production. TAM mutations in Stim1, Orai1 and Casq1 are thought to promote constitutively active Ca2+ entry that serves as an upstream driver for an age- dependent myopathy with TAs. However, the precise downstream cellular and molecular mechanisms involved remain to be elucidated. To date, there is no cure or effective treatment for patients suffering from TAM. To identify downstream pathogenic mechanisms, as well as test and validate effective therapeutic interventions, we generated knock-in mice with a G100S TAM mutation in Orai1 (Orai1G100S/+) and a separate line of mice with a D44N TAM mutation in Casq1 (Casq1D44N/+). Consistent with that observed in TAM patients, Orai1G100S/+ mice exhibit a myopathy characterized by weakness, exercise intolerance, elevated creatine kinase levels and TAs, while Casq1D44N/+ mice exhibit a milder, later onset phenotype with an age-dependent increase in TAs. We also found that TAs are reduced and force production increased after housing Orai1G100S/+ mice for 6 months in cages with voluntary running wheels. We will use these TAM mouse models to investigate mechanisms of disease pathogenesis, muscle adaptations, and test novel therapeutic interventions. The Overall Hypothesis of this proposal is that gain-of-function TAM mutations in Orai1 and Casq1 result in uncontrolled, constitutive Ca2+ entry during early muscle development that drives a transcriptional program that initially reduces aberrant Orai1 function, but ultimately, leads to a myopathy characterized by TAs. We further hypothesize that the myopathy and TAs in Orai1G100S/+ mice can be mitigated by early and late intervention with exercise mimetic therapy. Aim 1 will characterize age- and sex-dependent changes in SOCE function, muscle phenotype, TAs, muscle proteome and mitochondrial function in Orai1G100S/+ mice. Aim 2 will characterize age- and sex-dependent changes in SOCE function, muscle phenotype, TAs, muscle proteome, and mitochondrial function in Casq1D44N/+ mice. Aim 3 will assess the therapeutic potential of early and late intervention with an exercise mimetic (150-500 mg/kg/day AICAR using osmotic minipumps) in preventing and reversing, respectively, the myopathy observed in Orai1G100S/+ mice. Overall, the results will provide important new insights into the pathogenesis of TAM and assess the therapeutic potential of exercise mimetic therapy in mitigating TAM disease progression.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT Olfaction is an evolutionarily conserved sensory system, and olfactory cues uniquely interact with limbic functions including memory and emotion in healthy individuals. Deficits in olfaction are a common finding in multiple neurodegenerative diseases that also disrupt memory and emotion. However, the mechanisms underlying these olfactory deficits, as well as those underlying normal olfactory-limbic functions, are unknown. Previous studies show that strong reciprocal anatomical connections link primary olfactory brain regions, including the posterior piriform cortex (pPIR) to limbic structures, including the ventral CA1 region of the hippocampus (vCA1). vCA1 is connected to primary olfactory brain regions via polysynaptic connections through the entorhinal cortex, but recent studies have also established monosynaptic projections to vCA1 directly from pPIR, which may provide another feedforward route by which olfactory information can reach vCA1. The structure of these connections and their role in encoding and integrating olfactory information remain poorly understood. Additionally, while odorant-tuning has been previously reported in dorsal hippocampal neurons, odor responses in vCA1 remain uncharacterized. The central hypothesis of this proposal is that vCA1 receives olfactory information along structured projections from pPIR and encodes information about odor identity in patterns of neuronal activity. In Aim 1, neuroanatomic studies will identify principles of spatial organization of feedforward projections from pPIR to vCA1. Viral-based tracing approaches will be used to elucidate the cell-types in pPIR that project to vCA1 and to determine the topographic organization of their axonal arborizations within vCA1. In Aim 2, neurophysiologic studies will determine the coding of olfactory stimuli in vCA1. Extracellular electrophysiology will be used to record vCA1 responses during presentation of olfactory stimuli, and the coding of odorant identity in single neurons and populations of neurons will be evaluated using statistical and computational approaches. This proposed study advances Theme 1 of the NIDCD’s 2023-2027 Strategic Plan to identify and characterize neural circuits involved in normal central olfactory processing. The short-term significance of this research is that it will provide fundamental basic science knowledge of the structure and function underlying healthy olfactory coding in a higher-level limbic brain region. The long-term objective is to enable future studies of central mechanisms underlying olfactory deficits in neurodegenerative diseases known to affect ventral hippocampus. This research training project will be carried out by the applicant in the Padmanabhan Laboratory at the University of Rochester. This environment is optimally suited to providing the applicant training in advanced computational approaches for neuroanatomic and neurophysiologic analyses and professional development in the field of chemosensory research. This training fellowship will prepare her to perform independent research on chemosensation within the field of neurology as a physician-scientist.

NSF Awards · FY 2025 · 2025-08

Quantum technologies promise the creation of environmental sensors which outperform classical devices. However, a quantum advantage in sensitivity is challenging in practice because of the fragility of the quantum states they employ. In this project, the research team will create a table-top sensor that exhibits quantum enhanced sensitivity without the necessity of using fragile quantum states. The platform that makes this possible uses focused laser light to hold a nanoscale sized bead, an arrangement called an optical tweezer. The optical tweezer, by using additional laser beams and electronic signal processing, can be controlled to create states of bead motion which mimic quantum states. These novel states of motion can be used as a sensing and metrology platform which surpasses the standard quantum limit, with estimated sensitivity enhancements of approximately one thousand. The research promises to uncover a new fundamental understanding in nanoscale optical physics and will also create a sensor that could impact a variety of fields across the natural sciences. Some example applications include detecting gravitational waves, searching for non-Newtonian gravity and testing quantum wavefunction collapse models. The project will also expose high school students and undergraduates to the excitement of optical physics, motivating them to consider future education and careers in STEM. In parallel, graduate students will be trained as optical scientists prepared to make an impact on future knowledge and the technology economy. Levitated nanoparticles in ultra-high vacuum optical tweezers provide a novel platform to realize and emulate tabletop quantum phenomena at room temperature. The research program will create a new frontier known as levitated optomechanics that utilizes optically mediated nonlinear dynamics to create macroscopic mechanical states of nanoparticle motion. By the controlled dynamic coupling of two transverse oscillation modes of the levitated oscillator it will be possible to engineer nonlinear dynamics. When the coherent motional coupling occurs at the sum of the two oscillator’s natural oscillation frequencies the optical tweezer dynamics mirror that of a nondegenerate parametric oscillator (NDPO). The synthesis of NDPO-like dynamics presents an opportunity to prepare two-mode squeezed states. Building on these novel levitated optomechanical states, NDPO and beamsplitter interactions will be combined to create a nonlinear phonon interferometer that possess Heisenberg-limited measurement sensitivities in the oscillator’s average phonon number. The proposed research will create new fundamental knowledge in nanoscale nonlinear quantum phononics, and have technological impact in small-size, lightweight and low-power sensors that exhibit a quantum advantage in sensitivity. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-08

In this project the source of methane from the North American Great lakes to the atmosphere will be estimated. Three ship excursions into all five lakes are planned. Methane levels and physical and biological properties will be measured in the surface water. These data will be combined with earlier measurements to capture water-to-air methane transfer from the whole Great Lakes system. Machine Learning will be used to predict methane fluxes from physical and biological properties, many of which are observable from space using satellites. The amount of methane leaking into Lake Erie from natural seeps and gas and oil wells will also be estimated from its radiocarbon content. The proposed work will combine new and existing datasets to estimate diffusive methane emissions from the North American Great Lakes – the largest liquid freshwater system on Earth. This will provide a critical test for models that are used to estimate global freshwater methane emissions, which may significantly overestimate emissions from large lakes. This project will make high-resolution measurements of dissolved methane in surface waters of all five Great Lakes on three proposed research cruises using a novel underway system. The new measurements will be merged with existing data collected using a similar system on previous cruises, yielding a combined methane dataset that captures the seasonal cycle and potential flux hotspots associated with river discharge, natural seeps, and gas wells. Machine learning models will be trained with this data to map methane disequilibrium between the lake surface and air, allowing the lake-atmosphere methane flux to be calculated at high resolution. Researchers will also conduct incubation experiments and stable isotope analyses to construct mixed layer methane budgets for each Great Lake and employ radiocarbon fingerprinting to trace the contribution of fossil methane through the Lake Erie water column. These analyses will allow researchers to distinguish the roles of in situ aerobic methanogenesis, leakage from oil and gas wells, and other external methane sources in driving methane emissions from the Great Lakes. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract: Inheritance and Reprogramming of Maternal Chromatin during Zebrafish Maternal Zygotic Transition Zygotic genome activation (ZGA) is a pivotal event during the maternal-to-zygotic transition (MZT), the developmental period shortly after fertilization when gametic genomes undergo reprogramming. Epigenetic reprogramming of the parental genomes is essential to prepare the zygotic genome for transcription activation. Additionally, the localization of transcription machinery such as transcription factors and RNA Polymerase II to zygotic genes plays a crucial role in their precise transcriptional activation. However, it has remained unknown how maternally provided transcription repressors function to prevent precocious zygotic transcription activation prior to ZGA. Using the genomic and molecular approaches, we have discovered certain loci may function as transcription repressors potentially via sequestering transcription machinery including transcription factors and RNA Polymerase II from developmental genes. During the lead-up to ZGA, the chromatin accessibility at these loci is drastically decreased and this decrease coincides with increased accessibility and subsequent nascent transcription at developmental genes. I also found that the decrease in accessibility of these loci is associated with heterochromatin establishment at these loci. I hypothesize that specific loci function as a sink and sequester transcription machinery including RNA Polymerase II to silence zygotic gene transcription until the epigenetic repression of these loci leads to the release of RNA Polymerase II to drive nascent transcription at zygotic genes. Using a combination of genomic, molecular, and imaging approaches, I will use mutants that inherit these loci with accessibility lower than that in wildtype and mutants that fail to silence these loci at ZGA to investigate their functions in the regulation of ZGA timing. These studies would demonstrate transcription machinery sequestration as a novel mechanism of ZGA regulation.

NIH Research Projects · FY 2025 · 2025-08

This project will utilize an in vitro model of the human blood-brain barrier (hBBB) to study how systemic inflammation following surgery can lead to neuroinflammation and delirium, particularly in cases where patients have BBB damage from a neurodegenerative disease such as Alzheimer's Disease (AD). Post-operative delirium (POD) is a common complication in older adults and can lead to permanent cognitive impairment. As patients with pre-existing dementia are particularly vulnerable to brain injury from delirium, delirium superimposed on dementia or DSD is given special consideration in this project. Currently there is a lack of treatments for DSD because the mechanism is unknown. To help ourselves and others study the mechanism of DSD, we will adapt and advance an in vitro “tissue-on-a-chip” system called the µSiM-hBBB which uses cells derived from human induced pluripotent stem cells to create patient-specific models of the blood-brain barrier (BBB). We have previously demonstrated that this system can mimic the barrier function of the human BBB including its response to acute inflammation. The central hypothesis of this project is that pericyte support is key to the maintenance of a healthy BBB and that loss of pericytes, a characteristic seen in neurodegenerative diseases, increases neuroinflammation in response to systemic inflammation. The first Aim will apply the µSiM-hBBB with novel engineered membranes to identify the mechanism by which pericytes loss leads to weaking of barrier properties in DSD. The second aim will be to use cells from a syngenic iPSC lines that are ApoE3 homozygous or ApoE4 homozygous to study the role of ApoE isoform in creating a ‘diseased’ BBB and whether ApoE3 pericytes can restore barrier function. The final aim will advance the µSiM-hBBB to include an additional compartment with microglia, the resident immune cells of the brain. The activation of microglia will serve as a direct measure of neuroinflammation in the model. Successful completion of the project will clarify how pericytes provide support to the BBB and how their absence may underlie vulnerabilities to brain injury following systemic inflammation. By advancing our tri-culture, patient-specific platform to include ‘disease’ models, we will create a valuable new tool for the field to study the mechanisms of neuroinflammation following surgery, and a platform to discovery new therapies to prevent brain injury in the most vulnerable populations. This work will be completed at the University of Rochester, a tier 1 private research university which facilitates high-level research in a highly collaborative environment. The project will be supported by a team of collaborators and advisors who are experts in various aspects of the proposed project. The PI of the project will take additional courses for training and work with her sponsor and mentors for career development. The training plan will prepare for a career as an independent researcher, including attending conferences, publications, international and industry collaborations, and leading a journal club.

NIH Research Projects · FY 2025 · 2025-08

The University of Rochester Clinical and Translational Science Institute (CTSI) Research Career Development Program is committed to preparing translational scientists and forming these individuals as “T-shaped” professionals who possess deep disciplinary expertise and the ability to communicate across disciplines.  Our approach is aligned with the CTSI’s emphasis on creating innovative approaches that advance translational science and improve population health. We will support four K12 Scholars (2 each year) with appointments of two years duration. The objectives of our K12 program are to: 1) Recruit outstanding Scholars and provide each with a foundational curriculum in translational science and scholar-centric training that incorporates the essential characteristics of a translational scientist; 2) Enhance Scholars’ training experience, and facilitate networking through collaboration with other CTSA hubs and UR training programs; 3) Leverage the CTSI’s priorities and robust resources in three areas of specializations – Clinical Trials, Dissemination and Implementation, and Digital Health/Emerging Artificial Intelligence in Translational Science; and 4) Continuously evaluate and identify areas for quality improvement in response to evolving needs.  We have an outstanding roster of Program Faculty that includes 70 dedicated and established Mentors from three University of Rochester Schools (Medicine & Dentistry, Nursing, and Arts, Science, and Engineering) to provide rich and multidisciplinary expertise. Training and career development will occur in a structured environment that comprises core programmatic and customizable elements, with a carefully selected mentorship committee with complementary research expertise, guided by each Scholar’s background and career goals in order to promote a successful transition to becoming an independent translational investigator. Recruitment and selection plans include an emphasis on finding outstanding candidates. We will seek continued feedback about our Program from the External Advisory Committee and Research Education Committee, CTSI Directors and the CTSI Branch Leadership Team. Working in harmony with the CTSI’s Impact and Continuous Quality Improvement team, we will use a highly comprehensive set of metrics to continuously measure the effectiveness of our program and be rapidly responsive to needed improvement. This program will train the next generation of independently funded leaders who will transform the translational research landscape and accelerate discoveries.

NIH Research Projects · FY 2025 · 2025-08

The University of Rochester Clinical and Translational Science Institute (CTSI) is the clinical and translational research engine of the University of Rochester Medical Center. Over the last 19 years, the CTSI has catalyzed translational research across the university, building a robust clinical and translational science ecosystem. Our mission is to accelerate the translation of discoveries to clinical therapies and population health, with impactful and measurable outcomes at local and national levels. We pursue that mission through innovative translational science, leveraging our deep expertise in informatics, community engagement, workforce development, clinical trials, population health research, ethics, and our extensive national engagement. The CTSI framework for translational science is embodied in our overarching theme of “Research Without Walls”. We work closely with our external partners and collaborators to move beyond the physical and virtual confines of institutions and translational barriers, to accelerate discovery. During this next project period, we will organize around two major themes: 1) Translational Science (TS), removing translational barriers by using cutting-edge informatics, innovative translational artificial intelligence/machine learning (AI/ML) solutions, and accelerating clinical trials, and 2) using TS to improve health for all through community-engaged research, shared values and priorities, and decreasing barriers to access and implementation in translational research. These efforts will speed the translation of novel therapeutics, AI/ML tools, and discoveries to improve health for all people. Our specific aims address specific translational barriers and support Research Without Walls: (1) Advance translational science (TS) by catalyzing the development, dissemination, and implementation of innovative and impactful research. The UR CTSI will grow our comprehensive program in TS as a rigorous and independent discipline, focusing on measurable impact. (2) Accelerate Translational Research for all stakeholders, and improve health for all populations, by working with our collaborators, our learning healthcare system, community, and stakeholders. Building on our extensive community engagement programs, we will expand community-driven research with a focus on improving health for all. (3) Advance innovative informatics and analytics to improve the speed, rigor, and reproducibility of clinical and translational research. (4) Equip a talented translational science workforce with tools to speed the translation of discoveries to clinical application with innovative TS training across the TR workforce; and (5) Collaborate across the CTSA Consortium to rapidly respond to evolving national research and public health priorities and emergencies. Our CTSI has tight integration of population health research, basic and clinical research data and analytics, training programs for a skilled translational research workforce, implementation science programs, community engagement and collaboration, and regulatory science methods for the digital era, supporting our ability to improve health for all.

NIH Research Projects · FY 2025 · 2025-08

PROJECT ABSTRACT Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder that results in neuronal cell death. AD pathology involves protein aggregation, with tau protein being a primary driver of the disease. However, the mechanisms that initiate aggregation and pathological tau accumulation remains unclear. Neurons are energetically demanding cells. Mitochondria are central in maintaining their ATP levels and AD models have decreased ATP production. Thus, mitochondrial dysfunction is a hallmark of AD. Damaged and dysfunctional mitochondria lead to decreased energy and elevated reactive oxygen species (ROS) production, which can severely impact neuronal health. Interestingly, mitochondrial dysfunction has been linked to promoting and even preceding tau pathology in AD. Tauopathy mouse models, such as the P301S tau mice, present with mitochondria dysfunction and increased ROS prior to pathological tau accumulation. Additionally, mice lacking superoxide dismutase (SOD), an essential antioxidant enzyme, had increased pathological tau that was alleviated by treatment with exogenous antioxidants. These studies, and others, suggest there is a direct relationship between tau pathology and mitochondria. However, mitochondrial function and ROS production are difficult to isolate experimentally, so it is unclear what the effect of each is on tau pathology. Therefore, in this proposal, we will be utilizing approaches that have spatial and temporal control to target mitochondrial function and ROS production and determine the effect on tau pathology. In Aim 1, we will use chemo- and optogenetics to examine the role of ROS production in initiating tau pathology. With our approaches, ROS will be localized to specific cellular compartments and generated at different levels. The ability to control the amount and type of ROS will allow us to categorize ROS into two types: signaling and damaging. We will assess the effect on tau pathology, with preliminary data suggesting ROS signaling increases the levels of pathological tau. In Aim 2, we will target a light-activated proton pump to the mitochondria P301S tau neurons. The goal of this aim is to recover the mitochondrial function with the activation of the proton pump, as P301S tau mice have been demonstrated to have reduced energy production early on in their development. Thus, improving the mitochondrial function may alleviate the accumulation of pathological tau species in the P301S tau neurons. For both of the aims, we will use both in vitro primary neurons and ex vivo organotypic brain slices from mice. The experiments that I have proposed are readily achievable and will advance the field in identifying mechanisms involved in tau pathology and, ultimately, AD progression.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract Parkinsonism is a progressive neurodegenerative disorder that is characterized by loss of dopaminergic neurons. Various environmental factors like exposure to Mn has been implicated in PD etiology. Although we have known that Mn exposure can induce neuronal death and TH neuron toxicity for decades, the functional relevance of overexposure of Mn is still not clearly understood. Mn has also been recently shown to act interact with various PD related genes, like α-synuclein and LRRK2 suggesting a complex gene-environment interactions. Further, various studies in rodent models of Mn toxicity have shown that Mn leads to molecular changes in the brain in a time-dependent manner. However, studying these molecular changes in a cell-specific manner at the protein level has been difficult due to the lack of a model system. Although single-cell RNA sequencing technology has provided some insight, understanding the proteome of the dopaminergic neurons at various stages of Manganese toxicity will provide key insight into early and late changes associated with these neurons. We propose to use the Cell type specific In vivo Biotinylation of Proteins (CIBOP) approach to study the proteome of TH neurons in vivo. The overarching hypothesis is using the CIBOP approach, we will successfully identify the proteomic signatures of TH neurons at different stages of Mn-induced neurotoxicity. Further, this model system will identify potential drug targets that can modify Mn-induced neurodegeneration and will also provide a tool for the field that can be used to study other cell types as well as the peripheral nervous system. In Aim 1, we will generate the TurboID/TH mice and will confirm the biotinylation of TH neurons in not only different regions of the central nervous system but also the peripheral nervous system. Further, we will expose these mice to Mn and perform proteomics to identify TH-specific changes in the molecular signatures at different stages of Mn toxicity. We will perform various bioinformatic analyses, including pathway analysis and MAGMA analysis, to further identify specific pathways altered in the TH neurons. Aim 2 will involve mechanistic validation of the top hits from our proteomic studies in our Drosophila model of Mn exposure that we developed. This model recapitulates various motor and non-motor symptoms of PD. We will use a variety of scalable tools like behavioral assays, HPLC, and seahorse as endpoint assays in flies. Further, to add human relevance, we will also use patient-derived iPS cells to validate our findings in Drosophila. Having a complementary team at Yale and the University of Rochester will help us complete this ambitious, exploratory proposal. While Dr. Rangaraju's group at Yale is an expert in CIBOP and mouse generation, we have expertise in flies, iPSC, and mechanistic studies in the field of Manganese neurotoxicity.

NIH Research Projects · FY 2025 · 2025-08

Project Summary In addition to the ethical considerations of using animals for biomedical research, the high costs, low throughput, and limited translation of mice motivates their reduction and replacement with human tissue-on-chip (hTOC) for disease modeling, drug development, and discovery. One frontier in hTOC development is the modeling of aging as a confounding factor in disease. Our focus is on the blood-brain barrier (BBB), which is known to become less robust at regulating the passage of cells and molecules from blood as people age. Age- related changes in the BBB include cellular and transport changes that make the brain more vulnerable to injurious circulating factors and neurodegeneration. This includes impairment of lipoprotein receptor related protein-1(LRP-1), which leads to amyloid beta (Ab) accumulation in the brain, a hallmark of Alzheimer’s disease (AD). In addition, the presence of the Apoe4 allele, a risk factor for AD, accelerates most of the aging related changes in the BBB. Traditional animal models of AD and the BBB lack human relevance. Importantly, the mouse does not naturally develop human neurodegenerative diseases, including AD, and must be genetically engineered to approximate the condition. In animals that do naturally develop AD or cognitive decline such as non-human- primates or canines, the age-of-onset is too long for practical progress. For these reasons we will combine induced-pluripotent stem cell (iPSC) and microphysiolocial systems technologies with small molecule ‘aging’ cocktails to develop the first hTOC aged model of the blood brain barrier: the µSiM-aBBB (microphysiological system enabled by a silicon membrane-aged BBB). We will model geriatric vulnerabilities to genetic predisposition of the Apoe4 allele in the BBB by mirroring the cellular changes that occur during aging having shown preliminary induction of senescence, shifts in protein expression and increases in barrier permeability in our aged model. Thus, I hypothesize that consistent with the onset of AD occurring in older patients homozygous for Apoe4, aged cellular phenotypes combined with the Apoe4 mutation produce a BBB that is intrinsically compromised compared to Apoe4 or aging alone. To test this hypothesis, I will pursue two aims. Aim 1 will establish and characterize our model, the µSiM-aBBB using colorimetric assays, immunohistochemistry, permeability assays and ELISAs. Aim 2 will determine how the presence of the genetic risk factor, Apoe4, combined with aging affects barrier integrity and function in the BBB using RNA sequencing as well as the methods mentioned in aim 1. The proposed experiments will create a novel tool that can be used to determine ways to prevent barrier dysfunction under compromised conditions. This project will demonstrate the value of hTOC models to emulate human health and disease and expand our knowledge on the combined effect of genetics and aging on the human BBB.

NIH Research Projects · FY 2026 · 2025-08

Trained immunity is a biologic process in which prior immune stimuli durably ‘trains’ innate immune cell responses to future stimulation. Trained immunity is driven by changes in glycolysis and its metabolites, leading to histone modifications, DNA methylation, or changes in non-coding RNA (ncRNA) that immune programs subsequent monocyte/macrophage responses to either be greater or lessened. Trained immunity research has largely focused on how pathogen derived molecules immune train monocytes and macrophages (mono/macs), but there are also indications of cell based trained immunity. We recently made the novel discovery that resting platelet interactions with mono/macs via platelet CD47 increased glycolysis and durably programmed mono/macs through changes in histone methylation to limit TLR responses. This was the first demonstration of endogenous cell mediated innate immune training. We now propose the novel idea that in healthy conditions, resting platelet-monocyte interactions limits monocyte TLR responses, that are overcome by platelet activation. Because platelets are small, they circulate at the interface between endothelial cells and leukocytes, ideally positioning platelets as sensors of both vascular health and tissue injury/infection. How activated platelets induce and amplify immune responses has received an increasing amount of attention, including significant work from our group. However, studies have also shown that normal platelet counts maintain immune homeostasis and our recent manuscript provides a mechanistic framework for how resting platelets immune train monocytes to a tolerant phenotype. We found that circulating monocytes from thrombocytopenic (low platelet count) mice produced more inflammatory cytokines in response to TLR ligands. Resting platelets express CD47 that interacts with circulating monocytes to induce glycolysis dependent changes in histone methylation, epigenetically modifying mono/macs to a more immune tolerant phenotype. Thrombocytopenia (clinically defined as a platelet count less than 150,000/µL) independently associates with dysregulated monocyte responses, increased plasma cytokines, prolonged morbidity, and increased mortality. A decline in platelets may also independently lead to long-term changes in mono/mac responses, for example, some COVID-19 patients have persistent/recurrent thrombocytopenia beyond the infection, and with it, prolonged inflammation. However, little is known about the mechanisms and the long-term implications of thrombocytopenia on immune responses. Hypothesis: Resting platelet-monocyte interactions immune trains monocytes to a quiescent phenotype. Aim #1. To determine the platelet-mediated signaling that leads to monocyte immune programming. Aim #2. To determine the functional outcomes of resting platelet-mediated monocyte immune programming. Aim #3. To determine the functional consequence of a loss of platelet-monocyte interactions in disease contexts.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY The mucopolysaccharidosis (MPS) disorders are a set of heterogeneous progressive, life-limiting disorders with variable multi-system complications, including highly diverse effects on the central nervous system (CNS), ranging from rapid neurocognitive decline, often with intense behavioral dysregulation, to mild memory issues. While there has been an explosion in therapy development for MPSes, the ability to measure a convincing response to therapy is complicated by the variable clinical courses across, and within, phenotypes. Incredibly divergent clinical trial approaches internationally had hindered data comparison and raised questions as to whether methodologies were accurately measuring cognitive and adaptive endpoints. In response, two prior international MPS consensus conferences developed guidance for MPS trial design and implementation, particularly for therapies targeting CNS effects. Given rapid advances in the past four years in knowledge about treatments, disease pathology, and the patient/family experience of MPS disorders, it is critical to update the guidance to keep pace with this surging field. The main objective of the Third Consensus Meeting on Neurocognitive and Functional Endpoints in MPS Clinical Studies is to launch a Delphi consensus process to modernize guidance for MPS clinical studies targeting both the CNS and multi-functional impacts of the disorders. The specific aims are to: 1) Update recommendations for endpoint measurement of CNS impacts of MPS across the globe; 2) Improve representation of the diverse needs of MPS disorders, broadening the set of endpoints to be meaningful for how patients/families feel and function; 3) Mentor trainees/early stage investigators (ESIs) on (i) identifying issues in neurocognitive and other functional endpoints and clinical trial execution, (ii) writing literature review talks for the conference, and (iii) composing a manuscript for peer review. A 2-day, in person meeting with a diverse MPS expert panel (researchers, clinicians, advocates) and mentored participation by trainees/ESIs will develop statements for a virtual Delphi process. The proposal's significance is its emphasis on diversity and global representation of a broader set of functional endpoints for MPS clinical studies. Major outcomes of this conference will be to develop modern recommendations for selection and implementation of endpoints that are clinically meaningful to patients/families across the globe, and to enhance career development for trainees/ESIs. This proposal's health relatedness is its potential to guide investigators and industry in trial designs that reliably evaluate CNS response to therapy. The ultimate goal is to accelerate the success of clinical programs for new therapies, and inclusive treatment targets, to improve the lived experience of people touched by MPS.