Washington University

NIH Research Projects · FY 2025 · 2025-02

PROJECT SUMMARY/ABSTRACT Renal osteodystrophy (ROD) is a complex disorder of cortical bone quality and strength. Impaired cortical bone is due to the combined actions of elevated parathyroid hormone (PTH) levels and changes in bone hormones as a result of kidney failure. ROD affects nearly all patients with chronic kidney disease (CKD) and results in cortical bone loss, cortical-type fractures and cardiovascular events. The current goal of ROD treatment, to re- duce high bone turnover due to renal hyperparathyroidism, is contraindicated in the presence of low turnover yet reliable ways to determine low turnover status are lacking. The Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend that treatment is guided by the biomarkers PTH and bone specific alkaline phosphatase (BSAP) and not to treat when turnover is low. However, despite these recommendations, cortical- type fracture incidence has doubled in dialysis patients over the past 25-years, a failure in fracture reduction due in part to PTH and BSAP being developed to identify turnover in trabecular rather than cortical bone. Further- more, although KDIGO recommends tetracycline-labeled bone biopsy to define turnover and guide treatment, the histomorphometry is also based on analysis of trabecular and not cortical bone, the latter being the primary site of PTH action. Our published preliminary data suggest that trabecular turnover is a poor surrogate for cortical turnover, with only moderate correlations between bone compartments (R2 59%). Thus, there is an unmet need to identify biomarkers with high diagnostic accuracy and clinical utility for the identification of low cortical turnover, used without or without trabecular turnover, to guide treatment decisions and for use in clinical trials. In our published data, we hypothesized that an a priori defined subset of microRNAs (miRNA) that regulate osteoblast (miRNA-30c, 30b, 125b) and osteoclast (miRNA-155) development would be accurate biomarkers of low cortical turnover. In 23 CKD patients with bone biopsies, the areas under the curve for discrimination of low from non- low turnover were 0.866, 0.813, 0.813, and 0.723 for miRNAs-30b, 30c, 125b and 155 respectively, 0.925 for a panel of the 4 four miRNAs combined, while PTH and BSAP, individually and together, did not discriminate in this population. Based on these findings, our central hypothesis is that circulating miRNAs discriminate ROD cortical bone subtype. In a cohort of 90 CKD patients with low, normal, and high turnover (30/group; Aim 1) we will use miRNAseq to identify novel miRNAs that correlate with ROD type and determine if their combination with the preliminary panel enhances discrimination. In 40 ROD patients managed with strategies that change turnover from high to low or low to high (n=20/group; Aim 2), we will determine if changes in histology-based turnover are reflected by changes in the optimized panel and if the circulating miRNA panel mirrors bone-tissue miRNA ex- pression. Then, we will determine if the panel is related to bone quality and strength (Aim 3). Our results will determine if the circulating panel can serve as a biomarker for guiding ROD management. This high impact proposal has the potential to result in a paradigm shift in the non-invasive diagnosis and management of ROD.

NIH Research Projects · FY 2026 · 2025-02

Project Summary/Abstract Bone is the most common organ site of metastasis in breast cancer (BC), with occurrence rates of 70% in ER+, 46% in TNBC, and 50% in HER2-enriched cases. In bone metastases, breast tumor cells secrete factors to enhance osteoclast (OC) mediated bone destruction which can result in severe bone pain, fractures, and spinal cord compression. Immune therapy provides long-lasting remissions and even cures many cancers; however, it is significantly less effective in breast cancer (BC)- only 5-6% of metastatic breast cancer patients are eligible for immune checkpoint blockade (ICB). It is recognized that the presence of bone metastases confers resistance to ICB. Previous studies show BC can have high levels of infiltrating myeloid cells, which promote immune suppression and resistance to ICB. However, we recently uncovered a novel mechanism that requires acid and cytokine production with GM-CSF through which breast cancers induce the evolution of myeloid cells to a pro- tumor immune suppressive phenotype. We found a vicious cycle driven by acid and cytokines that fuels cross talk between myeloid cells and tumor cells to promote immune suppression. We showed that blockade of tumoral GM-CSF genetically and pharmacologically restored ICB efficacy in ER+ and TNBC preclinical bone metastases. However, GM-CSF is important for dendritic cell biology and is not an ideal therapeutic target. This led us to investigate targeting of acid and acid signaling to disrupt tumor evolution towards immune therapy resistance. It is established that the bone marrow environment is significantly more acidic than other organ tissues and that BC in this setting secretes factors that modulate myeloid cell heterogeneity towards osteoclasts, which contribute to bone pain and bone destruction. While neutralizing acid in the TME has been tried, the results are limited in part by compensatory increases in tumor acid production. We identified that acid signals in both myeloid cells and in tumor cells through cAMP via the heterotrimeric G protein subunit G-alpha S (GNAS). Our preliminary data showed that disruption of GNAS in either tumor cells or myeloid cells decreased levels of acid-induced cytokines and the progression of bone metastasis and the evolution to an immune suppressive phenotype. Collectively, our data provides a strong rationale to pursue the hypothesis that disruption of acid-induced GNAS- dependent signaling will lead to molecular and phenotypic diversity across the tumor and myeloid cells throughout the bone organ resulting in sensitivity to immune therapy, decreased bone tumor burden and progression to bone destruction. We will use genetic and pharmacologic approaches to delineate the mechanisms of acid-induced GNAS signaling during tumor progression in bone. We will integrate our single cell RNA-Seq (scRNA-Seq) analyses of genetically modified myeloid and tumor cells, with myeloid and tumor cells from breast cancer patients bone metastases to understand the molecular diversity that leads to metastasis. Given our track record of translating preclinical mechanistic studies into clinical trials, this proposal could have significant translational impact by developing a novel approach to inhibit metastasis and recurrence.

NSF Awards · FY 2025 · 2025-02

Quantum computers leverage quantum phenomena such as superposition and entanglement in quantum bits (qubits), enabling them to solve certain computational problems exponentially faster than classical computers. The successful realization of quantum computers has the potential to transform diverse fields such as drug discovery, quantum chemistry, biology, cryptography, image processing, optimization, and machine learning by addressing computational challenges that are infeasible for classical systems. Estimates suggest that general-purpose quantum computers capable of solving real-world problems will require 10⁴–10⁵ physical qubits. A significant obstacle to scaling quantum computers to this level is the hardware infrastructure, which currently relies on room-temperature rack electronics for qubit control and readout, along with bulky, connectorized microwave components—such as circulators and amplifiers—inside dilution refrigerators. This project aims to address these limitations by developing energy-efficient, low-cost, and compact cryogenic chips that enable scaling quantum systems to support thousands of qubits. The research focuses on advancing cryogenic Complementary Metal-Oxide-Semiconductor (CMOS) integrated circuits (ICs) for qubit control pulse generation and superconducting chip technology for on-chip circulators. These innovations are expected to accelerate breakthroughs in quantum computing while also benefiting related fields such as satellite communication, space-based telescopes, and cryogenic electronics. Furthermore, the project seeks to foster seamless integration between circuit design and quantum physics, laying the foundation for a diverse and skilled workforce in this multidisciplinary research domain. To achieve this, the project will implement a range of educational and outreach initiatives, including online courses, undergraduate research opportunities, career development workshops for K-12 students, and the creation of open-source infrastructure. The research activities are organized into three thrusts: cryogenic (4K) CMOS IC development, superconducting chip development, and system integration with superconducting qubits operating at 10-100mK. First, a fully analog, low-power, and scalable qubit control scheme will be demonstrated using CMOS ICs operating at 4K, eliminating the need for room-temperature rack electronics. Unlike current digital-intensive control schemes, this project explores low-power microwave pulse generation using analog filter synthesis, enabling significant power savings compared to state-of-the-art digital qubit control circuits. Analog multiplexing schemes will be explored to reduce the cabling overheard between the 4K to 10mK stages. Second, time-modulated Josephson Junction-based non-reciprocal devices will be developed to replace the bulky and costly ferrite-based circulators and isolators currently used in dilution refrigerators. These on-chip, superconducting circulators are expected to offer drastically reduced size and cost when compared to their ferrite counterparts. To aid easier integration with the qubits, these superconducting circulators will be designed to achieve to low intermodulation power while achieving low-loss transmission and high isolation at the input frequency. Finally, the cryogenic-CMOS ICs and superconducting circulators will be integrated with superconducting qubits to demonstrate a fully integrated closed-loop system for qubit control and readout. 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 · 2025-02

Examining system-wide implementation of new flexibilities to the National School Lunch and Breakfast Programs PROJECT SUMMARY BACKGROUND: Cardiovascular diseases (CVD) are the leading cause of death in the US and the underlying pathophysiological processes are evident in adolescence. Risk factors for CVD include obesity and prevention of obesity during adolescence can minimize adult CVD. Unfortunately, the prevalence of youth obesity in the US has nearly doubled in the past 20 years. Disparities in nutrition and healthy food access in schools and within certain communities contribute to higher prevalence of obesity among Hispanic, black, and low-income youth. The National School Lunch and Breakfast Programs (NSLP/SBP) are a complex system involving food suppliers, school food service directors, and student consumers. In 2018, a significant policy change to the NSLP/SBP allowed schools to decide if they wanted to implement relaxed school nutrition standards for milk, whole grains, and sodium. Such policy changes can lead to inefficient and inequitable implementation, ultimately affecting youth food consumption and health-related outcomes. GOAL: This proposal seeks to describe the impact of NSLP/SBP policy changes and flexibilities on the many levels involved in implementing these programs and to identify leverage points for which effectiveness and equity of implementation might be meaningfully and sustainably improved. AIMS AND METHODS: This is a three-phase study that takes a comprehensive approach, leading to the elucidation of more effective and equitable school food policy development and implementation. Phase 1 will assess current flexibility implementation practices and determinants of decision-making process. For this phase, we will engage School Nutrition Association (SNA) members: a nationally representative sample of over 4,000 school districts. Data collected will be merged with state level school data to understand how decisions relate to participation and health-related outcomes. Phase 2 involves interviewing food industry actors to understand how NSLP/SBP policy changes result in decisions to change food supply and distribution. Phase 3 seeks to develop an agent-based model (ABM). We will use this ABM as a “virtual policy laboratory,” analyzing ways to improve effective and equitable district-level implementation of the NSLP/SBP in silico and providing tools to inform real-world policymaking. All study phases will rely on close collaboration with key practice partners. INNOVATIONS AND IMPACT: This study is innovative and impactful because it will be the first to: (1) use the combination of an implementation science framework- the Consolidated Framework of Implementation and the Racial Equity and Policy Framework to assess and document implementation of flexibilities among school districts nationwide; (2) examine how decisions to implement flexibilities to NSLP/SBP result in inequitable food provision to youth; and (3) inform USDA rule- making and final rules in real time. These findings will contribute toward addressing school nutrition-related health inequities including those associated with enhanced risk of cardiovascular disease into adulthood.

NIH Research Projects · FY 2022 · 2025-02

PROJECT SUMMARY Children and adolescents with glomerular disease have unique and potentially modifiable risk factors for compromised bone health, but our current understanding of skeletal fragility in glomerular disease is lacking. In the first large population-based cohort study, we recently found that primary glomerular disease was independently associated with a >45% increased risk of incident spine and hip fracture, and that hip fracture risk was >1.5-fold greater in patients younger vs. older than 40 years of age. Mechanisms that drive increased fracture risk in glomerular disease are not clear but likely multifactorial. Our prior work in the Neptune cohort demonstrated that glomerular disease is associated with disturbances in vitamin D and mineral metabolism, and patients with glomerular disease are also exposed to medications which may negatively impact bone health. Identifying modifiable factors that compromise bone strength will facilitate the development of strategies to reduce fractures and other skeletal complications across the lifecourse. The primary objectives of this study are to: (1) determine the impact of glomerular disease on bone strength and (2) investigate the pathophysiologic underpinnings of impaired bone strength in glomerular disease. The proposed multi-center study will leverage the infrastructure of the NIH-funded CureGN prospective cohort study and the resources of two health systems [Children’s Hospital of Philadelphia (CHOP)/University of Pennsylvania (Penn) and Columbia University Medical Center] with expertise in state-of-the-art high-resolution bone imaging and biopsy methods, to conduct the first prospective, longitudinal study to assess determinants of impaired bone quality and strength in glomerular disease. 100 CureGN participants (60 adults/40 children) will be evaluated at baseline and 12 months and compared to age-, sex-, race-, and body mass index-matched healthy HR-pQCT adult and child reference populations. The new 2nd generation high-resolution peripheral quantitative computed tomography (HR-pQCT) device will be used to assess bone microarchitecture and generate micro-finite element analysis (µFEA) estimates of bone strength. We will also determine the DXA measures of areal BMD and bone mineral content (whole body, spine, hip and radius) that reflect bone deficits captured by HR-pQCT. Tetracycline double labeled transiliac crest bone biopsy specimens will be collected from a subset of 20 adult CureGN participants and analyzed by 2D histomorphometry; by microCT for 3D cortical and trabecular microarchitecture and estimated strength by finite element analysis; and by Nanoindentation/Raman spectroscopy for bone mechanical and matrix-level characterization. Concurrent clinical and biochemical profiling will allow for assessment of predictors of prospective changes in biomechanical competence and cortical and trabecular microarchitecture by HR-pQCT as well as tissue-level bone matrix and mechanical properties. The results of this study will serve specifically to inform future multicenter clinical trials of interventions to mitigate the effects of glomerular disease on bone health and fracture risk in children and adults with glomerular disease.

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY Malaria is the deadliest vector born disease, responsible for 249 million cases and 608,000 deaths in 2022. Malaria parasites replicate asexually in red blood cells where they digest up to 80% of host hemoglobin into globin peptides and heme. Heme is an essential cofactor, but is redox active in its free form. Parasites detoxify the majority of hemoglobin-derived heme by sequestering into inert hemozoin. Heme biosynthesis is inactive in blood stages, suggesting that blood stage parasites scavenge a portion of hemoglobin-derived heme for heme-requiring processes. As blood stage parasites mature, hemoglobin digestion increases, yet cytosolic heme concentrations remain constant at approximately 1.6 µM. How do parasites maintain cytosolic heme concentrations? To test the hypothesis that Plasmodium utilizes heme binding proteins to maintain heme homeostasis and that these heme-binding proteins will be essential for parasite viability, two orthogonal approaches will be taken: one unbiased approach and one directed approach. For the unbiased approach, parasite heme-binding proteins will be identified using a cutting-edge click-chemistry based method. Tagged conditional knockdown parasites will be generated to determine essentiality, expression, and localization of candidate proteins. To assess the involvement of candidate proteins in parasite heme handling, dose response assays will be used to assess the susceptibility of knockdown parasites to antimalarials that are known to disrupt heme homeostasis. In addition, heme species will be quantified under wild type and knockdown conditions using a pyridine-based heme fractionation assay and a genetically encoded heme biosensor. For the direct approach, the role of Heme Detoxification Protein (PfHDP; PF3D7_1446800) in heme homeostasis will be investigated. Recombinant PfHDP can bind heme and promote hemozoin formation in vitro. While PfHDP knockdown parasites have a severe growth defect, these parasites display no discernable defect in hemozoin formation. To investigate the hypothesis that PfHDP is involved in parasite heme handling independent of hemozoin formation, it will first be determined if PfHDP binds heme within the parasite basally or when heme homeostasis is disrupted. Next, sensitivity of PfHDP knockdown parasites will be assessed to quinoline antimalarials that are known to increase cytosolic heme concentrations. Finally, levels of cytosolic heme, hemozoin, and hemoglobin will be quantified under wildtype and PfHDP knockdown conditions using the pyridine-based heme fractionation assay and a genetically encoded heme biosensor. Interfering with heme detoxification has proven an effective antimalarial strategy. However, resistance to the traditional hemozoin biosynthesis inhibitors has limited their therapeutic use. Results from the experiments proposed here will provide insight into plasmodial heme homeostasis mechanisms. These results will reveal novel parasite proteins that can be exploited for future drug development and may provide insight into novel heme handling mechanisms in other organisms.

NIH Research Projects · FY 2026 · 2025-01

Title: Regulation of primary and secondary alveologenesis by FGF signaling pathways Summary: Alveologenesis is the final phase of lung development where the surface area of the lung is increased by subdividing alveolar saccules through the formation of secondary septae (septal ridges), followed by thinning of the septal walls to generate an efficient air/blood gas exchange organ. Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth in which alveologenesis is impaired. BPD often results in chronic respiratory disease. However, besides Vitamin A and supportive care, no therapies exist to promote lung alveolar and vascular development to improve the outcomes of infants with BPD. Alveologenesis occurs in several stages in mice and humans. The initial expansion of alveolar surface area occurs in the absence of alveolar myofibroblasts (MyoFB) in the saccular stage. In the classical or first stage of alveologenesis, MyoFB and other mesenchymal and epithelial cells regulate the formation of secondary septae. During the second stage of alveologenesis, some additional alveoli are formed and, importantly, the septal walls thin through loss of mesenchymal cells and maturation of the microvasculature to a single layer capillary network juxtaposed with AT1 cells. The mature alveolar wall ensures efficient air/blood gas exchange in the adult lung. An in-depth understanding the mechanisms that regulate alveolar septation and septal wall maturation will be required to develop therapies for premature infants with BPD and for developing potential therapies for adult lung regeneration. However, there are specific knowledge gaps about the identity and regulation of progenitors that give rise to MyoFB, the functions of MyoFB and other mesenchymal cell types, and the mechanisms that terminate and clear MyoFB from the lung at the completion of secondary septation. Fibroblast Growth Factor 18 (Fgf18) is expressed at high levels in MyoFB and AT1 cells during alveologenesis. In preliminary data, we show that conditional inactivation of Fgf18 in the neonatal lung results in impaired alveologenesis and increased expression of Fgf9 in mature MyoFB. Through lineage tracing of Fgf18- expressing cells, we find that MyoFB are cleared from the lung after the first stage of alveologenesis but that Fgf18-expressing AT1 cells are retained, suggesting that FGF18 could be involved in septal wall maturation. In this proposal, we use a combination of unique genetic tools to target specific cell populations in the neonatal lung, single nucleus RNA sequencing, and cell sorting coupled with single nucleus ATAC sequencing, to identify the cellular mechanisms by which the FGF signaling pathway regulates cellular interactions, cell proliferation, differentiation, and death, during the first and second stages of alveologenesis. Our research goals include the identification of novel transcriptional mechanisms that regulate MyoFB function during primary alveologenesis, and cellular mechanisms by which FGF signaling regulates septal maturation during secondary alveologenesis. This research will impact our understanding of pathogenic mechanisms affecting lung maturation in BPD and mechanisms that could regulate differentiation and expansion of MyoFB in interstitial lung disease.

NIH Research Projects · FY 2026 · 2025-01

ABSTRACT Acute respiratory distress syndrome (ARDS) and Sepsis are frequently encountered in critical care and lead to high morbidity and mortality. Despite decades of large clinical trials, other than antibiotics, no effective pharmacotherapies have been identified. Heterogeneity in both syndromes is increasingly recognized as a principal cause for these negative trials. To address this heterogeneity, we used latent class analysis (LCA) with clinical data and protein biomarkers to identify two distinct molecular phenotypes, called the Hyperinflammatory and Hypoinflammatory phenotypes. Independently, in multiple cohorts of ARDS and sepsis, the phenotypes have different outcomes and responses to therapies, offering a potential route to precision-based trials. Translating the phenotypes into the acute clinical setting has been challenging, as LCA models are incompatible for bedside use due to their complexity and protein biomarkers that discriminate the phenotypes don’t have rapid point-of-care (POC) assays. To address this, we have developed and validated a machine learning model, called the clinical classifier model (CCM), which can assign phenotypes using vital signs and laboratory values only. The primary objective of our proposal is to develop and validate an automated electronic health record (EHR)- embedded CCM system that classifies molecular phenotypes at the bedside, enabling future phenotype-enriched trials. Before such trials can be conducted, we need to broaden our understanding of the phenotypes and validate the CCM comprehensively. First, we will evaluate phenotype transition and the CCM’s performance longitudinally over time by using well validated biomarker-informed models to identify the molecular phenotypes in two previous ARDS trials (ROSE and FACTT) and one observational cohort of sepsis (MARS) at multiple timepoints (Aim 1A). We will then evaluate the performance of the CCM to identify these phenotypes at each timepoint (Aim 1B). Second, to enable bedside phenotype classification, we will develop an EHR-embedded CCM system that will automatically extract its component variables and feed it to the CCM to enable rapid classification of the molecular phenotypes (Aim 2A). We will silently run the EHR-embedded system in patients enrolled in the PRECCISE cohort and validate it prospectively against biologically derived phenotypes at multiple timepoints (Aim 2B). Third, comprehensive knowledge of the distinct epidemiology of phenotypes will enable more efficient future trial design. To do this, after using the CCM to classify molecular phenotypes in 78,000 critically ill patients with ARDS and Sepsis, we will use multistate modelling to map phenotype-specific hospital trajectories and outcomes (Aim 3A). We will also use this cohort to determine optimal trial design factors by conducting phenotype-specific target trials emulation of interventions previously associated with differential responses in the phenotypes (corticosteroids, fluids strategy, and PEEP strategy) (Aim 3B). Completion of our specific aims would be a game changer for precision medicine in critical care, as the EHR-embedded CCM system would harness the clinical potential of the molecular phenotypes, paving the way for phenotype-enriched trials.

NIH Research Projects · FY 2026 · 2025-01

Project summary Posttranslational arginylation on proteins installed by arginyltransferase ATE1 is a critical modification for cardiovascular and heart development. The absence of this modification in ATE1 knockout mice was embryonically lethal with various signs of cardiovascular defects, emphasizing the importance of arginylation in physiological processes. Existing methods have proposed plausible arginylation sites on a handful of proteins, most of which have not been further validated or functionally investigated. Therefore, protein arginylation remains a vastly understudied field. It is still largely unclear how many proteins are arginylation substrates in cardiac tissue/cell proteomes, and what the effects of arginylation are on cardiovascular development? In this proposal, we will first establish a chemical proteomics platform for enriching the arginylation sites to facilitate the discovery of this challenging PTM. We will apply this technology to cardiac cells and clinical heart tissues to comprehensively profile the arginylation sites hidden in cardiovascular networks. In addition, our preliminary data discover that another cardiovascular-related molecule, homoarginine, is a proteinogenic amino acid, we thus will use isotopic homoarginine to unbiasedly discover the occurrence and distribution of the “homoarginylome” and homoarginine-associated metabolites in cardiovascular samples as well. These investigations will provide insights into the biological effects of homoarginine as an amino acid building block and a metabolite. We next focus on the elucidation of protein arginylation function in selected systems. A combination of mass spectrometry, biochemistry, and next-generation sequencing techniques will be used to study the conformational alterations of nucleosome after arginylation of histones to understand how epigenetic mechanisms can be regulated by arginylation during cardiomyoblast differentiation. By controlling the calreticulin arginylation levels, we will also study the impacts of arginylation on cardiac differentiation and development using stem cell and cardiology techniques. To further explore the therapeutic potential of protein arginylation, we aim to establish the arginylation targeting chimera (ArgTAC) technology for targeted PCSK9 arginylation and degradation. Successful degradation of PCSK9 by this arginylation system will potentially provide a novel therapeutic strategy in lowering LDL particles leading to improved cardiovascular conditions. Since protein degradation is the only known mechanism to remove protein arginylation, we will further explore the novel possibility that enzymes exist for de-arginylation of proteins (reversing arginylation). Towards this, we will apply CRISPR whole genome screening to identify putative de-arginylation enzymes before validation using enzymatic assays to characterize their de-arginylation activity. The proposed studies will unveil the prevalence and noncanonical biological roles of this essential PTM, and the novel technologies from this proposal will greatly benefit the research fields of protein arginylation, epigenetics, and cardiovascular disease.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Neural circuits are comprised of a rich network of neurons and associated glia that communicate through chemical signals. These signals are essential for proper development of neural circuits, and removal of these signals often impairs synapse development, circuit wiring, and circuit function. During development, animal experience drives activity-dependent remodeling of neural circuit structure and function during brief windows called critical periods. Critical periods are thought to set the ground state for neural circuit wiring, ensuring proper circuit connectivity and synaptic stability, though this hypothesis remains to be tested. Recent work indicates that astrocyte-derived signals regulate critical period closure across diverse circuits and animal models. In Drosophila, the motor circuit exhibits a critical period of activity-dependent structural remodeling at the embryo/larval transition. Astrocytes first associate with motor dendrites during peak motor plasticity, and ablating astrocytes is sufficient to extend the critical period. Genetic screening revealed that astrocyte-driven critical period closure is dependent on the expression of several cell surface molecules, including Neuroligin 2 (Nlg2) and Dally/GPC5. Astrocyte-specific knockdown of these signaling molecules extended critical period plasticity, whereas astrocyte-specific overexpression drove precocious critical period closure. To understand the mechanisms that establish and maintain neural circuits to drive animal behavior, it is important to examine the long-term consequences of altered critical period timing on circuit structure and function. I hypothesize that altering the timing of critical periods will induce long-term changes in motor circuit structure and function to produce distinct motor behaviors. I will use the complementary binary expression systems, Gal4/UAS or LexA/LexAop, to manipulate the expression of astrocyte-derived nlg2 and dally to extend (Aim 1) or precociously close (Aim 2) the motor critical period while I simultaneously assess motor circuit structure and function. Specifically, I will evaluate long-term changes to circuit connectivity, synaptic stability, motor output, and locomotor behavior by assessing these features at successively later stages spanning circuit development to the mature circuit. The completion of these experiments will provide insights into how altered critical period timing affects circuit development at the synaptic and cellular levels, and will directly link these changes to motor behavior. Thus, my goals meet priority area #4 of the BRAIN Initiative, “Demonstrating causality: Link brain activity to behavior with precise interventional tools that change neural circuit dynamics.” The role of astrocytes in closing critical periods has only recently been uncovered. This discovery opens a new intervention point for investigating the development and long-term maintenance of neural circuits. As this role of astrocytes is conserved from fly through mouse, I anticipate that the results of this project will be broadly applicable across distinct systems and circuits.

NIH Research Projects · FY 2026 · 2025-01

Sepsis is the leading cause of death in intensive care units and often results in multiorgan failure caused by dysregulated immune responses to infection. There are over 700,000 sepsis cases in the U.S. annually, and approximately 250,000 people die as a result. Despite our understanding of the pathology of sepsis, the treatment options are limited. During sepsis, neutrophils are excessively recruited to the inflamed endothelium in multiple organs and contribute to tissue damage. Furthermore, proinflammatory neutrophils interact with platelets and form microthrombi, exacerbating thrombo-inflammatory conditions. Thus, the goals of this proposal are to understand the molecular mechanisms regulating neutrophil proinflammatory and adhesive activities in sepsis and identify an effective therapeutic strategy for treating the disease. In our latest study, we have demonstrated that neutrophil downstream regulatory element antagonist modulator (DREAM) is a crucial transcriptional repressor that promotes neutrophil recruitment during TNF-α-induced inflammation. Mechanistically, neutrophil DREAM suppresses the expression of A20 (Tnfaip3), an endogenous inhibitor of nuclear factor-κB (NF-κB) signaling and enhances neutrophil proinflammatory and adhesive activities through IκB kinase β (IKKβ) activity. In this project, we will study whether neutrophil A20 signaling contributes to vaso- occlusive events and organ damage in SCD. In this project, we will study whether neutrophil A20 signaling contributes to organ damage in sepsis. In Aim 1, we will determine the molecular basis of neutrophil A20 signaling in regulating neutrophil proinflammatory function under septic conditions. In Aim 2, we will utilize two-photon intravital microscopy to investigate the pathological role of neutrophil A20 signaling in neutrophil recruitment and pulmonary microcirculation in septic mice. In Aim 3, we will determine the contribution of neutrophil A20 signaling to cell-cell aggregation in the blood of septic patients and illness severity. These studies will employ biochemical, cell biological, and intravital imaging approaches. Since little is known about neutrophil A20 signaling in sepsis, the proposed study will identify a novel molecular and cellular mechanism mediating excessive neutrophil recruitment and organ damage in sepsis, which can help design an effective therapeutic strategy.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Staphylococcus aureus infection in otherwise healthy adults and children is a significant cause of morbidity, mortality, and economic loss. The unique ability of S. aureus to cause a wide range of infections and toxin- mediated syndromes highlights this organism’s vast array of encoded virulence factors, and ability to utilize these factors to modulate the host-pathogen interaction. While each of the body's tissues that can be infected by S. aureus pose distinct physiological and immunological challenges to the microbe, we are interested in understanding whether S. aureus leverages a common mechanism that is ‘tissue-independent’ to subvert host immune defense. Extensive research, including our own studies, supports the targeting of S. aureus -toxin (Hla) as a virulence factor to protect against infection. The interaction of Hla with its eukaryotic receptor ADAM10 provides an additional window of opportunity to evaluate whether host-specific factors that modify ADAM10 expression or cellular activity impact susceptibility to S. aureus disease. We have previously demonstrated that S. aureus incites endothelial injury through VE-cadherin cleavage and elicits platelet-neutrophil clustering on the injured endothelium dependent on Hla-ADAM10 interaction. As neutrophil-endothelial cell interactions are well described to play a critical role in host defense to infection, we now propose to understand on a mechanistic basis how ADAM10 modulates key endothelial-neutrophil interactions early in the context of S. aureus infection. Relying on a unique repository of transgenic mice, in vivo imaging capabilities, and microbiologic tools to evaluate S. aureus within the tissues, we will generate a spatiotemporal analysis of the interaction between neutrophils and the endothelium. These studies will focus on the initial cellular and molecular interactions that shape the early outcome of infection in distinct tissues, assessing the role of ADAM10 as a ubiquitously expressed protease that contributes to pathogenesis. Through this research program, we will have an opportunity to define a how the host-pathogen interaction may be shaped by a central defect in the early host response. The successful completion of these studies may enable analysis of short-term targeted therapy of ADAM10 to improve disease outcome.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY/ABSTRACT We have shown that Ly49 family of surface receptors mark CD8 Tregs in mice. Ly49 refers to a family of receptors for MHC class I that is primarily expressed by natural killer (NK) cells. A subset of CD8 T cells express inhibitory Ly49 family members, which contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in their cytoplasmic domains. Beyond their utility as markers of CD8 Tregs, however, the functional contribution of these Ly49 receptors to CD8 Tregs has not been investigated. Ly49+ CD8 T cells have long been known to be highly responsive to IL-15, but the role of IL-15 in the function of CD8 Tregs is also not known. It has also been argued that the transcription factor Helios is needed for CD8 Treg function. Yet experiments to date have not clearly distinguished the role of Helios in the development of CD8 Tregs from the ongoing need for Helios while CD8 Tregs perform their regulatory functions. Integrating our results and these outstanding questions, our central hypothesis is that immunization expands the sub-population of CD8 Tregs that can resolve a given immune response, and Ly49 and Helios are required for the development and function of these CD8 Tregs. The relevance of these questions for human health and disease was made clear by our recent study from us of the human counterpart to Ly49+ CD8 Tregs. In our recent study, we show that KIR+ CD8 T cells were elevated in the blood of celiac disease patients and individuals with several other autoimmune diseases. Our study thus argued that KIR+ CD8 T cells function to suppress self-reactive CD4 T cells and are transcriptionally and phenotypically equivalent to mouse Ly49+ CD8 Tregs. Therefore, a better understanding of the determinants of Ly49+ CD8 Treg function may therefore apply to an important population of human regulatory T cells. The efforts undertaken in this project could help to inform future approaches to harness KIR+ CD8 Tregs for the treatment of autoimmune diseases in human patients.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY/ABSTRACT Eating disorders (EDs) are common, disabling, and costly, yet less than 20% of those with EDs ever receive treatment. As such, our team established a coached app for EDs. Though coached apps are lower cost relative to therapy, they come with significant implementation barriers given the need for human support. One solution is to program chatbots that mimic aspects of human coaching. Still, it is recognized that engagement with digital mental health interventions can be challenging, making it important that an ED treatment chatbot be efficient, ideally with the most effective components delivered first. To date though, little is known about which components are most effective in reducing ED symptoms. The goal of this study is to fill this gap by optimizing an automated chatbot program to treat EDs. We will build on our programmatic research in this area and prior use of the multiphase optimization strategy (MOST) to test four candidate ED treatment components in an optimization randomized control trial (ORCT). These candidate components, which map onto ED putative mechanisms, target: 1) overevaluation of weight/shape; 2) dietary restraint; 3) emotion dysregulation; and 4) resisting urges to binge. Our multidisciplinary, multisector team has experience developing, evaluating, and deploying digital ED interventions. We include industry and non-profit partners, including the National EDs Association (NEDA; largest EDs non-profit in the U.S.), assuring real, sustained impact. For our ORCT, we will enroll N=800 adults who screen positive for an ED and are not in treatment, recruited through NEDA’s online EDs screen, which reaches 200K+ per year, or social media. We will randomly assign participants in a carefully-balanced 24 factorial design to receive some combination of the candidate ED treatment components (i.e., each combination from zero components to four components). In Aim 1, will estimate the individual and combined contributions of the four candidate ED treatment component on changes in ED psychopathology, as well as on ED behavior frequencies, comorbid symptoms, and clinical impairment at 1-, 2-, and 6-months post- randomization. We will also examine moderation of component effects. In Aim 2, we will examine the effects of each candidate component on its proposed target, and determine if those changes are associated with reductions in overall ED psychopathology. Finally, in Aim 3, we will identify the optimized chatbot package that is effective, producing the best expected improvement in ED outcomes, while remaining efficient in the use of participant time. We will also explore component ordering that may best accommodate participants with different engagement levels. To inform decision-making about immediate dissemination of the optimized chatbot, we will compare the optimized chatbot to the control version. We will also identify any differences in the optimized chatbot as a function of participant priorities and characteristics (personalization). This study has high potential to offer streamlined EDs care via a chatbot that can be scaled infinitely, along with real impact nearly immediately, rather than the long translation gap widely discussed.

NIH Research Projects · FY 2026 · 2025-01

Reducing the burden of chronic adverse health outcomes, including diabetes, hypertension, obesity, asthma, depression, heart disease, cancer, and preterm birth is a top U.S. public health priority. While evidence suggests that these health outcomes are a result of complex mechanisms across the life course, studying exposures to multiple environmental toxicants beginning in the in utero period has the potential to elucidate causal mechanisms underlying the burden of chronic diseases. The Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) cohort is a prospective pregnancy cohort of more than 1000 mother-child pairs in Los Angeles, California. MADRES examines environmental and social determinants of maternal and child health outcomes both during and after pregnancy. A wide range of data are collected via interviewer-administered questionnaires and validated instruments, as well as anthropometric and body composition data, and a broad suite of biospecimens from both mother and child. Environmental exposures were assigned to residential addresses of participants across time (e.g., ambient and traffic-related air pollution) or measured in stored biospecimens (e.g., PFAS, metals, emerging chemicals of concern). The MADRES cohort is a unique resource and one of the largest US environmental health pregnancy cohorts. The proposed project would capitalize on the significant investment to date and would allow for re-engagement of inactive participants, continued follow-up and maintenance of staff infrastructure, collection of biospecimens for future studies, new opportunities for enhancing the environmental health sciences workforce, and increased capacity for data sharing with the scientific community. We propose the following four specific aims: (1) Maintain, enrich and support the continuation of the MADRES cohort; (2) Enhance the existing MADRES biospecimen repository to annually collect blood and urine from mothers and blood, urine and saliva from children to preserve for future studies; (3) Expand data sharing and quality assurance protocols for the MADRES cohort; and (4) Provide opportunities for early-stage investigators from the undergraduate to postdoctoral levels. We will work across the U24 consortium of cohorts to promote data sharing best practices, sharing of tools, and development of novel metrics and common measures for conducting collaborative analyses across cohort studies.

NIH Research Projects · FY 2026 · 2025-01

Project Summary/Abstract: Acute lung injury (ALI), clinically known as the acute respiratory distress syndrome (ARDS), is a major cause of ICU morbidity and mortality. ALI/ARDS is an inflammatory lung injury characterized by alveolar barrier disruption and is triggered by both infectious and non-infectious injury. Since no treatment options are directed to the underlying ALI biology, there remains an unmet need to target the mechanisms of ALI. Essential early on for optimal lung repair is the formation of a provisional matrix, which is orchestrated by matricellular proteins that facilitate dynamic interactions between structural matrix proteins and cells directed into the site of injury. Our overarching goal is to better understand early matricellular events in the injured lung, and the mechanisms that are critical for the stabilization of the provisional matrix to identify targetable pathways. Thrombospondin-1 (TSP1) is a matricellular protein that binds to structural matrix proteins and is part of the early provisional matrix. Platelets are a major source of TSP1 and, upon platelet activation, TSP1 is released from α- granules onto the platelet membrane where TSP1 undergoes a conformational change through disulfide interchange mediated by extracellular protein disulfide isomerase (PDI). We posit this conformational change opens a cryptic region of TSP1 and enhances TSP1 anti-protease function. Strikingly, platelet and megakaryocyte-specific (plt/MgK) Thbs1 cKO mice exhibit increased lung permeability with exaggerated neutrophil responses, and enhanced matrix remodeling in the airspaces following lung injury compared to WT mice. The airspace proteome of plt/MgK Thbs1 cKO mice is enriched in proteolytic enzymes that degrade the extracellular matrix (ECM), neutrophil granule contents, increased fibrillar collagen COL1A1, and proteins involved in ECM biosynthesis. Using lung intravital microscopy and 3D scanning microscopy, we show that cKO mice exhibit increased MgK recruitment to sites of collagen in areas of alveolar leak and interstitial space compared to WT mice. These findings lead us to hypothesize that TSP1 is critical for the spatiotemporal control of early matricellular events in the injured lung by stabilizing ECM proteins and regulating cellular activation and inflammation. Utilizing pharmacologic blockade, genetic mouse models, advanced optical imaging, cutting-edge spatial proteomics, untargeted mass spectrometry, and a human ARDS cohort, we propose to (1) determine whether plt/MgK TSP1 instructs neutrophils at the provisional matrix to restrain their activation through PDI; (2) evaluate the mechanism by which plt/MgK TSP1 regulates early matrix remodeling, collagen expression and stabilization; and, (3) investigate the role of TSP1 in the control of MgK and platelet mobilization in the injured lung. Defining the role of TSP1 in the formation of an optimal provisional matrix and barrier repair could prove useful in the rational design of targeted therapeutics.

NIH Research Projects · FY 2026 · 2025-01

Project Summary/ Abstract Congenital and perinatal infections are a leading cause of fetal and infant morbidity and mortality. There is increasing evidence that brain injury in babies with congenital and perinatal infections is caused not only by direct injury from the pathogen itself, but also may be due to the inflammatory or immune response to the pathogen. Targeted immunotherapies that allow pathogen control and removal but minimize bystander brain injury are largely unexplored. This proposal investigates the role of the receptor tyrosine kinase, Mertk, in cognitive and behavioral dysfunction in mice after congenital Zika virus (ZIKV) infection. Recent global epidemics link congenital ZIKV infection to neurodevelopmental abnormalities including microcephaly, intracranial calcifications, ventriculomegaly, and cognitive and behavioral impairment. Recent data indicate that ZIKV- exposed children without major structural brain abnormalities at birth may still have cognitive and behavioral deficits. Mertk, a receptor tyrosine kinase expressed by astrocytes and microglia, has been implicated in autoimmune, infectious and oncologic processes. It is not expressed by neurons, so immune-specific pathways can be probed without disturbing neuronal biology. Mertk facilitates microglial- and astrocyte- mediated synaptic pruning during early brain development and also mediates phagocytosis of cells and cellular debris in the brain. The hypotheses to be tested are: (1) Increased prenatal and early postnatal Mertk signaling during congenital ZIKV infection mediates immune-mediated neuronal injury; (2) increased postnatal Mertk signaling in microglia and astrocytes during congenital ZIKV leads to increased phagocytosis of mature neurons and synaptic pruning; and (3) increased Mertk signaling due to congenital ZIKV infection mediates abnormalities in functional connectivity, cognition, and behavioral deficits following congenital ZIKV infection. Understanding mechanisms of brain injury in ZIKV-exposed children is critical for providing interventions that improve neurodevelopment once ZIKV is detected. The proposed mechanisms also have broader implications for the effects of other neuroinflammatory insults on the developing brain. This mentored career development award provides the applicant, a uniquely trained pediatric neurologist with expertise in medical image analysis, formal training in animal models of early neurodevelopment along with advanced neuroimmunology and developmental neuroscience research methods, including immune cell profiling, histochemical analysis of brain tissue and optical imaging of functional brain cortical connectivity. The environment for the proposed research is an institution that is deeply committed to development of early career physician scientists and provides the applicant direct access to field leaders in developmental neuroscience, infectious diseases and widefield optical imaging. The training and data that will result from this award will provide a foundation for the applicant to transition to an independent physician scientist and lead critical, rigorous studies in the development of mouse models of congenital and perinatal infections that affect the developing brain.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Epithelial tissues are multilayered with varying elasticity and geometry in different layers, e.g., gut epithelium, lungs, or skin. Cells aggregate or migrate in different regions of tissues, as needed for various biological demands of disease and development, by sensing and responding to both mechanical and biochemical properties of their extracellular matrix (ECM). In wound healing, tumor invasion, and embryogenesis, epithelial leader cells generate mechanosensitive protrusions and coordinate their forces with follower cells for directed migration to fill gaps and voids in epithelial layers and tissues. This transmission of forces and mechanotransduction signaling spans across length scales, from cell-ECM adhesions, cell-cell junctions, and cytoskeletal network into the nucleus. We have shown that epithelial cells mechanosense extracellular matrix (ECM) stiffness, confinement, and fiber architecture. Building on these classic mechanobiology studies, we have also shown that epithelial cells store mechanical memory of their past environments, which informs their future migration and generates matrix memory through active remodeling of 3D collagen microenvironments. Additionally, disruption of nuclear export imparts concurrent epithelial and mesenchymal states. However, there are significant gaps in knowledge about how epithelia sense tissue defects and wounds, whether the force requirement for cell migration changes with environment topography, and how nuclear mechanosensing causes disorder in epithelia. These gaps in knowledge require novel bioengineering approaches to decouple these multivariate problems. In this MIRA program, we will study epithelial mechanosensing, response, and memory in three broad areas. First, we study how epithelial cells sense extracellular wounds of varying collagen types and matrix stiffness, and how cytoskeletal reinforcement and depth-mechanosensing overcome and heal ECM wounds. Second, we examine whether the classic force-dependent fast epithelial migration can occur with lower forces by changing ECM fiber alignment, and how spatiotemporal coordination of extracellular force transmission and intercellular mechanotransduction governs such force-effective migration. Third, we connect dysfunctions in nuclear transport and nucleocytoplasmic communication to epithelial disorder, unjamming, and migration. In these projects, we also ask whether epithelial cells remember their past extracellular stimuli and whether such memory alters their future response. These projects bring novel mechanobiology perspectives to conventional epithelial biology and could reveal new responses at different time and length scales, such as mechanical memory, depth-sensing, and epithelial transitions through nuclear mechanics. This work employs and nurtures diverse perspectives due to its inherently multidisciplinary approach in biophysics, engineering, and cell biology. Our results will highlight how the mechanically complex extracellular environments proactively regulate epithelial mechanosensing and may inform new insights and therapies for dysfunctional embryonic development, cancer, injury response, and wound healing.

NSF Awards · FY 2025 · 2025-01

Multivariate and functional time series are prevalent and routinely collected in many fields. Statistical inference of such time series is a fundamental problem in modern time series analysis and has broad applications in many scientific areas, including bioinformatics, business, climate science, economics, finance, genetics, and signal processing. Compared with existing methodologies, this research project will provide nonparametric inference procedures that can accommodate a wide range of dimensionality and require weak assumptions on the data generating processes. The methodology ensuing from the project will be disseminated to the relevant scientific communities via publications, conference and seminar presentations, and the development of open-source software. The project will involve multiple research mentoring initiatives, including efforts on broadening participation, and will offer advanced topic courses to introduce the state-of-the-art techniques in time series analysis. The project will provide a broad range of interdisciplinary training opportunities at all educational levels and will contribute to the future workforce professional development. The project will develop a systematic body of methods and theory on inference for both multivariate (including high-dimensional) time series and functional time series based on sample splitting (SS) and self-normalization (SN). Recently, the SN technique has been advanced to the inference of high-dimensional time series, but it requires the use of a trimming parameter. Also, its scope of applicability is limited to high-dimensional time series with weak panel dependence which might be unrealistic in many modern time series applications. In turn, the existing SN for functional time series relies on dimension reduction by functional principal component analysis and, hence, the resulting procedure may be powerless when the alternative is orthogonal to the space spanned by the top principal components used in the procedure. To address these major limitations, this project will develop a new unified framework based on SS-SN, in conjunction with inference for multivariate and functional time series, and investigate its utility in application to analysis of time series of low, medium, high or infinite dimensions. 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 · 2025-01

PROJECT SUMMARY The primary goal of this NRSA F32 proposal is to determine the contribution of endogenous opioids in dorsal raphe nucleus to motivational and affective dysregulation during chronic pain. Chronic pain is a complex disease state which is associated with comorbidities such as depression, anxiety, and increased risk of suicide. However, the primary target of analgesic research has been peripheral and spinal sensory mechanisms despite emotional unpleasantness being a key feature of the human pain experience. Exogenous opioids are the gold standard for pain relief but are associated with many negative side effects. The endogenous opioid system is well known to powerfully modulate both analgesia and affective and motivational neural circuits. It is therefore essential to understand how this system may be contributing to the emotional component of chronic pain states. Historically, dorsal midbrain nuclei such as dorsal raphe nucleus (DRN) and adjacent periaqueductal grey have been shown to be important sites of opioid action. However, the specific role of opioid peptides within the DRN during chronic pain has not been characterized despite studies showing opioid activity here can also powerfully modulate pain and motivated behaviors. Preliminary data from our lab indicate that CRISPR-Cas9 disruption of preproenkephalin (PENK) in DRN enhances aversion. Specifically, DRNPENK knockdown increases allodynia following a mild acute pain state and decreases time spent investigating an aversive odor. This increase in aversion is similar to behavioral changes observed in chronic pain states. Therefore, the goal of this NRSA F32 is to determine how DRNPENK contributes to the motivational and affective behavioral dysfunction resulting from chronic pain. First in Aim 1, we will use dual-color 1-photon endoscopic imaging to examine how enkephalinergic and non-enkephalinergic neurons encode evoked and non-evoked pain as well as motivational behaviors before and after the development of chronic pain. In Aim 2 we will determine whether suppression of DRNPENK neuron activity elicits a pain-like phenotype in naïve animals using designer receptors exclusively activated by designer drugs (DREADDs). Finally, in Aim 3 we will test the therapeutic potential of activating DRNPENK in a chronic pain state. We will use DREADDs to activate DRNPENK neurons both with and without CRISPR-Cas9 disruption of enkephalin peptide to specifically interrogate the function of this peptide in chronic pain-induced behavioral dysregulation. Together, these studies will provide insight into the role of endogenous opioids within a unique dorsal midbrain nucleus on motivational and affective behavioral dysregulation during chronic pain. This will lead to a better understanding of chronic pain pathophysiology and more effective potential neurochemical targets for therapeutic intervention.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY / ABSTRACT Gastric cancer is a leading cause of cancer-related deaths worldwide and carries a dismal prognosis in the United States. A critical pre-neoplastic stage and determinant of oncogenic risk is the development of pyloric metaplasia. However, we still have a limited understanding of how pyloric metaplasia develops and expands in the setting of chronic inflammation. My laboratory’s long-term goal is to characterize new and potentially targetable pathways in pyloric metaplasia. We recently and unexpectedly identified the response to double-stranded RNA (dsRNA) as the most upregulated pathway across two distinct models of murine pyloric metaplasia. dsRNA signaling was initially described as an innate immune response that induces type I interferons (IFNαβ) during viral infection. Its role in gastric pre-neoplasia had not been studied, however. Our previous work confirmed that dsRNA accumulates in metaplastic gastric epithelium in germ-free mice and in humans, and recent evidence indirectly suggests that the response to dsRNA is downregulated in human gastric cancer. dsRNA signaling therefore represents an under-appreciated pathway in gastric epithelial injury and tumorigenesis. The objective of this proposal is to establish how dsRNA signaling contributes to gastric pre-neoplasia. To address this, we specifically deleted a central regulator of dsRNA signaling, ADAR1, from gastric parietal cells (Adar1ΔPC). Consistent with a role for dsRNA signaling in pre-neoplasia, Adar1ΔPC mice spontaneously developed pyloric metaplasia and gastric dysplasia. Further molecular characterization found that mitochondrial RNA (mt- RNA) accumulated within the gastric epithelium of Adar1ΔPC stomachs, implicating mt-RNA as a potential trigger of epithelial dsRNA signaling. Single-cell RNA sequencing and flow cytometric analyses demonstrated a sustained and transcriptionally upregulated dsRNA response throughout the gland that was independent of adaptive immunity. We have therefore developed a tractable model of gastric pre-neoplasia that we will use to understand how dsRNA signaling promotes a pre-cancerous gastric environment. Aim 1 will examine how distinct sources of dsRNA activate dsRNA signaling within gastric epithelium, using an established gastroid system, new murine models, and innovative in vitro approaches. Aim 2 will rely on genetic mouse models and bone marrow chimera experiments to determine how epithelium- and immune-mediated IFNαβ signaling connects the dsRNA response to gastric pre-neoplasia. The proposed experiments are logical extensions of our previous work. They also establish new foundational tools and exciting research avenues that can be completed within the award period. The importance of this application is to enhance our mechanistic understanding of a previously unexplored and therapeutically targetable pathway in gastric pre-neoplasia that can be broadly applied to pre-neoplastic states across other epithelial tissues.

NIH Research Projects · FY 2026 · 2025-01

: Parkinson’s Disease (PD) is a neurodegenerative disease that causes symptoms such as tremor, bradykinesia, and freezing of gait, as well as sleep disturbance, autonomic dysfunction, and abulia. PD patients particularly struggle to initiate and maintain actions, which causes gait freezing, leading to falls. PD results from dysfunction in motor circuitry, including connections between subcortical structures such as substantia nigra and striatum, as well as primary motor cortex, which drives voluntary movement. Recently, our group rewrote the textbook diagrams of motor circuitry. We described a previously unrecognized Somato-Cognitive Action Network (SCAN) which is interspersed between effector-specific regions of primary motor cortex (foot, hand, mouth) (Gordon et al., Nature, 2023). The SCAN is engaged by coordinated rather than isolated actions, and it is strongly preferentially connected to other cortical regions important for action planning and control, autonomic function, and arousal. Many SCAN functions (drive to act, gait, autonomic control, arousal, motor coordination) are affected in PD. Further, clinical targets for neuromodulation in PD are connected to SCAN. Thus, SCAN dysfunction might be an important aspect of PD pathophysiology and resulting symptoms. Critically, recent technical advances in noninvasive functional neuroimaging allow us for the first time to reliably evaluate the connectivity of motor systems, including SCAN, into the deep subcortical structures most relevant for PD. Using these patient-oriented techniques, we will first test whether PD-relevant subcortical structures—including clinical targets for PD—are connected more strongly to the SCAN circuit than to effector-specific M1 foot, hand, and mouth regions. We will then test whether these subcortical-to-SCAN circuits are altered in PD patients to a greater degree than effector-specific circuits. . This work will advance a new conceptualization of PD as a disorder of SCAN rather than of traditional effector-specific M1, which will revolutionize how we think of the disorder. Localizing PD disruption to specific portions of M1 could aid with evaluation of patients using these advanced, noninvasive fMRI techniques, and can provide precision targets of interest for other imaging modalities. Noninvasive mapping of cortico-subcortical connectivity will enable optimal target definition for neuromodulatory treatment of PD. Reconceptualizing PD as a disorder of SCAN, a system for integrated action, rather than of M1 circuits for isolated movement, may spur development of alternate symptom evaluation tools oriented around this framework. Finally, localizing M1 sites of disruption in PD opens the possibility of treating PD using cortical stimulation, a less-invasive alternative to deep brain stimulation.

NSF Awards · FY 2025 · 2025-01

The workshop will allows researchers to share research ideas and discuss interesting research problems. The workshop will focus on topic areas of Trustworthy AI, Resilient Networks, and others. The workshop program will include keynote speeches, lightning talks, and round-table discussions, designed to spark innovation, deepen technical exchanges, and lay the groundwork for a shared vision of cybersecurity research. By facilitating these critical interactions, the workshop aims to advance the state of the art in cybersecurity, develop a roadmap for future research collaborations, and promote long-lasting partnerships. The proposed workshop seeks support to cover the venue facility costs and the travel expenses for invited participants from U.S. institutions to attend a research workshop in Washington, D.C., on March 3-4, 2025. By enabling in-person exchanges among leading researchers, the workshop aims to foster impactful collaborations in cybersecurity research. 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 · 2025-01

This Major Research Instrumentation (MRI) grant supports the purchase of a 3D printer capable of printing features ranging from the nanometer (billionth of a meter) scale to the micrometer (millionth of a meter) and centimeter scales. It will accelerate research by enabling the advanced manufacturing of tiny devices and machines, fostering new ideas in biology, medicine, physics, and engineering, and furthering national priorities in these areas. To build new knowledge of both natural and engineered systems at the molecular and cellular scales, researchers need to manufacture tools that can interface directly with these systems. Traditional additive manufacturing (or "3D printing") can create arbitrarily shaped objects based on computer models, but most existing printers have limited resolution and are unable to fabricate extremely small and complex structures. This award enables the acquisition of a 3D printer that uses a precision laser beam to print objects from a variety of plastic materials, with feature sizes smaller than human cells. These capabilities will allow researchers to probe cell and tissue behaviors, better understand diseases, enhance chemical reactions, explore the optical, electronic, and thermal properties of materials, and create novel devices and microrobots. The discoveries made will have applications in energy, healthcare, environmental science, and materials science, with the potential to benefit society and the U.S. economy for years to come. As a unique manufacturing resource in the Midwest, this advanced 3D printer will also inform engineering education, including increasing the participation of students in technical disciplines, through its incorporation into training, workshops, and outreach activities to the regional academic community and K-12 students. Among the tools capable of achieving submicron feature resolution, conventional semiconductor processing typically yields "flat" topographies. The resolution of even the best conventional 3D printers is two orders of magnitude larger than what is needed to interface with microscopic structures. Two-photon polymerization laser lithography enables rapid prototyping and wafer-scale production of 3D structures with submicron precision. This technology uses a lower-energy near-infrared laser to solidify the printing material only when photoresin molecules simultaneously absorb the energy of two photons. This 3D printer will create structures ranging from nanometer to millimeter scales across centimeter-sized areas. The diverse research team will (i) fabricate micro-/nanophotonic integrated circuits and optical devices, (ii) explore the fundamental mechanobiology of cells and tissues, (iii) develop stretchable electronics for sensing and measurement, (iv) discover new phenomena in atomically thin materials, and (v) probe the behavior of microswimmers using cell-scale acoustofluidic actuators, among other programs in device physics, transport phenomena, and biology/medicine. Thus, the 3D printer will advance both fundamental and applied research across many fields. 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 · 2025-01

Ushering in a new era of spectrum sharing requires dynamic spectrum access (DSA) that natively supports both primary and legacy users, while creating new opportunities for spectrum utilization. A comprehensive blend of technical, economic, and policy-based solutions is required to realize this vision, including potential modification to existing cellular standards to ensure that future 6G standards are inherently “sharing native”. Precise, low-latency, and localized spectrum usage monitoring that is aware of and integrated with the cellular Physical (PHY) and upper layers in the networking stack is essential for facilitating effective spectrum utilization and sharing in Spectrum Era 4. However, existing spectrum sharing systems typically rely on a separate monitoring network comprising dedicated, costly, and sparsely deployed spectrum sensors, e.g., the Citizens Broadband Radio Service (CBRS) networks rely on an environmental sensing capability (ESC) sensor network deployed in coastal areas to detect transmissions from Navy vessels and radars. This project aims to realize a transformative vision for spectrum sensing in Spectrum Era 4, which supports dense and in-situ spectrum sensing with significantly enhanced sensing resolution across the temporal and spatial domains, improved energy efficiency, and cooperative sensing strategies that are aware of the cellular protocols. As such, it has the potential to revolutionize the next generation of cellular technologies (e.g., 6G and beyond) to be sharing native with significantly enhanced spectrum awareness and sensing resolution. This project targets the following scientific contributions from three interdisciplinary and interrelated research thrusts. (i) Development of ultra-efficient, single-shot, analog cross-correlators (X-Corr) capable of computing the cross-correlations between input signals and template waveforms across varying lags, enabling spectrum sensing with ultra-low latency. Using the margin computing paradigm, analog X-Corr with superior energy efficiency and (>1,000 TOPS/W) can be designed and realized in integrated circuit (IC) implementations without compromising the computing speed or precision. (ii) Design of protocol-aware configuration and adaption for X-Corr to enable fine-grained, in-band spectrum sensing. This allows for detailed sensing of spectrum occupancy and detection of interference signals at the symbol or slot level (a few to 10s of microseconds) with both known and unknown features (e.g., for airborne and ground radars) and employ diverse PHY layers (e.g., 5G New Radio and Wi-Fi). (iii) Optimized deployment and configuration of a network of densely deployed X-Corr sensors to facilitate cooperative, in-situ spectrum sensing that is aware of the communication standards. Such a network also enhances the ability to localize and track interference sources with significantly lower latency and cost. Evaluation of the proposed research includes analysis, simulations, IC implementations, circuits-system co-design and integration, as well as field experiments using local and community wireless testbeds. 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.