Ut Southwestern Medical Center

NIH Research Projects · FY 2025 · 2022-06

PROJECT SUMMARY Human norovirus (HuNoV) is the leading cause of acute gastroenteritis in the United States, resulting in $4.2 billion in direct health system costs annually. Due to underlying immunosuppression and the lack of effective antiviral therapeutics, transplant patients may develop serious sequelae from HuNoV infections. Though bacterial gut microbiota has been shown to enhance replication and pathogenesis of enteric viruses in preclinical models, its role in HuNoV infection remains largely unknown. In this project, we aim to gain greater mechanistic insights into how gut microbiota modulate HuNoV infection in transplant patients. Our central hypothesis is that transplant patients with symptomatic HuNoV infection will have a gut microbiome signature showing an enrichment of specific gut microbiota (Enterobacteriaceae) that facilitate infection of HIEs, and those who develop chronic symptoms from HuNoV infection will have a concomitant depletion of specific gut microbiota that modulate host innate immune responses (type 1 interferons). In Aim 1, we will further define both gut microbiome and host factor differences in transplant patients ±HuNoV infections. First, we will establish a larger cohort of adult and pediatric transplant patients and collect longitudinal stool specimens. Then, we will perform comprehensive gut microbiome profiling (metagenomic shotgun sequencing and bacterial qPCR) to confirm our preliminary results. We predict that HuNoV-infected transplant patients will have significantly different gut microbiota signatures compared to uninfected counterparts, and that higher intensity of immunosuppression and high antibiotic load will correspond with chronic diarrhea in HuNoV-infected transplant patients. In Aim 2, we will determine if Enterobacteriaceae facilitate HuNoV infection using an in vitro HIE model. First, we will infect jejunal HIEs with HuNoV and co-incubate HuNoV with various Enterobacteriaceae spp. Then, we will perform RNA extractions and quantitative HuNoV RT-qPCR to evaluate the effect of co-incubating various Enterobacteriaceae spp. on viral replication. We predict that Enterobacteriaceae promotes HuNoV infection of HIEs. If this is the case, we will investigate if this is a phenomenon observed only in HBGA-expressing members of Enterobacteriaceae. In Aim 3, we will determine if transplant patients with chronic symptomatic HuNoV infections have different systemic cytokine signatures compared to uninfected counterparts. We will perform bulk cytokine analysis on serum samples utilizing Isoplexis, a novel functional proteomic profiling platform. We predict that transplant patients with chronic diarrhea from HuNoV infection will exhibit a paucity of genus Bacteroides, resulting in depletion of type 1 interferons, which then leads to a decreased Th1 immune response, increased Th2 immune response and increased expression of Th2-predominant cytokines (IL-4, IL-5, IL-10). The proposed experiments, training and didactic coursework in this K23 will equip the candidate (Dr. Chong) with unique skillsets that will enable her transition to independence as a physician scientist in gut microbiota-HuNoV interactions in transplant patients.

NIH Research Projects · FY 2025 · 2022-06

A pH Responsive Transistor-like Nanoprobe for Sensitive Detection of Unknown Primary Cancers of the Head and Neck Project Summary/Abstract Approximately 65,000 cases of Head and Neck Squamous Cell Cancer (HNSCC) are diagnosed each year in the US and arise in the mucosal lining of the upper aerodigestive tract and spread to local lymph nodes. In some cases, the primary tumor is too small to be detected, with enlarged nodes being the only manifestation of HNSCC. These unknown primary cancers (UPCs), often induced by human papilloma virus (HPV), usually arise in the mucosa of Waldeyer's ring, the lymphatic tonsillar tissues of the pharynx. Finding UPC is significant and impactful addressing an unmet need with long term oncologic and functional outcomes improved by locating and removing UPC. However, their detection is impaired by the corrugated, cryptic surface, and nodularity of lymphatic tissue which decreases the sensitivity of physical examination while the vascularity and fluorodeoxyglucose (FDG) avidity of the lymphoid tissue obscure small tumors by computerized tomography (CT) and positron emission tomography (PET). We have invented a library of ultra pH sensitive (UPS) nanoprobes, covalently conjugated to indocyanine green (ICG) that respond to acidic tumor microenvironment, with a concomitant sharp change in their fluorescence state from OFF to ON. One such nanoprobe, ONM-100, has been developed and studied in a Phase 1 and ongoing FDA approved Phase 2 clinical trial. it has been shown to be well tolerated with no serious adverse events, compatible with surgical endoscopes, and able to detect a variety of cancers including HNSCC in real time. Based on these data we hypothesize that ONM-100 used as an adjunct to SOC panendoscopy can improve detection of UPC. To test our hypothesis, we will (1) Compare the sensitivity and specificity of activatable probe ONM-100 for cancer detection to always ON probes for tumors in Waldeyer's ring; (2) Detect HPV-mediated HNSCC in patients after systemic administration of ONM-100 comparing fluorescence to true-positive cancers; (3) Detect UPC in patients after systemic administration of ONM-100. Successful execution of this project will provide precise excision of UPC and avoidance of intense adjuvant therapy for UPC patients significantly improving care and outcomes for these patients who suffer greatly from less oncologically effective imprecise overtreatment.

NIH Research Projects · FY 2026 · 2022-06

Summary/abstract This research program focuses on uncovering the biological roles of glycoconjugates. Part of this effort is devoted to the development of chemical biology tools for glycoscience research. In the past, we have developed photocrosslinking sugar analogs that can be incorporated into cellular glycoconjugates and used to covalently crosslink glycoconjugates to their binding partners in a native context. These reagents can be used to identify glycan-dependent binding interactions, and to characterize where and under what conditions that these interactions occur. Over the next five years, we will further expand the scope of experiments that can be performed by preparing additional photocrosslinking sugars, developing new methods for their incorporation, and evaluating their incorporation into additional glycoconjugates. Using one of these photocrosslinking sugars, we made the unexpected observation that cholera toxin can bind fucosylated glycoconjugates in addition to its canonical receptor, the ganglioside GM1. Over the next five years, we will determine the molecular structure of fucosylated glycoconjugates recognized by cholera toxin and characterize their role in host cell intoxication. These studies are supported by our long-term collaboration with the Yrlid group (University of Gothenburg) and their expertise in studying cholera disease mechanisms. Our studies of cholera toxin receptors led us to become interested in the diverse glycoconjugates that line the intestinal and respiratory epithelia. A CRISPR screen designed to identify genes that modulate cholera toxin binding to cell surfaces identified a number of candidate genes that may function in the regulation of glycosylation by diverse mechanisms. Over the next five years, we will characterize novel regulators of glycosylation and determine how they shape the glycome, modulating glycan features such as polyLacNAc chain length and the degree of fucosylation. The long-term goal of these studies is to determine how glycan features vary among individuals, their association with disease states, and their impact on host-microbe interactions.

NIH Research Projects · FY 2025 · 2022-06

PROJECT SUMMARY The nucleolus is one of the largest membraneless cellular organelles, responsible for ribosomal RNA (rRNA) transcription, rRNA processing, and ribosome assembly. Nucleolar size and number are often correlated with protein synthesis rate and proliferative capacity of a cell. Seminal studies have shown that increased nucleolar size and number are common features of many cancers and that nucleolar defects are associated with neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases. Nevertheless, fundamental information is still lacking on the molecular players and mechanism that control the dynamic assembly and activity of the nucleolus in health and disease. We identified a novel nucleolar protein named ZNF692 that is necessary to maintain nucleolar integrity and activity. Knocking down ZNF692 resulted in abnormal ring-like nucleolar morphology, as well as compromised protein synthesis. Our preliminary results indicate that ZNF692 interacts with multiple nucleolar proteins, including NPM1, as well as rRNA processing and ribosome assembly factors. Our hypothesis is that ZNF692 assembles a hub for ribosome biogenesis in the nucleolus by simultaneously recruiting pre-rRNA, ribosomal proteins, and ribosome biogenesis factors. We will define the molecular mechanism regulated by ZNF692 in ribosome production (Aim 1). We will define the domains of ZNF692 that regulate nucleolar integrity and activity (Aim 2). We will then determine how ZNF692 may regulate nucleolar assembly and dynamics (Aim 3). Our work has the potential to provide fundamental data on the mechanisms and key regulators of nucleolar activity and could become the basis for the development of novel approaches to alter nucleolar activity in diseased cells.

NIH Research Projects · FY 2025 · 2022-06

Project Summary The irradiation at ultra-high dose rates, namely FLASH-RT, can substantially reduce normal-tissue toxicities while maintaining tumor response (so-called the FLASH effect), compared with the irradiation at conventional dose rates (CONV-RT). Although many preclinical and some clinical studies demonstrated the potential benefit of FLASH-RT, the effectiveness of FLASH-RT for general cancer patients is to be further validated through clinical trials. By far the only commercially available system that can deliver ultra-high dose rates needed for general- purpose clinical FLASH-RT is the proton modality, such as our IBA system. However, the state-of-the-art treatment planning method, i.e., intensity modulated proton therapy (IMPT), only optimizes the dose and does not directly optimize the dose rate or the FLASH effect. A missing prerequisite for proton FLASH-RT clinical trials is a compatible treatment planning method with FLASH optimization capability. The key innovation and enabling technology in this project for clinical FLASH-RT is the first-of-its-kind FLASH optimization engine via SDDRO, which was recently recognized by PTCOG 59 as the Michael Goitein Best Abstract Award in Physics for its innovation and impact for FLASH-RT (Gao et al 2021). To the best of our knowledge, SDDRO is the only method that can optimize the FLASH dose rate as well as the dose. Our preliminary work (Gao et al 2020) for lung patients has demonstrated that, compared with IMPT, SDDRO substantially improved the FLASH-dose-rate coverage (in order to have the FLASH effect for reducing normal- tissue toxicities) while preserving the dose coverage, e.g., increasing of the target-surrounding volume receiving ≥40Gy/s from ~40% to at least 98%, and the lung volume receiving ≥40Gy/s from ~30% to ~80%, which occurred at high-dose and high-uncertainty locations with high-risk radiation-induced toxicities. Such improved FLASH coverage is especially critical for reducing normal tissue toxicities given the hypofractionation nature of FLASH-RT. Given our innovative SDDRO, IBA proton machine with ultra-high-dose-rate capability, academic-industrial partnership with IBA, FLASH radiobiology and dosimetry expertise, we are uniquely positioned to develop novel SDDRO methods with FLASH optimization capability that is currently unavailable and urgently needed for clinical FLASH-RT, including (1) general SDDRO methods with realistic FLASH models, machine characteristics, and delivery mechanisms (transmission beams, conformal energy filters, or joint); (2) translation of SDDRO methods into our IBA system, with end-to-end validation and verified FLASH dosimetry. The completion of this project will render novel SDDRO methods with FLASH optimization capability that is currently unavailable and urgently needed for clinical FLASH-RT, and set the stage for FLASH animal studies and clinical trials.

NIH Research Projects · FY 2025 · 2022-06

Matricellular proteins are constituents of the extracellular matrix (ECM). They are normally expressed highly during embryonic development but absent/low in adult tissues unless activated by cues for tissue remodeling. Matricellular proteins shape ECM properties through interactions with structural proteins, growth factors, and cell receptors during organ development and differentiation. In an attempt to identify molecular signatures unique to irreversible cardiac fibrosis, we performed proteomics of fibrotic heart and liver and found that cartilage intermediate layer protein 1 (Cilp1) is differentially upregulated in the infarcted heart. Cilp1 is normally associated with bone and cartilage development. Its function and mechanism of action in adult heart diseases are unknown. We generated Cilp1 knockout (KO) mice from commercial Cilp1fl/fl mice and transgenic (Tg) mice with Cilp1 overexpressed in myofibroblasts. While deletion of Cilp1 reduced adverse cardiac remodeling upon myocardial infarction (MI), overexpression of Cilp1 worsened it. Cilp1 is expressed predominantly in cardiac fibroblasts. We hypothesize that fibroblast Cilp1 promotes inflammation and myofibroblast proliferation upon MI injury. We now generated fibroblast conditional fbKO mice (PostnMCM;Cilp1fl/fl and Tcf21MCM;Cilp1fl/fl that contain a tamoxifen inducible Cre-recombinase expression cassette within Periostin (Postn) and Tcf21 genetic locus, respectively). Aim 1. To determine the cell-type specific function of Cilp1 in post-MI cardiac remodeling. We will delete Cilp1 in cardiac fibroblasts before and post-MI day (d) 1 & d4 to investigate its effect on cardiac remodeling, including cardiac function, inflammation, myofibroblast proliferation/differentiation, and collagen remodeling. We will also perform proteomics of myofibroblasts isolated from these mouse hearts. The role of fibroblast Cilp1 in regulation of gene transcription in various heart cell types will be investigated with single-nuclei RNA-seq of infarcted WT and Cilp1 fbKO hearts at post-MI d3. Aim 2. To establish the molecular function of Cilp1 and its mechanism of action. Preliminary studies showed that Cilp1 protein in culture medium promotes myofibroblast proliferation via the mTORC1 pathway and binds scavenge receptor CD36. Cilp1 may interact with cell receptor/growth factor, promoting cell proliferation and inflammatory gene expression via receptor-mediated signaling pathways. To test this hypothesis, we will identify the minimal functional domain(s) of Cilp1 via mutagenesis and potential Cilp1- binding partners using both screen- and candidate-based assays and will establish how Cilp1 may act as a paracrine factor to regulate the cellular phenotypes of various heart cell types via receptor-mediated signaling pathways. We will also measure blood level of Cilp1 in mice before and after an anti-fibrogenic therapy upon MI injury. Matricellular proteins are clinically tractable owing to their accessibility to systemically delivered therapeutic reagents. Our preliminary studies established a pathological role of Cilp1 in post-MI remodeling. This proposal will establish how Cilp1 instructs development and differentiation of heart cells and gene expression to promote adverse remodeling, thus providing mechanistic insight on how to target this protein.

NIH Research Projects · FY 2026 · 2022-06

Determinants of cell state reprogramming PROJECT SUMMARY Forced expression of transcription factors (TFs) can reprogram cell state. The discovery of direct reprogramming has been a catalyst for our understanding of the molecular and genetic drivers of cell state. However, despite its successes, only a handful of successful reprogramming cocktails have been identified, the conversion process is often inefficient, and the mechanistic reasons for reprogramming failure are often unclear. Thus, a key obstacle to further progress is our incomplete understanding of the determinants and mechanisms of cell state conversion. Our long term goal is to understand the genetic and molecular basis of cell state, which has important implications for synthetic control of cell state for regenerative medicine. Towards this goal, the objective of this proposal is to elucidate the molecular and cellular determinants of cell state reprogramming. Specifically, we seek to address several fundamental gaps in knowledge on cell state reprogramming with three central research directions: 1) Epigenetic determinants of cellular reprogramming, 2) Genetic and temporal determinants of cellular differentiation, and 3) Initial cell state determinants on reprogramming. This scope is made possible by our innovative platform that couples multifactorial, pooled perturbation with multidimensional readouts for each cell spanning perturbations (induced TFs), mechanisms (epigenome), and phenotypes (transcriptome). By tracing thousands of individual cells on their path to reprogramming across a multitude of distinct perturbations, our high throughput functional experiments will reveal insights and suggest mechanisms for the determinants of reprogramming. Our rationale is that learning these fundamental rules of reprogramming will improve our understanding of the molecular basis of cell state and enable improved approaches to manipulate it.

NIH Research Projects · FY 2026 · 2022-05

Project Summary: Glycogen metabolism is impaired in >20 individual rare genetic diseases. Several of these diseases are caused by the formation of insoluble glycogen, which deposits in polyglucosan bodies (PBs). Without treatment currently available, PB accumulation causes pathology in liver, muscle, heart, and/or brain tissue. The mechanisms underlying the prevention of pathogenic insoluble glycogen are poorly understood. The PI’s work with established mouse models of polyglucosan body diseases links both glycogen phosphate and branching directly to glycogen solubility and imply a functional interdependence of phosphate and branching. The objective of this proposal is to identify how phosphate covalently linked to glycogen and glycogen branching impacts glycogen solubility in health and disease, and whether genetic modulation of each factor can decrease pathogenic PB accumulation in vivo. Utilizing novel in vitro and in vivo approaches, the proposed work will test the central hypothesis that glycogen phosphorylation and glycogen branching 1) are interrelated cellular processes that affect the solubility of glycogen, and 2) that when genetically manipulated can improve the physiological functionality of glycogen. Aim 1 characterizes the impact of glycogen phosphate, branching, and associated proteome on the precipitation risk of soluble glycogen in mouse models with insoluble glycogen accumulation. Analyses and experimental manipulation of these parameters will provide a mechanistic explanation for the structural changes in soluble glycogen that lead to glycogen insolubility. Aim 2 focuses on the impact and regulation of phosphorylation during glycogen synthesis, to interrogate glycogen phosphate as part of a GBE1-regulated protection mechanism of the cell to prevent glycogen insolubility. Aim3 determines the potential of enhanced branching in the prevention of insoluble glycogen. The impact of branching on glycogen precipitation risk will be characterized, and a new therapeutic approach for polyglucosan body diseases will be provided. This proposal uses established mouse models with PB-triggered pathology. In addition, two new mouse lines were generated, to separately modulate glycogen phosphate and branching in vivo. Combined with state-of-the-art glycogen biochemistry and proteomics, these new tools provide a unique opportunity to tease apart the interrelations of glycogen phosphate and branching and their effects on glycogen solubility. The proposed work can (1) shift the paradigm of glycogen phosphate being detrimental for glycogen solubility to phosphate as a protection mechanism from glycogen insolubility, (2) reveal regulatory connections between glycogen branching and phosphorylation, as well as (3) lead to the discovery of unknown glycogen kinases. It will (4) lay the ground work for new therapeutic approaches for polyglucosan body diseases and (5) provide a better grasp of vital cellular processes related to glycogen metabolism with implications for several rare diseases.

NIH Research Projects · FY 2026 · 2022-05

Project Summary/Abstract Lipid signaling plays a critical role in the regulation of organismal physiology and metabolic expenditure. Imbalances in lipid homeostasis can deleteriously impact health and cells within the organism tightly regulate lipid absorption, synthesis and metabolism to accommodate energetic demands and ensure energetic reserves later in life. Cells stockpile energy reserves under ample metabolic resources through SREBP-regulated lipogenesis. Yet, less clear is how cells regulate lipid homeostasis under nutrient depleted conditions and in particular, how cells sense metabolic demand and respond by increasing nutrient absorption. Our examination of several lipid depletion paradigms in C. elegans has identified a highly responsive small G protein, RAB-11.2, which is transcriptionally activated upon defects in the isoprenoid/mevalonate synthesis pathway. Through further investigation, we have discovered a new mechanism linking the nucleocytoplasmic dynamics of the nuclear hormone receptor, NHR-49, with nutrient absorption through RAB-11.2. Through the proposed five-year research period, we aim to define the molecular mechanism by which cells sense and respond to their need for de novo lipid synthesis. Our preliminary data suggests that cells sense their capacity to breakdown lipids through monitoring the availability of a particular prenol lipid synthesized through the isoprenoid pathway, geranylgeranyl pyrophosphate. Under conditions of high homeostatic lipid levels, geranylgeranylation of RAB-11.1 enables it to bind and sequester NHR-49 to cytosolic transport vesicles in a transcriptionally inactive state. Under lipid limited conditions caused by starvation or defective lipolysis/β- oxidation, cells lack the resources to synthesize GGPP through the isoprenoid pathway, which prevents RAB- 11.1 from binding vesicles and disrupts endocytic recycling pathways required for nutrient absorption. Due to the inability of its RAB-11.1 binding partner to associate with vesicles, NHR-49 is release from cytosolic vesicles and translocates to the nucleus where it activates transcription of several metabolic enzymes, nutrient transporters and RAB-11.2 to re-establish nutrient absorption.

NIH Research Projects · FY 2025 · 2022-05

Heart failure (HF) disproportionately affects the elderly who predominantly develop HF with preserved left ventricular (LV) ejection fraction (HFpEF), for which no efficacious therapies exist. Pulmonary hypertension (PH) – the most clinically recognized expression of pulmonary vascular dysfunction (PVD) – is a risk factor for incident HF and is present in upto 83% of patients with prevalent HFpEF, among whom it portends worse outcomes. PVD is therefore an attractive therapeutic target in HFpEF, but its pathophysiology is complex with variable contributions from elevated left atrial pressure, pulmonary parenchymal injury, and intrinsic pulmonary vascular dysfunction. A critical barrier to understanding PVD in HFpEF is a lack of knowledge regarding the anatomic alterations in the pulmonary vasculature underlying abnormal hemodynamics. The investigative team has pioneered development and validation of advanced image processing pipelines to quantify pulmonary venous and arterial remodeling on non-contrast chest computerized tomography (CT) scans. Their published and preliminary data from smokers in the NHLBI-funded COPDGene study show that pulmonary vascular remodeling associates with RV dysfunction and worse functional capacity, and is more frequently observed in HF. They now propose to extend these findings to a community-based cohort of older adults to define the role of pulmonary vascular remodeling in the development of HFpEF. This proposal’s central hypothesis is that activation of pro-inflammatory and pro-fibrotic pathways promotes pulmonary vascular remodeling, partially via concomitant LV dysfunction and pulmonary parenchymal injury, leading to PH, RV dysfunction, and ultimately HF. This project will leverage recently completed chest CT (for CAC) and echocardiography in 1,579 Atherosclerosis Risk in Communities (ARIC) study participants at the 7th study visit (2/2018-11/2019; age ~81±4 yrs). Novel CT-based measures of pulmonary vascular remodeling and parenchymal injury (fibrotic, emphysematous), and advanced 3D and strain-based echo measures of RV function will be performed. These data will be integrated with clinical assessments, outcomes surveillance, aptamer-based proteomics, and genomics to help define the most relevant targets to prevent progressive PVD in the very elderly. Specific aims include: (1) Define the extent to which LV dysfunction and pulmonary parenchymal injury promote pulmonary venous and arterial remodeling in the very elderly; (2) Determine the extent to which pulmonary vascular remodeling predicts RV dysfunction, reduced functional capacity, and incident HFpEF; and (3) Identify proteins and protein networks that predict pulmonary vascular remodeling. Replication will occur in COPDGene and the Framingham Heart Study, and Mendelian randomization analyses will identify the subset of potentially causal associations. Quantifying pulmonary vascular remodeling will identify pathophysiologically distinct morphologic PVD sub-phenotypes enabling more precise application of existing therapies, while discovery of associated molecular pathways may inform novel therapeutic targets.

NIH Research Projects · FY 2025 · 2022-05

Heart failure poses a major public health challenge in the United States, with a growing prevalence. An expanding number of medications have been shown to improve survival in patients with heart failure with reduced ejection fraction (HFrEF). The list of guideline-directed medical therapies (GDMT) includes beta-blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor-neprilysin inhibitors, and mineralocorticoid receptor antagonists. When used in combination, these medications reduce all-cause mortality by > 50%. Nonetheless, fewer than 25% of eligible patients receive 3 or more of these medications, at any dose, with particularly low rates of utilization among low SES individuals. The polypill refers to a fixed-dose combination of medications in a single pill, aimed at reducing pill burden and improving adherence. The polypill strategy offers a means by which therapy with multiple medications can be conveniently initiated at an early stage of disease, increasing the overall therapeutic benefit accrued over time. This is particularly relevant in settings where patients experience barriers to care due to high costs, frequent lab tests, and need for multiple follow up visits. We propose a single-center, pragmatic trial of a polypill-based strategy for the treatment of HFrEF in a low-income, racially-diverse population. We will enroll 175 adults with HFrEF (left ventricular ejection fraction [LVEF] < 40%) receiving care at Parkland Hospital who are not on optimal, target dose of guideline-directed medical therapy at a large county hospital in Dallas, TX. Participants will be randomized to receiving a polypill or usual care. The primary endpoint of the study is the change in LVEF, and the key secondary outcome will be change in circulating NT-proBNP levels, quality-of-life, six minute walk distance, and the adherence to guideline directed medical therapy at 12 months. We hypothesize that use of a polypill-based strategy in HFrEF will be feasible and lead to improved left ventricular systolic function, NT-proBNP levels, quality of life, and adherence to target dose guideline directed medical therapy compared with usual care.

NIH Research Projects · FY 2026 · 2022-05

Abstract The primary cilium is a microtubule-based dynamic cellular appendage that is found in many cell types. Cilia transduce cellular responses to extracellular signals, particularly to the morphogen hedgehog in vertebrates during differentiation and proliferation, regulating morphogenesis in multiple tissues. However, the mechanisms by which cilia-specific signals are maintained and propagated to direct downstream pathways during morphogenesis is not well understood. Understanding signaling at cilia requires mechanistic understanding of trafficking to cilia, isolating ciliary from extraciliary functions of signaling molecules, and studying functional consequences directly in tissues without disrupting cilia. My group is one of the foremost in studying cilia-specific signaling from subcellular to organismal scales, while preserving ciliary morphology. We identified the ciliary trafficking adapter Tulp3 and key repressors of hedgehog pathway, Gpr161 and Ankmy2, both of which function via cAMP signaling regulated by cilia. We postulate that the inherent complexity of ciliary signaling can be understood by examining how signals are maintained in and propagated uniquely by cilia (compartmentalization) and how cilia direct positive and negative regulation in downstream pathways (counterregulatory signaling). Over the next five years, we will directly study how compartmentalization and counterregulatory signaling at cilia regulates morphogenesis in different tissues. By leveraging our expertise in ciliary trafficking and hedgehog pathway repression, and by using innovative mouse models, we will study the effect of ciliary signaling in the following contexts. First, we will determine how counterregulatory signaling in cilia regulates renal tubular homeostasis. We hypothesize that Tulp3 cargoes function as cystogenic ciliary signals that are normally inhibited by polycystins. We propose to identify cystogenic drivers in cilia by identifying and perturbing cargoes of Tulp3 in preventing cysts. Second, we will determine the role of ciliary cAMP signaling in neural tube patterning and closure. We hypothesize that hedgehog pathway repression by cAMP-protein kinase A signaling at cilia regulates neural tube closure. We will determine role of adenylyl cyclase and protein kinase A compartmentalization in the cilium-centrosomal complex in regulating hedgehog signaling strength, neural tube patterning, and closure. Third, we will determine how cilia regulated repression of hedgehog pathway affects tissue morphogenesis. We will test ciliary contributions to repression thresholds required for specific morpho-phenotypic outcomes by perturbing ciliary compartmentalization of Gpr161 and adenylyl cyclases. Through this research we will identify the features and consequences distinctive to signaling by cilia in directing tissue emergent properties. Our work is cross-disciplinary and is supported by collaborators with expertise in proteomics, nephrology, neuropathology, human genetics and embryology. Our research will expose new entry points for understanding complex ciliopathy phenotypes and define translational opportunities for treating diseases caused by ciliary dysfunction.

NIH Research Projects · FY 2026 · 2022-05

PROJECT SUMMARY There is an urgent need to fully understand the fundamental mechanisms governing brain development during the early postnatal period, a period that is critical in establishing the correct brain wiring for lifelong behavioral and cognitive functions and a period during which, unsurprisingly, symptoms of many neurodevelopmental disorders (NDDs) start to manifest. The functional maturation of the postnatal brain is highly influenced by neuronal activity, but the mechanisms by which neuronal activity drives synaptic and circuit maturation are poorly understood. It is particularly challenging to gain a whole brain view of the maturation process because, in addition to the tremendous heterogeneity within the neuronal population, activity-dependent maturation is highly variable across the brain, with different regions undergoing maturation at different times and speeds. To meet this challenge, we have developed a genetic tool to capture the neuronal populations as they undergo activity-dependent circuit maturation. With this tool combined with tissue clearing and whole brain volume imaging, we propose to construct, for the first time, a spatiotemporal map of postnatal whole brain circuit maturation. We will also examine the whole brain impact of developmental interventions, paving the way to creating a discovery platform to study NDDs. Finally, taking advantage of our ability to distinguish neurons that have undergone activity-dependent maturation from their less mature counterparts, we propose to uncover molecular mechanisms underlying activity-dependent brain development. Our proposed research will provide much-needed knowledge of postnatal brain development, and ultimately inform the design of future therapeutic interventions to ameliorate symptoms of NDDs.

NIH Research Projects · FY 2026 · 2022-05

Abstract Neuronal systems must adapt to fast and slow changes in the environment. A classic example is the visual system which can adjust to changes in several orders of magnitude in light levels within just seconds. Adaptation has also been observed on a much longer time scale, such as seasonal changes in the light period. In Drosophila, shifts to an extended light period trigger a reduction in the size of rhabdomeres, the light-sensitive organelle of photoreceptors, and a down regulation of their synaptic active zones. We recently discovered that regulation of this structural plasticity depends on the unfolded protein response (UPR). After just one night with continued light exposure, both the IreI and the PERK arm of the UPR are activated. Interference with the normal regulation of the UPR results in the loss of visual neurotransmission and severe structural deterioration of rhabdomeres, the microvillar arrays that house the key elements of the phototransduction cascade. This phenotype was observed for fic and BiP mutants that interfere with the regulation of the activity of BiP, a major regulator of the UPR. Screening for additional elements of this pathway, we identified an unconventional kinase-like protein, called Allnighter, as a candidate. Its sequence predict that this protein may be a kinase acting in the secretory pathway. Preliminary data indicate that, similar to fic and BiP mutants, an extended light period causes allnighter mutants to lose visual neurotransmission and structural integrity of rhabdomeres. This proposal aims to characterize the mechanisms regulating photoreceptor structural plasticity and the specific role of Allnighter in this process. Specifically, we will test how regulation of two key stress pathways, the unfolded proteins response and autophagy, contributes to structural plasticity and the mechanisms by which the Allnighter protein modifies both of these pathways. Completion of these experiments will significantly enhance our understanding of the mechanism that drive structural plasticity of photoreceptors and maintain visual acuity during long-term adaptation.

NIH Research Projects · FY 2025 · 2022-04

PROJECT SUMMARY Driver mutations in genes encoding the metabolic enzyme isocitrate dehydrogenase (IDH) are present in >80% of lower-grade gliomas and the high-grade tumors that arise from them. To identify new therapeutic targets for this incurable disease, our laboratory recently conducted an unbiased drug screen and discovered that IDH oncogenes confer dependence on the de novo pyrimidine nucleotide synthesis pathway for glioma cell survival. Despite our identification of this vulnerability, the molecular mechanism linking IDH mutations and dependence on de novo pyrimidine nucleotide synthesis is unknown. Therefore, I developed a platform to comprehensively profile nitrogen metabolism in patient-derived IDH mutant glioma stem-like cells (GSCs) treated with either vehicle or an inhibitor of mutant IDH, identifying the contribution of glutamine to pyrimidine nucleotides as among the most differentially regulated metabolic networks between these conditions. I subsequently found evidence of disjunction between the two main routes for pyrimidine nucleotide production: de novo synthesis and salvage pathways. Both pathways contribute to synthesis of uridine monophosphate (UMP), the metabolite from which all other pyrimidine nucleotides are derived. My research revealed that although IDH mutant GSCs use both pathways to produce UMP, these cells preferentially use UMP derived from the de novo pathway to synthesize pyrimidine nucleotides downstream of UMP. This phenotype was not observed in human astrocytes, suggesting that it may be tumor specific. I hypothesize that IDH mutant glioma cells are dependent on de novo pyrimidine synthesis because they harbor a novel metabolic enzyme complex that channels UMP from the de novo synthesis pathway to downstream pyrimidines. I will test this hypothesis through three studies. First, I will evaluate whether this pyrimidine synthesis partitioning phenotype is unique to IDH mutant GSCs by performing stable isotope tracing studies across a panel of IDH mutant and IDH wild-type patient-derived GSCs. Second, I will test whether pyrimidine biosynthesis enzymes form a complex in IDH mutant GSCs but not in human astrocytes using immunofluorescence microscopy and immunoprecipitation with Western blotting. Third, I will test the relevance of pyrimidine synthesis pathway disjunction for de novo pyrimidine synthesis inhibitor therapy with in vivo stable isotope tracing. I will perform these experiments in conjunction with treatment with a de novo pyrimidine synthesis inhibitor in a patient-derived orthotopic xenograft model of IDH mutant glioma. The proposed research has the potential to uncover new modes of regulation of nucleotide metabolism and answer vital mechanistic questions surrounding a new synthetic lethality-based treatment strategy that is poised to enter clinical testing in patients with IDH mutant glioma.

NIH Research Projects · FY 2026 · 2022-04

Modified Project Summary/Abstract Section Over half of all new HIV infections in the US in 2017 occurred in 48 high-incidence counties and rural states known as HIV “hotspots”, indicating a need to intensify HIV prevention efforts in these regions. Preexposure prophylaxis (PrEP) can reduce new HIV infections by 99%, but PrEP use is limited in hotspots in the South where HIV incidence is highest. The carceral system is a prime location to engage persons in PrEP, as many people who pass through jails and prisons have risk factors for acquiring HIV. Implementing PrEP in jails, where people at risk are often temporarily detained, can have a high public health impact given rapid turnover back to the community. Because virtually no jails in the South offer PrEP due to resource constraints and competing priorities, there is a critical need for strategies to implement PrEP in this setting. Our central hypothesis is that a rigorously-developed PrEP implementation strategy can improve linkage to community PrEP care for persons released from southern jails. The objective of this proposal is to develop, implement and evaluate a multicomponent PrEP implementation strategy for the Dallas County Jail, the 8th largest jail in the nation and located in an HIV hotspot. We will leverage our robust partnerships with stakeholders in the jail, public health department, and community as we follow a well-established EPIS (exploration, preparation, implementation, sustainment) framework. The implementation strategy will include locally-adapted, evidence-based tools for identifying candidates for PrEP, engaging them in shared decision-making about PrEP, and navigating them to PrEP care at community reentry. We will rigorously evaluate our implementation strategy using a type 3 effectiveness-implementation hybrid study, which prioritizes implementation outcomes while also collecting clinical outcomes. Our specific aims are to: 1) Assess facilitators and impediments to PrEP evaluations in jail and linkage to PrEP at jail release; 2) Refine a multicomponent PrEP implementation strategy for the Dallas County Jail; and 3) Implement and evaluate the PrEP implementation strategy. We will use mixed-methods to evaluate implementation processes (feasibility, acceptability, penetration and sustainment) and clinical outcomes for PrEP evaluations and linkage, and an interrupted time series to measure changes in HIV/STI testing and diagnoses. Our study team includes experts in HIV, PrEP, implementation science, qualitative research, and clinical care for incarcerated populations. This project is significant in its potential to impact HIV incidence in a highly affected population in an HIV hotspot. The work is innovative in using implementation science to improve PrEP for incarcerated populations and is directly responsive to NOT-MH-20-024, “Implementation Science to Advance the United States HIV Prevention and Treatment Goals.” Our strategy is scalable and with guidance from Dissemination Consultants, can serve as a model for future public health initiatives in other carceral settings, directing PrEP in a patient-centered manner to those most likely to benefit in order to maximize impact on HIV incidence.

NIH Research Projects · FY 2026 · 2022-04

PROJECT SUMMARY / ABSTRACT A fundamental function of the nervous system is to determine salience of sensory stimuli in the environment and accordingly regulate attentional response to them. Salience is dynamic. What is salient to an animal changes from moment to moment in accord with its experience and current physiological need. A prime example observed widely across species is the salience of food-associated stimuli. These stimuli are salient for food-deprived animals and therefore demand their attention. By contrast, food-associated stimuli lose their salience when animals become satiated. This indicates that neural circuits that control attentional behavior integrates the information of hunger and satiety. Appropriately determining salience based on current need and thereby regulating attention is essential for survival and its dysregulation is associated with neuropsychiatric disorders. However, it is not known what neural circuits mediate attentional behavior and how these circuits integrate internal information of hunger and satiety. Here we propose to use Drosophila as a model to dissect neural circuits that control attentional behavior to food-associated olfactory stimuli in accord with hunger and satiety. We employ a multidisciplinary approach that combines a novel behavioral assay, a novel bidirectional neural activity reporter, genetic and optogenetic manipulations, and in vivo recording of neural activity to test our hypothesis that a dopamine-modulated olfactory center, the mushroom body, plays a key role in appropriately computing salience of food-associated odors based on current hunger state. In Aim 1, we will establish that the salience of food odor is modulated by hunger state and will determine the role of mushroom body in generating attentional response to olfactory stimuli. In Aim 2, we will identify hunger-sensitive dopamine neurons, whose activity is modulated by signals reflecting hunger and satiety. In Aim 3, we will identify mushroom body output that integrates information of food odors and hunger state to drive attentional behavior. Together, our studies will reveal the neural mechanisms that regulate attentional behavior in response to food-associated odors in accord with hunger state. The functional organization of the Drosophila mushroom body exhibits remarkable similarity to that of the mammalian striatum and its dopamine input, and the dopamine circuits in mammals have long been implicated in computation of salience. Therefore, we expect that our project will contribute to providing an understanding of the operational principles of neural circuits that mediate salience determination.

NIH Research Projects · FY 2026 · 2022-04

Project Summary/Abstract Inorganic phosphate (Pi) is used in excess as a preservative and flavor enhancement in processed foods. Accordingly, 25% US adult consume Pi at 3-4 fold higher than the recommended daily allowance on a regular basis. While the impact of dietary Pi excess in the setting of chronic kidney disease has been well- studied, its impact on human health in the general population remains incompletely understood. Our recent study in mice demonstrated that dietary Pi loading that mimic the level of US adult consumption leads to reduced spontaneous locomotor activity, exercise capacity, and reduced resting metabolic rate when in normal mice by impairing skeletal muscle mitochondrial function and fat oxidation. These metabolic changes were related to downregulation of numerous genes involved in fatty acid release, transport, and oxidation. Furthermore, our pilot study from the third examination of the Dallas Heart Study (DHS-3) provided support for the animal data as a robust association between higher dietary Pi intake and lower in vivo mitochondrial function using 7-Tesla 31P magnetic resonance spectroscopy and oxygen uptake during exercise was observed. More importantly, an association between higher dietary Pi intake and markers of insulin resistance, including higher liver and muscle fat content was uncovered. Therefore, we propose an ancillary study to the already funded 3rd examination of the DHS to test the impact of dietary Pi excess on physical activity and cardiorespiratory fitness. We will also conduct a randomized crossover study to determine if this phosphotoxicity on the muscle mitochondrial function and exercise capacity is restored by lowering dietary Pi content, which is independent of total energy intake and other nutritional components. The proposed translational studies in otherwise healthy humans have the potential to shift current clinical practice paradigms by identifying phosphate as a key modifiable cardiometabolic risk factor in the general population.

NIH Research Projects · FY 2026 · 2022-04

Summary The balance between inhibitory and excitatory neurons is established early in development in a process dominated by the interplay between the transcriptional activator PTF1A and the repressor PRDM13 in multiple regions of the nervous system. Initial cell fate decisions that ultimately give rise to inhibitory neurons in the dorsal spinal cord, cerebellum, and retina depend on the early activity of these fate-specifying transcription factors (TFs). PTF1A, like other early- acting basic helix-loop-helix (bHLH) factors, acts as a `master regulator' by triggering downstream genetic cascades. Such TFs have profound effects by restricting progenitor developmental potential long before the appearance of mature neurons. In the absence of PTF1A, neural progenitors fail to generate inhibitory neurons and aberrantly assume an excitatory neuronal fate. Thus, the spatial and temporal control of PTF1A expression controls the formation of the inhibitory/excitatory balance in multiple neuronal circuits. In Aim 1 we will examine the in vivo requirement for a dorsal neural tube specific enhancer for Ptf1a at the molecular, cellular, and behavioral levels. PRDM13, a transcriptional repressor and a direct target of PTF1A, ensures correct specification of dorsal spinal cord inhibitory neurons by repressing genes essential for specifying the alternative excitatory neuronal fates. Because PRDM factors can have methyltransferase activity and/or can recruit other chromatin modifying enzymes, and PRDM13 may bind to bHLH TFs, PRDM13 may provide a molecular link between these factors and accompanying changes in the epigenetic landscape during neuronal subtype- specification. Indeed, PRDM13 binds many similar genomic sites as PTF1A and another bHLH factor ASCL1. In Aims 2 and 3, we will probe PRDM13 functions in the developing nervous system, and test the hypothesis that PRDM13 is recruited to bHLH bound sites to facilitate repressive chromatin modifications to repress transcription through these sites.

NIH Research Projects · FY 2026 · 2022-03

Project Summary Enteroviruses A, B, C, D are important pathogens that can cause a range of diseases including myocarditis, encephalitis, meningitis, conjunctivitis, hand, foot and mouth disease, and acute flaccid myelitis. Disease outcomes can be severe or fatal, particularly in neonates and children. The host innate immune response generally controls these viruses. However, the cell intrinsic antiviral mechanisms that mediate this host defense are not well defined. Here, we propose to identify and characterize host antiviral genes encoding both constitutively expressed (non-inducible) and interferon-stimulated gene (ISG) antiviral effectors. In Aim1, we will examine TRIM7, a constitutively expressed E3 ligase that we recently showed inhibits enterovirus replication by targeting a viral protein for degradation. We hypothesize that TRIM7 is a pan- enterovirus restriction factor in vitro and in vivo. In Aim 2, we will leverage our expertise in ISG screening technology to test the hypothesis that only a limited set of genes are true effectors of the interferon-induced antiviral response to enteroviruses A-D. We will characterize antiviral effector mechanisms of action, and we will use novel lipid nanoparticle gene delivery strategies to demonstrate antiviral efficacy in vivo. Both Aims will be achieved by a combination of biochemical, virological, and genetic approaches in cell-based assays and in mouse models of enterovirus infection and pathogenesis. Completion of the proposed aims will provide fundamental knowledge about the specific molecules that confer cell intrinsic protection against these enteroviruses. These studies may additionally inform the development of pan-enterovirus therapies based on the mechanisms of these naturally occurring antiviral defense proteins.

NIH Research Projects · FY 2026 · 2022-03

Extracorporeal Membrane Oxygenation (ECMO) is a form of cardiopulmonary bypass which provides days to weeks of life-saving support to critically ill children and adults whose illness is progressing despite maximal conventional therapies. Use of ECMO is expanding rapidly and it has supported >71,000 children worldwide. Advances in ECMO have allowed more children to survive an otherwise fatal illness, however neurological injury reduces survival by 50-60% and leads to significant long-term neurologic morbidity. Only half of ECMO survivors have normal neurobehavioral outcomes. The underlying disease and ECMO may both disrupt cerebral autoregulatory mechanisms and cause neuroinflammation, which may also disrupt autoregulation. Disrupted cerebral autoregulation predisposes the brain to hemorrhagic or ischemic injury via excessive or inadequate perfusion, yet it is not monitored during ECMO. Current clinical tools do not predict neurological injury, greatly inhibiting the development of neuroprotective protocols. Specifically, there is no monitor to continuously assess the state of cerebral autoregulation, forcing clinicians to rely on imperfect systemic surrogates that may not reflect risks of impending neurological injury. The long-term goal of this research is to develop continuous non-invasive bedside monitors for critically ill patients. The primary goals of this proposal are to (1) test the hypothesis that continuous point-of-care optical monitoring of cerebral autoregulation can predict neurologic injury after the first 48 hours of ECMO and (2) demonstrate that optically measured indices of cerebral autoregulation are associated with neuroinflammatory biomarkers in serial blood samples throughout ECMO. A pilot study led by the Pl has demonstrated the feasibility of using advanced non-invasive optical monitors to assess cerebral autoregulation and cerebral perfusion in pediatric ECMO patients. Our ongoing pilot study has shown disrupted autoregulation indices correlate with neurological injury found on post-ECMO imaging. This proposal will utilize diffuse optics to longitudinally monitor cerebral autoregulation and inflammation throughout ECMO in a large pediatric population (0-18 y.o., n=125). In Aim 1, we will demonstrate that alterations in optical metrics of cerebral autoregulation during ECMO predict neurological injury found on intra-ECMO CT. In Aim 2, we will demonstrate that optical metrics of cerebral autoregulation measure the temporal course of neuroinflammation, as evidenced by biomarkers in lab-based blood assays. If successful, the work of this interdisciplinary team of physical scientists, clinicians, and neuroscientists will establish the value of continuous quantitative optical monitoring of cerebral autoregulation to prospectively identify periods of high risk of injury during ECMO. These results will enable the development of brain-focused cardio-pulmonary bypass protocols (e.g., blood pressure titration) to reduce the rate of neurologic injury and associated mortality and morbidity in ECMO patients.

NIH Research Projects · FY 2026 · 2022-03

PROJECT SUMMARY Recently, the development of MR-LINACs has made high-quality online adaptative radiotherapy a clinical reality to account for the daily anatomical variations to preserve the treatment quality. MR-LINACs, combining modern radiotherapy linear accelerators (LINACs) with on-board magnetic resonance imaging (MRI), offer excellent soft-tissue contrast to allow accurate organ and tumor segmentation to precisely capture the daily anatomical changes of each patient. Coupled with advanced adaptive treatment planning systems, MR-LINAC is the ideal platform for online adaptive radiotherapy and will bring cancer radiotherapy to a new level of precision and personalization. However, this new format of radiotherapy also comes with new challenges for patient safety and plan quality checks that cannot be satisfactorily addressed with traditional quality assurance (QA) tools: 1) With the patient lying on the treatment couch waiting for the treatment to start, there is mounting pressure on the team to move through the workflow as fast as possible, which may increase the likelihood of making mistakes and thus an effective QA procedure is even more important. 2) Each adapted plan warrants a new QA process, adding substantial burdens to an already extremely time-constrained process. A QA process with high efficiency is needed. 3) Conventional QA procedures are quite complex, involving inputs from many stakeholders, and thus are human-power demanding and error-prone. An automatic QA procedure requiring minimal human interventions and communications is highly desired. 4) In addition to checking the quality of the adapted segmentation and treatment plan, it is also crucial for a QA procedure to ensure their consistency with the physician’s intentions/preferences in the original plan. 5) A QA tool that is able to predict the plan deliverability prior to treatments, without actually irradiating the patients, is needed for online adaptive radiotherapy. The overarching goal of this project is to develop an Artificial Intelligence (AI)-based QA system to address these urgent unmet clinical needs for MR-LINAC online adaptive radiotherapy, with four main components to: 1) intelligently assess the quality of the adapted target and organ-at-risk segmentations and their consistency with those in the original plan; 2) intelligently assess the quality of the adapted plan and its consistency with the original plan; 3) efficiently perform 2nd dose check with an AI-based near real-time independent dose engine; and 4) predict the measurement-based QA results of plan deliverability using prior knowledge and new adapted plan information. We have two Specific Aims: 1) System development, including data acquisition for AI model training, and development of four AI models; and 2) System translation and validation at multiple institutions, including developing transfer learning algorithm and package for automated model commissioning; and translation, fine-tuning and evaluation of the developed AI systems. The successful conduct of the proposed project will result in the first intelligent, efficient, reliable, and independent QA system to facilitate unleashing the full potential of MR-LINAC online adaptive radiotherapy to advance cancer care.

NIH Research Projects · FY 2026 · 2022-03

PROJECT SUMMARY - We began to quantify household- and community-level interactions in 2019 with our project, “Comprehensive Profiling of Social Mixing Patterns in Resource Poor Countries” (“GlobalMix”, grant R01 HD097175-01) to investigate human-to-human interactions relevant for respiratory infection transmission. This proposal will build on existing GlobalMix study infrastructure to estimate LMIC-specific epidemiologic parameters for COVID-19. In the proposed study, we will connect field epidemiology and mathematical modeling approaches by estimating the rate of, and heterogeneity in, household-based transmission of SARS- CoV-2 through longitudinal cohort approaches. We will use this information in conjunction with highly-granular data on social interactions from GlobalMix to identify key epidemiological parameters for COVID-19, including the community-level force of infection and attack rates within households. We will then use this information to build LMIC-specific dynamic models, to evaluate the impact of key interventions to reduce transmission: vaccination and non-pharmaceutical interventions such as face masks, shelter-in-place policies and school closure. This work will be completed in three specific aims: Aim 1: Quantify COVID-19 transmission across contact networks within the household environment. We will conduct longitudinal respiratory disease surveillance in households participating in the GlobalMix study. We will collect longitudinal samples of respiratory specimens from household members for identification of COVID-19 and other respiratory pathogens such as influenza. This information will be overlaid on contact network data from GlobalMix. Aim 2: Estimate key epidemiological features of SARS-CoV-2 and other respiratory pathogens in LMIC settings. We will collect blood specimens from GlobalMix study participants and test for antibody levels (IgG) against SARS-CoV-2. We will calculate age-specific infection fatality rates (IFRs) and use antibody titers to infer time of infection and calculate community-level incidence over time. We will generate age-structured seroprevalence curves, which will provide a robust measure of exposure across the age range. Together with the contact data from GlobalMix, we will infer age-specific transmission probabilities that will be used as inputs into the network models in Aim 3. Samples will be stored for future testing, including antibody avidity and T/B cell activation. Aim 3. Estimate the impact of control measures on COVID-19 in LMIC. We will use the epidemiological parameters estimated in Aim 1 and the setting- and age-specific force of infection estimates from Aim 2 to parameterize dynamic network-based mathematical models of disease transmission. Models will incorporate social mixing data from GlobalMix to project the impact of extended shelter-in-place policies, policies concerning the use of face masks, and the introduction of a SARS-CoV-2 vaccine.

NIH Research Projects · FY 2025 · 2022-03

PROJECT SUMMARY Preventing kidney stone progression remains a serious obstacle in public health, despite advances unravelling the underlying mechanisms of stone formation. Kidney stone disease, often along with excruciating pain, is highly prevalent around the globe, affecting nearly 12% of the world population. In the United States, the estimated lifetime prevalence of kidney stone disease is approximately 10.6% in men and 7.1% in women. Following their initial episode, stone formers are at higher risk for recurrent stone formation, with more than 50% experiencing a recurrence within 10 years, reflecting the inadequacies of current prevention regimens. In addition, the formation of stone disease is strongly associated with long-term complications of chronic kidney disease and end-stage renal disease, along with significant morbidity, mortality as well as burden of health care cost. In response to PA-20-185, the overarching goal of this proposal is to maximize the efficacy of preventive strategies against kidney stone disease progression by developing clinical prediction tools as well as computational algorithms and software. More specifically, we propose novel evidence-accumulation-driven methods (1) to develop patient-level risk prediction models for kidney stone disease progression accounting for subtypes of stone conditions; and (2) to identify modifiable risk factors for stone disease progression by integrating historically existing prediction models into new EHR or registry datasets. We will apply and validate the proposed methods to real-world data, including the UTSW Mineral Metabolism Stone Registry, the PUSH trial conducting by the Urinary Stone Disease Research Network (which is a clinical research network funded by NIDDK), and the Swiss Kidney Stone Cohort. The success of this project will fill the knowledge gap of kidney stone disease progression, and lead to a predictive toolbox to inform clinicians on the risk of kidney stone progression, thereby facilitating timely clinical decision-making and implementation of targeted strategies to prevent or reduce stone disease progression.

NIH Research Projects · FY 2026 · 2022-03

Modified Abstract Section ABSTRACT Type 2 diabetes (T2D) screening remains suboptimal in spite of well-recognized, national screening guidelines. In the US, 7.3 million adults with T2D and 74.5 with prediabetes (PDM) remain undiagnosed. In spite of opportunistic screening in clinical practice, nearly one-third of primary care patients have undiagnosed dysglycemia (PDM + T2D). To close screening gaps, new strategies are needed. We adapt evidence-based approaches from cancer screening to conceptualize T2D screening as a multi-step process (risk assessment, screening invitation, test ordering, and test completion) requiring coordination across patient, provider, and health system interfaces. We previously developed the Parkland Dysglycemia Detection Program (PDDP) – an EHR-based, multicomponent population health T2D screening intervention that automates risk assessment, bulk orders screening tests, and facilitates bulk patient outreach via screening invitations. The PDDP closes multiple gaps in the screening process and supplements opportunistic screening in clinical practice. In our PDDP pilot study, a single, generic ‘overdue for screening’ invitation had a 41% response rate vs. 13% in usual care alone. Of those completing screening, 37% had PDM and 5% had T2D, representing cases ‘missed’ by opportunistic screening alone. Although the PDDP helped close overall screening gaps and detected cases of undiagnosed dysglycemia, response rates to generic invitations were similar across racial/ethnic subgroups (Hispanics 42%; NH Blacks 41%; NH whites 39%) and those with known PDM vs. unknown glycemic status (38% vs. 41%). To address known screening and outcome differences in racial/ethnic minorities and those with PDM, improved screening is needed. In this proposal, we seek to improve the PDDP response in racial/ethnic minorities and those with known PDM to close screening gaps. To accomplish this, we will develop Targeted (by race/ethnicity), Tailored (by known PDM vs. unknown glycemic state) (TT) screening invitations (Aim 1) to increase engagement of high risk subgroups. We will then conduct a 3-arm split-cluster RCT (Aim 2) to evaluate the efficacy of PDDP-delivered TT screening outreach + navigation of non-responders vs. PDDP-delivered generic invitations to improve screening completion in high risk patients and evaluate the effectiveness of the TT PDDP and Generic PDDP to improve screening completion vs. usual care, opportunistic screening. Lastly, we will conduct cost-effectiveness analyses (Aim 3) to compare direct costs and the cost per patient screened and case found across the three study arms. Together, these findings will provide actionable evidence on clinical and cost-effective ways to close screening gaps in high-risk patients. Because the PDDP is highly automated and scalable using a common EHR, our findings can be practically implemented in most health systems. Our findings will have important implications for clinics and health systems seeking to close T2D screening gaps and decrease screening differences through scalable, population-health T2D screening strategies to supplement opportunistic screening in usual care.