Baylor College Of Medicine

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY / ABSTRACT Atrial fibrillation (AF) contributes to at least 175,000 deaths per year in the US alone, and is a leading cause of stroke. AF is expected to affect twelve million people in the U.S. by 2030. Atrial fibrosis is a key disease feature linked to increased morbidity and mortality in patients with AF. Fibrosis (especially interstitial) creates a substrate for atrial re-entrant arrhythmias and is associated with therapy resistance. Dysfunction of atrial cardiofibroblasts (ACFs) that secrete excessive collagen into the extracellular matrix (ECM) is one of the important mechanisms leading to fibrosis. Our recent studies revealed that calcitonin (CT), a paracrine signaling molecule released by atrial cardiomyocytes (ACMs), suppresses collagen and other profibrotic ECM proteins production by ACFs. The long-term goal of this project is to dissect the molecular and cellular basis of the CT signaling pathway in relation to atrial fibrogenesis in AF in order to uncover new targets for future therapies in AF. The central project hypothesis is that reduced CT production by ACMs, miR-31-dependent downregulation of CT-receptor (CTR) expression, and activated BMP1 signaling downstream of the CTR promote atrial remodeling, fibrogenesis and AF progression. Two Specific Aims will be pursued: Aim 1) Determine whether miR-31-5p, via reduced CTR expression, drives atrial profibrotic remodeling and AF development, and Aim 2) Define the role of BMP1 and MGP in the CT/CTR signaling pathway in AF. This project is supported by a large amount of preliminary data that support the central hypothesis. The proposed studies will be performed in freshly isolated and cultured ACFs obtained from the right and left atria of patients with persistent AF (vs controls in sinus rhythm, or, in some cases, with paroxysmal AF), and from various genetic mouse models of spontaneous AF. Numerous new reagents and innovative multi-disciplinary approaches will be used to dissect the molecular basis of ACF phenotype changes and profibrotic remodeling driven by changes in the CT-CTR-BMP1 signaling axis. Impact: These studies are expected to underpin how suppressed CT/CTR signaling contributes to atrial fibrosis and arrhythmia development, and to serve as a platform for the validation of novel treatment modalities (up- and down-stream of CT/CTR axis) aimed at preventing atrial fibrogenesis and ameliorating AF development.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT – OVERALL Organic acidemias are a group of life-threatening disorders of intermediary amino acid metabolism. Initial signs and symptoms of the disorders include lethargy, poor feeding, seizures, and coma in the neonatal period. Life- threatening metabolic perturbations that occur during acute decompensation events may include metabolic acidosis, hyperammonemia, and hypoglycemia. For nearly 20 years, these disorders have been included on the Recommended Uniform Screening Panel (RUSP) for newborn screening, which has facilitated diagnoses and introduction of therapy. Prompt diagnosis and therapy have increased survival and consequently, uncovered long-term consequences of organic acidemias that include renal failure, cardiomyopathy, feeding and gastrointestinal pathologies, and neurological complications. However, the impact of these long-term complications is unclear, and the options for therapy for this cohort of individuals are limited. The emergence of the initial newborn-screened cohort of individuals with organic acidemias into adulthood highlights the significant unmet need for improved characterization of the natural history of these disorders and for clinical trial readiness as newer therapies are investigated. In response to this unmet need, we propose to establish a Rare Organic Acidemias Research (ROAR) Consortium as part of the Rare Diseases Clinical Research Network (RDCRN). The ROAR Consortium will be a collaborative network with the coordinating site in Houston, TX (Baylor College of Medicine/Texas Children’s Hospital) and consortium sites in Washington, D.C. (Children’s National Medical Center), Pittsburgh, PA (University of Pittsburgh), Minneapolis, MN (University of Minnesota), and Denver, CO (University of Colorado). Two patient advocacy groups, the Organic Acidemias Association (OAA) and Propionic Acidemia Foundation (PAF), will join the ROAR consortium as active members to provide input from the organic acidemia community, including patients and families. In addition, the consortium will collaborate with the intramural program at the National Human Genome Research Institute, which has longstanding clinical research experience in organic acidemias. In the initial cycle, this collaborative research network will work together to advance understanding of the natural history of the disorders and to lay the groundwork for future clinical trials of new therapeutic approaches for these disorders. We will accomplish this goal with the following aims: 1) To perform collaborative, multi-site, clinical and translational research in organic acidemias that will prioritize patient/community concerns, enhance knowledge, improve care, and advance clinical trial readiness, 2) To train and attract a cohort of investigators in organic acidemias research, 3) To serve as a hub for the development of innovative new strategies for managing and treating organic acidemias, and 4) To collaborate with two patient advocacy groups, the RDCRN Data Management and Coordinating Center, and other RDCRN consortia to advance care and educate patients, families, and healthcare providers across a broad spectrum of rare diseases.

NIH Research Projects · FY 2025 · 2025-09

(PLEASE KEEP IN WORD, DO NOT PDF) Hematopoietic stem cells (HSCs) must continually adapt to a range of environmental and physiological stressors that challenge protein homeostasis. While genetic and transcriptional regulation of HSC function has been extensively studied, there is little quantitative understanding of how proteostatic stress influences fate decisions in these cells. This project addresses that gap by integrating controlled perturbations of protein quality control pathways with state-of-the-art phenotypic, transcriptomic, and proteomic analyses. Preliminary work demonstrates that physiologic stressors—such as fever-range hyperthermia and altered oxygen tension—combined with targeted modulation of chaperones, proteasome activity, autophagy, and mitochondrial proteostasis, elicit reproducible and measurable shifts in HSC state. Aim 1 will systematically map how discrete proteostatic and metabolic stressors remodel high-quality murine HSC populations maintained in defined ex vivo culture conditions. By titrating the intensity of specific perturbations and environmental parameters, this aim will generate a dose-resolved atlas linking proteome remodeling to preservation or loss of stemness. Aim 2 will extend these assays to primary human CD34⁺ stem and progenitor cells to identify conserved stress-response programs that stabilize an HSC-like compartment. Cross-species analysis will define a core set of actionable proteostatic modules that predict favorable versus adverse fate trajectories. This research is significant because it will produce the first integrated, quantitative map of proteostatic stress–driven state transitions in HSCs. By treating proteostasis, oxygen, and temperature as orthogonal, tunable levers, the project offers an innovative framework for dissecting how environmental and intrinsic cues jointly shape stem cell fate. The resulting insights will not only inform strategies for optimizing ex vivo HSC maintenance, but also provide a foundation for translational approaches to preserve stem cell function in the context of physiological stress.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Urinary tract infections (UTIs) exhibit one of the most significant sex disparities among infectious diseases with UTIs in women being 20-40 times more likely than in men. In addition, 25-50% of elderly women suffer from recurrent UTIs (rUTIs) despite taking antibiotics, and over 25% of all elderly women experience persistent inflammation and lower urinary tract conditions such as overactive bladder/urge incontinence and interstitial cystitis/bladder pain syndrome. Given the strong association between bladder diseases and aging, and the fact that chronic bladder inflammation is highly prevalent in older women, age-associated immune disruption (so- called inflamm-aging) in the bladder likely mediates rUTI susceptibility. With 566 million people ≥65 years old worldwide and estimates of nearly 1.5 billion by 2050, there is a growing need to define the interactions between aging, chronic inflammation, and susceptibility to UTIs/rUTIs so that better treatments and prevention of these diseases will be possible. The hypothesis of this project is that the culprit behind many rUTI cases and lower urinary tract symptoms is a chronic inflammatory process characterized by organized lymphocytic aggregates in the bladder submucosa, termed bladder tertiary lymphoid tissue (BTLT). These are analogous to lymphocytic infiltrates in women presenting as cystitis cystica (CC) by cystoscopy. We have demonstrated that BTLT/CC are predominantly in women and female mice and are sites of antigen presentation, germinal center formation, and antibody production, and form in an age-dependent and sex-dependent manner. Despite this understanding, the mechanisms driving BTLT formation, maintenance, impact on rUTIs, and sex dependence are unknown. Using a mouse model of aging and chronic bladder infection and inflammation that closely parallels the clinical presentation of post-menopausal women with UTIs, we will elucidate the underlying immune and hormonal drivers that cause frequent recurrent UTIs and heightened lower urinary tract symptoms in a sex-dependent manner. Specifically, we will define the molecular drivers (Aim 1) and investigate the role of CXCL13, TNFα, and FCRL5 in BTLT initiation, maintenance, and structure will be investigated through targeted interventions in aged mice; Explore the role of BTLT in immune responses during UTI by depleting B cells and profiling B cell receptor repertoires, identifying clonotypes involved in UTI defense. (Aim 2); determine the cause-and-effect association between BTLT/CC and rUTIs; and define the influence of sex and estrogen on BTLT formation (Aim 3). This new concept of the interplay between aging, sex, infection, and local immune responses within the bladder generates many new important questions for the field. By elucidating the mechanisms, mediators, and triggers that drive BTLT formation, taking into consideration sex differences, this work will provide important insights into mucosal immunity in the aging bladder. Additionally, this work will establish the foundation for future development of biomarkers of functional immune system changes in older individuals to guide treatment strategies aimed at improving infection and inflammation outcomes.

NIH Research Projects · FY 2025 · 2025-09

– OVERALL The Houston – Nutrition and Obesity Research Center (H-NORC), sponsored by Baylor College of Medicine and The University of Texas Health Science Center at Houston, in the Texas Medical Center, the world's largest medical complex, will address a significant need for both Houston and the Gulf region of Texas. Texas is among the top ten states in the U.S. with the highest obesity rates, and the greater Houston metropolitan area has the highest obesity rate within the state. The primary objective of H-NORC is to foster new discoveries and scientific progress by supporting groundbreaking basic, translational, and clinical research in nutrition and obesity with the ultimate goal of enhancing public health. To serve these purposes, we will establish three Biomedical Research Cores that address crucial aspects of nutrition and obesity research, boost research efficiency, and encourage innovation: 1) Clinical and Translational Obesity Research Core; 2) Cellular and Molecular Metabolism Core; and 3) Neuroendocrine Core. These objectives will be pursued by a strong research base of highly collaborative H-NORC members (72 members with qualifying funding related to nutrition/obesity research with total Direct Costs of $31,329,400) operating within our three thematic areas: 1) Pediatric and Adult Obesity, Pathophysiology, and Therapy; 2) Nutrient Metabolism in Health and Disease; and 3) Brain Control of Feeding Behavior and Metabolism. The Administrative Core will provide oversight and guidance, monitor progress, and promote the growth of the Research Cores and H-NORC Programs. Additionally, two programs will enrich our research environment. The existing Pilot and Feasibility Program will continue to support new investigators beginning research careers in nutrition and obesity. The Enrichment Program will foster an educational and academic environment conducive to innovative research in nutrition and obesity. To further develop research capacity, we will involve investigators from both within and outside the fields of nutrition and obesity research in the H-NORC. Furthermore, to advance H-NORC's goals and mission, we will leverage academic and research partnerships within the greater Houston area, encompassing organizations both inside and outside the Texas Medical Center. H-NORC leaders comprise physicians, scientists, and administrators experienced in directing interactive, multidisciplinary programs and have a well- defined succession plan along with a comprehensive mentoring and development plan. We have obtained substantial organizational support and resources, will establish new cores, and leverage shared resources from existing NIH-funded centers, T32 programs, and other entities to create a robust, efficient, and integrated Nutrition and Obesity Research Center from Houston area organizations.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Epithelial cells of the intestine perform metabolic reactions to sustain energy requirements for supporting gut peptide secretion from hormone-producing enteroendocrine cells, carbohydrate and amino acid absorption by enterocytes, lipid synthesis and storage, and cell turnover. Acetate, a precursor to acetyl-CoA, is an essential intermediate metabolite driving vital cellular processes, including the TCA cycle and de novo lipogenesis. Acetate can be generated from N-acetylaspartate (NAA), an essential brain metabolite for myelin lipids. The only enzyme capable of cleaving NAA is aspartoacylase (ASPA), which generates acetate and aspartate. Although the importance of NAA breakdown and ASPA is known in the brain, its function in other tissues is unknown. I found that Aspa is highly expressed in the mid-villus enterocytes in the small intestine. I also demonstrated that inducible whole-body knockout of Aspa in mice increases insulinotropic hormones after glucose administration and that their ileum tissue harbors less aspartic acid. These observations, coupled with other literature, suggest that ASPA expression contributes to the endocrine functions of the intestine and furnishes metabolites derived from NAA within absorptive enterocytes. The goal of this proposal is to identify the fate of NAA-derived acetate and aspartate in cells of the small intestine by understanding how altered ASPA expression affects hormone secretion, enterocyte carbohydrate and lipid absorption, and cell turnover. To pursue this goal and to enhance my training in intestine biology and metabolism, I designed two Aims. In Aim 1, I will define how Aspa deficiency impacts gut hormones and nutrient metabolism using an intestine-specific Aspa knockout mouse model. In Aim 2, I will use intestine organoids to define how NAA hydrolysis contributes to intracellular pools of acetate and aspartate. Completing this project will identify the novel function of ASPA and NAA in the intestine, identifying insights into potential new cellular and metabolic functions of enterocytes and energy-carrying metabolites, which are potential contributors to metabolic dysfunctions in digestive diseases.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT End-Stage Kidney Disease (ESKD) in children is a challenging medical condition affecting growth, development, and quality of life. Nearly 10,000 children in the US rely on dialysis or kidney transplants. ESKD patients face a restrictive diet, impacting nutrition and overall health. Nutritional inadequacy in ESKD affects electrolyte balance, fluid status, blood pressure, and growth, especially in children. Medically tailored meals (MTMs) are a potential solution, delivered directly to homes or through dietitian-led culinary medicine (CM) education for caregivers. Balancing convenience and education poses feasibility challenges for both approaches. The Texas Children’s Hospital (TCH) serves a majority of urban, Hispanic, and African American pediatric ESKD patients. A proof-of-concept trial at TCH aims to compare CM-based MTMs and pre-prepared MTMs for ESKD pediatric patients. The trial involves 30 parent-child dyads, with data collected through Electronic Medical Records, surveys, and food recalls. Specific aims include: Aim 1 - Conduct formative research with key stakeholders (parents/caregivers [henceforth referred to as parents] of ESKD pediatric patients, dietitians, social workers, pediatric nephrologists) to obtain perspectives on managing ESKD specific dietary needs, pre-prepared MTMs, integrating CM with nutrition education and culturally-appropriate implementation strategies; and Aim 2 - Assess feasibility, acceptability, and preliminary impact with parent/child dyads (n=30). Hypotheses focus on the feasibility and acceptability of both interventions, with secondary hypotheses exploring the impact on parents’ behaviors and children’s diet quality. Exploratory hypotheses examine metabolic profiles. The study also aims to determine the budget impact of both interventions. The study aligns with PAS-20-86 Small R01s for Clinical Trials, addressing NIDDK's mission to gather preliminary data on feasibility, effectiveness, and cost-effectiveness of MTM approaches for ESKD pediatric patients. The significance of the study lies in its potential effectiveness, scalability, and sustainability for larger trials.

NIH Research Projects · FY 2025 · 2025-09

Abstract: Congenital Heart Disease (CHD) is the most common and life-threatening birth defect, caused by pathogenic variants in over 400 genes, with hundreds of thousands of Americans affected. Despite up to 90% of cases thought to be due to genetic variants, currently only <30% cases are resolved. Genetic diagnosis is critical, as it modifies prognosis, management, medical and surgical therapy, and future family planning. A large array of data relevant for genetic diagnosis is typically available due to near universal use of DICOM image formatting for echocardiography, standardized classification language for CHD, wide electronic medical record (EMR) adoption, and whole genome sequencing. However, only a fraction of these data are currently being used effectively. The search for pathogenic variants is currently manual, making it hard to harness valuable information from previously resolved cases. Interpretation of the genome is limited to only the ~1% that codes for protein. To address these gaps, we will develop a multimodal AI module that harnesses information from related cases to prioritize genes likely to harbor pathogenic variants and a variant identification module to identify likely causative variants from whole genome sequencing data. The gene prioritization and variant identification modules will be co-designed with input from stakeholders, integrated into an automated process, and validated while addressing key ethical considerations. By completing this project, we will harness previously untapped information to automate genetic diagnosis in CHD, thus enhancing patient outcomes, advancing understanding of CHD, and paving the path toward wider clinical and genetic applications of multimodal AI.

NIH Research Projects · FY 2025 · 2025-09

Project Abstract Effective communication requires understanding both the meaning of spoken words (semantics) and the identity of the speaker. This integration of semantics and speaker identity is vital for social interactions, yet the neural mechanisms supporting this process are not fully understood. This project investigates how the anterior cingulate cortex (ACC), a region involved with both language and social cognition, contributes to the integration of semantic content and speaker identity during natural conversations and speech comprehension. We propose that the ACC encodes semantics and speaker identity using distinct but related neural population subspaces, allowing efficient generalization across different speakers while maintaining specificity. To test this hypothesis, we will record single-neuron activity in the ACC of patients with epilepsy during both passive listening to podcast stories and active participation in natural conversations. Our specific aims are to delineate how ACC neurons respond to different semantic categories and speakers (Aim 1) and to determine how neural populations align these semantic representations across different speakers using neural subspace analysis (Aim 2). Our findings will have important implications for basic science research and understanding of communication disorders. This study will provide new insights into the neural coding of language and social information, improving the development of assistive communication technologies and neural prosthetics aimed at individuals with language impairments, such as those with autism or aphasia. Collectively, this proposal aims to elucidate single neuron dynamics in real-life communication and will provide me with the skills needed to continue social communication and language neuroscience research as a principal investigator.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY / ABSTRACT Postoperative atrial fibrillation (poAF) is a common complication of cardiothoracic surgery with an incidence between 10 and 50%, which typically peaks on day 2-3 following surgery. Moreover, poAF is associated with an 8-fold higher risk of recurrent AF (recAF) after hospitalization. While there is evidence that inflammatory mediators play a central role in the pathogenesis of poAF, there remains a fundamental gap in our understanding of the molecular drivers of this condition. Our pilot data reveal increased levels of infiltrating macrophages (Ms) and proinflammatory cytokines such as interleukin-6 (IL-6) and M migration inhibitory factor (MIF) in the pericardial fluid of patients who develop poAF vs those who remain in SR. Our preliminary studies reveal that the pericardial fluid from poAF patients alters gene expression in atrial cardiomyocytes (ACMs) and induces a profibrotic phenotype in cultured fibroblasts. Our lab has developed a novel mouse model of poAF that mimics key aspects of this condition in humans, including spontaneous episodes of AF around postoperative days (POD) 2-4. Single cell RNA sequencing (scRNAseq) of non-myocytes from mice with and without poAF after thoracotomy identified Ms as the most altered cell type in the atria of poAF mice. Bioinformatics analysis suggests that C-C chemokine receptor 2 (CCR2) is important for monocyte mobilization out of the bone marrow and recruitment of Ms into the damaged atria after surgery. Our data also suggest that the cytokine MIF plays a role in arresting Ms in the atria. Finally, our pilot data suggest that the inflammatory response during the early post-operative days accelerates atrial substrate development as pseudotime trajectory analysis of scRNAseq data revealed IL-6 and MIF among the top altered genes involved in M-atrial cardiofibroblast signaling. IL-6 was shown to upregulate miR-31, which in turn suppresses the expression of the calcitonin receptor (CTR), which we recently linked to profibrotic remodeling. Elevated levels of miR-31 suppress Calcr (CTR gene) expression, while selective disruption of miR-31-binding to Calcr mRNA in mice reduced fibrosis and AF burden. We hypothesize that infiltrating M release proinflammatory cytokines that promote triggered activity in ACMs leading to poAF, while M-mediated activation of ACFs promotes fibrosis and recAF. We will test this hypothesis in three major aims: Aim 1 will determine which factors released from the heart into pericardial fluid in poAF patients promote triggered activity in ACMs and a profibrotic phenotype in ACFs. Aim 2 will test which chemokine(s) and receptor(s) are necessary for poAF development a mouse model of poAF. Aim 3 will assess how M-induced suppression of calcitonin signaling within ACFs promotes fibrosis and recurrent AF after poAF. These studies are expected to reveal how altered infiltrating Ms contribute to proinflammatory and profibrotic remodeling and atrial arrhythmia development. In line with NHLBI’s mission to translate basic discoveries into clinical practice, our mechanistic studies into the interplay between inflammation and fibrotic remodeling may lead to new treatments for postoperative and recurrent AF.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract My overarching goal is to expand my role as a leader, nationally and internationally, in the design and conduct of NCI-funded clinical trials for children, adolescents and young adults with cancer – particularly those with hematologic malignancies. Within the Texas Children’s Cancer and Hematology Center (TXCH) and Dan L. Duncan Comprehensive Cancer Center (DLDCCC), I will work within my leadership roles to close gaps between disease teams. This will partially be done by continuing to lead a bimonthly High-Risk Hematologic Malignancies Conference which will bring together leaders and faculty from the currently siloed Leukemia, Lymphoma, IEC (CAGT), HSCT and hematopathology teams to provide a singular forum for clinical decision-making including opportunities to participate in clinical trials. The ultimate goal of this endeavor would be the creation of a shared clinic for the Pediatric Cancer Program (PCP) of the DLDCCC. This forum should not only be of benefit to patients, but should greatly increase enrollments to clinical trials run by each group. I will facilitate translation of TXCH laboratory work into successful implementation of NCI consortium clinical trials. I will also facilitate TXCH’s interactions with industry partners to identify new agents of interest to bring into the NCI-funded cooperative groups. Within the NCTN, I will continue to co-lead the development of COG study AALL2331 through the final steps of full concept CTEP approval, case report form (CRF) design, IRB submission and activation and lead AALL2331 through study completion. I will also continue my role as Co-Lead of the COG T-cell Task Force. In this role, I hope to help develop additional studies for T-cell ALL/LL and expand our collaboration with adult NCTN groups such as SWOG and Alliance. Finally, I hope to continue and expand my leadership role within TACL and serve as a liaison between TACL, COG and other NCI-sponsored trialists and consortia. Overall, I have a clear and demonstrated expertise in pediatric acute leukemias, novel therapeutics, interventional trial design and clinical research operations. In the next career phase, which would largely encompass the life of this grant, I am prepared to lead my first large international trial (AALL2331) and continue growth in my leadership positions as the DLDCCC Associate Leukemia Team Lead, DLDCCC COG PI, COG T-cell Task Force Lead, DLDCCC TACL Institutional PI and TACL SPC member. These positions will result in both the successful completion of and the development of novel clinical studies which, will either be directly NCI-sponsored or benefit the NCTN trial portfolio. The funding provided in this grant mechanism will be critical to provide the dedicated time needed to best fulfill these missions.

NIH Research Projects · FY 2025 · 2025-09

Rett syndrome is a severe neurological disorder caused by mutations in the MECP2 gene, affecting approximately 1 in 10,000 female births. About 70% of individuals with Rett syndrome experience epileptic seizures and nearly one-third of these cases are resistant to treatment, posing a substantial burden for patients. In my recent experiments, I observed an increase in both vascular density and branching within the hippocampus of Rett mice, as compared to wildtype controls. In mouse models of temporal lobe epilepsy, similar vascular changes are driven by vascular endothelial growth factor (VEGF) and contribute to epileptogenesis. Such phenotypes also correlate with the severity of disease in human temporal lobe epilepsy. However, given the broad transcriptomic consequences of MeCP2 dysfunction, it’s not clear whether hippocampal vascular abnormalities in Rett syndrome share the molecular origin or pathological consequences found in other disease models. Through this proposal, I will test the hypotheses that VEGF signaling drives the aberrant vascularization observed in the hippocampus of Rett mice, and that these vascular changes contribute to the development of epilepsy in this model system. This will be accomplished through the following specific aims: VEGF Signaling and Vascular Growth: I will evaluate whether increased VEGF expression in the hippocampus of Rett mice promotes angiogenesis through the activation of VEGFR2. I will measure the differential expression of VEGF and VEGFR2 in both Rett and wild-type tissues using histological methods and quantitative protein analysis. I will target VEGF and VEGFR2 with shRNA-mediated knockdowns to causatively determine the impact of VEGF signaling on vascular anomalies observed in Rett mice. Functional Implications of Angiogenesis in Epileptogenesis: I will employ longitudinal 2-photon imaging coupled with multi-channel EEG to determine the impact of increased vascularization in epileptogenesis in Rett mice. I will chronically inhibit angiogenesis or epileptic activity using pharmacological methods to reveal the relationship between these two phenomena. Through the proposed molecular, electrophysiological, and imaging studies, this project will establish the origins of aberrant hippocampal angiogenesis in Rett syndrome and determine if this phenotype contributes to Rett-associated epilepsy. It will thus provide fundamental insights into the progression of epileptic disease in Rett syndrome and potentially help to identify generalizable targets to treat or delay epileptogenesis for Rett and other disorders.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY / ABSTRACT HIV is known to be transmissible from mother to the developing fetus during pregnancy, leading to adverse health outcomes for both. Although HIV is linked to placental pathologies, there is still a large gap in knowledge about the mechanisms underlying HIV-associated pregnancy complications, despite four decades of research in general on HIV topics. The objective of this project is to investigate the role of intercellular conduits composed of F-actin microtubules that connect plasma membranes of neighboring cells enabling cytoplasmic continuing and intercellular transfer of cargo. These conduits are known as tunneling nanotubes (TNTs). Recent investigations by the PI and others have demonstrated that other viruses such as Zika and SARS-CoV-2 induce the formation of TNTs in placental trophoblast cells, and there is evidence they serve as a means of mitochondrial transfer and possibly viral transfer that promotes infectious spread. There is evidence that HIV induces TNT formation in neurons, but it is not known whether the virus has this effect on placental cells. Building on prior studies and ongoing work by the PI, the central hypothesis of this project is that HIV uses TNTs to spread infection in trophoblasts, and that TNTs mediate placental dysfunction by transferring damaged mitochondria and adversely reprogramming trophoblast metabolism. This metabolic reprogramming may contribute to placental dysfunction and adverse pregnancy outcomes. Aim 1 of this project will elucidate the molecular mechanisms of TNT formation between HIV-infected immune cells and trophoblasts. Aim 2 will determine the impact of HIV on mitochondrial dynamics and transfer and resulting trophoblast function. These two aims will be pursued during the final postdoctoral training period of the K99 phase. Aim 3 seeks to identify how HIV-exposed mitochondria reprogram trophoblast biology, impairing placental function and affecting fetal development in vivo. This third aim will be pursued during the R00 phase of the project. Successful completion of these aims will provide new insights into the mechanisms underlying HIV infection, identifying potential therapeutic targets to mitigate vertical transmission and placental pathologies caused by HIV and other viruses. During the mentored phase, the PI will gain expertise in primary cell culture, metabolomics, trophoblast organoids, and mitochondrial epigenetics to examine how HIV infects the placenta and disrupts cellular metabolism—establishing a foundation for the R00 phase. With guidance from the advisory team, this training and research will contribute to the identification of therapeutic strategies to improve outcomes for infants and individuals with HIV, while positioning the investigator to establish an independent, competitive R01-funded laboratory at the intersection of HIV, TNTs, placental biology, and mitochondria.

NIH Research Projects · FY 2025 · 2025-09

– Professional Development Core The Houston Area Incubator for Kidney, Urologic, and Hematologic Research Training (HAI-KUH) addresses key challenges related to recruitment, advancement, and retention of pre- and postdoctoral trainees and clinical fellows in the KUH fields. Successful career transitions of trainees into independent investigators require multi-faceted educational strategies, which include cross-cutting professional skills. The Professional Development Core will augment research experiences with an innovative professional development program that employs modern learning techniques and emphasizes active participation through faculty- and peer-led small group sessions and a mentored approach to individual development plans that includes skills development and career preparation. Through a comprehensive matrix of professional development resources that emphasize training excellence, the Professional Development Core will address the advancement and competitiveness of HAI-KUH trainees and improve their retention in KUH research fields in both academic and non-academic settings. Aim 1 is to develop a cohort of KUH trainees prepared to launch in their chosen direction by leveraging faculty-to-trainee, peer, and near-peer interaction plans through interactive monthly learning sessions that cover a range of essential cross-cutting skills, opportunities and feedback on oral presentations and scientific writing, and professional development bootcamps in the areas of entrepreneurship/commercialization and team science, as well as tailored training plans. Aim 2 is to enhance skills and trainee competitiveness through HAI-KUH pods, individual development plans, and a HAI-KUH Professional Development Dashboard, where the pods will function as an interactive unit to facilitate both horizontal (peer) and vertical mentoring to ensure that trainees take advantage of all resources available to them and to support the successful transition to independence. Aim 3 is to develop a cohort of preceptors and trainees trained in mentor and mentee best practices, optimizing training experiences and outcomes since mentor development and training rooted in mentoring best practices are critical for successful career transitions. Refinement of strategic approaches based on recurring cycles of evaluations will ensure that the activities are well integrated, in line with the overall vision and mission of HAI-KUH and complement the goals of the Networking and Training Cores. In synergizing with the large established training programs in the Texas Medical Center, the Professional Development Core will increase trainee competitiveness, support successful career transitions to independence, improve retention of trainees in research careers in both academic and non-academic settings, and, ultimately, impact the KUH research target areas as defined by the NIDDK.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Pyrrole-imidazole polyamides are a class of synthetic DNA-binding ligands that can be programmed to target specific DNA sequences, including repetitive DNA, in the human genome. The major scientific problem this proposal addresses is the development of two new classes of small, cell-permeable genome regulators to extend the capabilities of these molecules. This project aims to fill the critical gap in genome targeting by creating first-in-class small, cell-permeable genome editors that can be relationally designed to edit genomes for a variety of downstream functions. This objective will be pursued through 3 Projects: The expected outcomes include (1) the development of bifunctional polyamides capable of editing a tandem repeat of interest in cell and animal models, (2) the creation of polyamides to recognize 15–20 base pair motifs occurring only once in the human genome, and (3) the democratization of these molecules to place them in the hands of biologists. If successful, this project could lead to novel therapeutic strategies for not only repeat expansion disorders but genetic diseases broadly, providing new tools to researchers and advancing the field of precision genomic medicine.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Many drugs of abuse target G protein coupled receptors (GPCRs), including the opioids which have fueled the ongoing opioid abuse epidemic. Many of these compounds have substantial room for improving their therapeutic window by precisely tuning their signaling profiles. However, rational design of such compounds is difficult due to a lack of understanding of how these compounds alter the structure and dynamics of receptors to relay their pharmacological profile intracellularly to their signaling partners. Here we propose to generate chemical biology tools to facilitate the determination of molecular movies of GPCRs interacting with their signaling partners with time-resolved cryogenic electron microscopy. This will be complemented by the development of a new computational method to drive simulations from time-resolved cryogenic electron microscopy data in order to fully sample all of the transition and intermediate states involved in GPCR signaling. These methods will be applied to several ligands of various efficacies for a key receptor for drugs of abuse, and the insights used in ultra-high throughput virtual screening campaigns to identify novel allosteric modulations to stabilize specific intermediate states. Finally, allosteric compounds will be tested in rodent models of addiction to explore how modulation of these specific intermediate states attenuates the addiction liability of canonical drugs of abuse.

NIH Research Projects · FY 2025 · 2025-09

Abstract/Summary Bronchopulmonary dysplasia (BPD) is the most common infantile chronic lung disease that lacks curative therapies. The development of pulmonary hypertension (PH) increases BPD-associated mortality and morbidity. Persistent lung inflammation is central to the pathogenesis of BPD-associated PH (BPD-PH), which is characterized by alveolar and pulmonary vascular simplification and endothelial cell dysfunction. Therefore, this proposal aims to elucidate the mechanisms regulating inflammation in the developing lungs. Regulatory T cells (Tregs) are a subset of CD4+ T cells that regulate innate and adaptive immune responses, prevent tissue damage, and promote the resolution of lung inflammation and injury in adult rodents. Further, Treg density is altered in BPD infants. However, it is unclear if these cells contribute to BPD-PH pathogenesis. Our preliminary data indicate that hyperoxia (HO) exposure decreases Tregs, and Treg depletion potentiates HO-induced experimental BPD-PH in mice. Thus, we propose examining the mechanistic and therapeutic roles of Tregs in BPD-PH using well-established murine models and human biosamples. Our studies also show that Treg depletion decreases endothelial cell (EC) density in neonatal murine lungs. Healthy lung blood vessels are necessary for normal lung development, promoting tissue repair, and mitigating BPD-PH. The interactions between Tregs and lung ECs are unclear. Our compelling data show that Treg depletion increases inflammation and decreases the expression of the pro-angiogenic hormone, adrenomedullin (Adm), and its receptor, receptor activity-modifying protein 2 (Ramp2), in the murine lung ECs. We also show that Adm overexpression decreases HO-induced experimental BPD-PH. Further, we show that human BPD lungs have decreased EC Ramp2 expression and Tregs. Thus, we will test the central hypothesis that Tregs experimental BPD-PH in mice by promoting lung vascular growth, survival, and function via Adm signaling. We will use a unique combination of molecular, cellular, functional, and translational approaches to test this hypothesis. In Aim 1, we will use transgenic neonatal mice, flow cytometry, and single-cell RNA Seq to determine how HO and lipopolysaccharide affect Treg phenotype and function and if adoptive transfer (AT) of Tregs can mitigate experimental BPD-PH. In Aim 2, we will use Adm transgenics and innovative nanoparticles specifically targeting lung ECs to determine if Tregs regulate EC homeostasis and injury in the neonatal lungs via Adm signaling. Finally, in Aim 3, we will perform a prospective cohort study and use a well-curated lung biobank to examine the blood and lung Treg phenotype and density in human infants with and without BPD-PH and correlate them with the disease incidence and severity. We expect our studies to provide new insights into how inflammation and injury are regulated in the developing lungs, and provide a mechanistic rationale for targeting Tregs and Adm pathway to develop novel biomarkers and meaningful therapies for infants with BPD-PH.

NIH Research Projects · FY 2025 · 2025-09

Smokers are at increased risk for viral-induced respiratory failure and hospitalization. We have shown that cigarette smoking (CS) induces systemic inflammation characterized by increased interleukin 17A (IL-17A) expression in CD4 T helper (Th)17 cells in mice and humans. CS promotes Th17 cell differentiation in the lungs while reducing several key transcription factors critical in protecting against viral infection. Mice exposed to chronic CS and infected with influenza A virus (IAV) have increased IL-17A in the lungs, reduced flu-specific B cells, and increased mortality compared to controls. Consistently, in a prospective study, we have found that active smokers vaccinated against seasonal IAV have reduced flu-specific neutralizing antibody titers two months post-vaccination. Together, these findings indicate a strong link between smoking and reduced flu- specific memory B cell (Bmem) development. CD4 T follicular helper (Tfh) cells and dendritic cells (DCs) play a key role in mediating the selection and survival of B cells that differentiate into plasma cells, however, how CS changes their development or function remains unknown. Therefore, significant knowledge gaps include whether i) Tfh cells and DC numbers and/or function are perturbed in smokers with increased levels of IL-17A, and ii) B cell-Th17-axis impairs flu-specific antibody production and virus-specific Bmem development. Our central hypothesis states that CS increases IL-17A in the lungs which impairs the differentiation and/or function of Tfh subsets and DCs, decreasing protective immunity against IAV. We have assembled an outstanding team of physicians, immunologists, and bioinformatics to test our hypothesis with Specific Aims: Aim 1) Determine the mechanism of CS-induced loss of long-term protective flu-specific B cell immunity. Rationale: compared to controls, mice exposed to CS and IAV have increased Th17 cells in the lungs, reduced flu-specific antibodies, and blunted HA-specific B cell responses. This aim will test the hypothesis that active CS induces IL-17A in the lung that alters systemic and transcriptional factors required to produce protective Bmems. Aim 2) Determine flu-specific memory B cell function and transcriptomic changes in the lungs of smokers. Rationale: compared to controls, active smokers have increased Th17 cells and reduced flu-specific Bmems in the lungs. This Aim will test the hypothesis that ineffective expansion of flu-specific Tfh cell pool in the lung correlates with poor Bmem survival and lack of high-affinity antibodies against IAV in humans. Aim 3) Determine the mechanism involved in systemic immune responses to flu antigens in smokers. Rationale: compared to controls, active smokers show reduced neutralizing antibody titers following flu vaccination. This Aim will test the hypothesis that CS induces systemic changes to the immune cell transcriptome required to develop protective Bmems in response to seasonal flu vaccination. Impact: Unraveling the mechanisms for failure to develop protective antibodies against flu in smokers provides critical evidence for designing human clinical trials and testing new treatments for this at-risk population.

NIH Research Projects · FY 2025 · 2025-09

Enter the text here that is the new abstract information for your application The Houston Area Incubator for Kidney, Urologic, and Hematologic Research Training (HAI-KUH) aims to develop a highly qualified workforce to improve the health and quality of life of patients with nonmalignant Kidney, Urologic, and Hematologic (KUH) disease. HAI-KUH is based in Houston, one of the country's most populous metropolitan areas and home to the Texas Medical Center (TMC), the largest medical center in the world. Our network includes 58 training preceptors from 7 different institutions based in 8 sites (Baylor College of Medicine, Texas Children's Hospital, University of Texas Health Science Center at Houston (UTHealth), MD Anderson Cancer Center, Houston Methodist Research Institute, Rice University, Texas A&M University, and University of Houston). The preceptors have expertise in the KUH mission areas (20, 14, and 24 preceptors, respectively) and a variety of scientific backgrounds, including academic-private sector partnerships. Preceptor research interests include sickle cell disease, stem cell biology, chronic kidney disease, human genetics and development of the urogenital tract, neuromodulation of bladder function, urinary tract infections, and health economics and policy of kidney and urologic diseases. The program will not only expand existing training efforts but also support a variety of career paths, promote interdisciplinary research, and enhance training excellence in KUH mission areas. Our program emphasizes innovation, a foundation of leading biomedical science. We focus particular efforts on highly qualified graduate students and postdocs who will help us realize our long-term goals of attracting, launching, and retaining a pipeline of interdisciplinary KUH researchers to ultimately benefit those afflicted by KUH diseases. This TL1 component will oversee the appointment and mentoring of graduate students, postdoctoral fellows, and clinical fellows to the program. Trainees will be drawn from a typical pool of 100 eligible trainees or recruited nationally, with the program ultimately supporting 6 pre-docs and 6 postdoctoral or clinical fellows. With the Professional Development Core (PDC), the TL1 will assess trainees’ individual needs and interests and facilitate customized training pathways, including exposure to and training in skills that will prepare them for academic, entrepreneurial, policy, or other careers. The TL1 will ensure that trainees receive high-quality mentored research experiences by selecting, training, and evaluating mentors. Trainees will participate in small interdisciplinary groups that will enable peer-to-peer and near-peer mentoring to promote their scientific and career development and will have a variety of enrichment opportunities facilitated by the PDC and Networking Core. Finally, HAI-KUH enjoys exceptional support from multiple institutions in the Texas Medical Center, ensuring the program's success and advancement of health treatment options for patients with KUH diseases.

NIH Research Projects · FY 2025 · 2025-08

Project Summary Relapsing fever (RF) Borrelia are vector-borne pathogens that causes significant morbidity and mortality in low- and middle-income countries, while we are also observing the emergence of the disease in populated regions of North America. Pathogenic spirochetes are transmitted by the human body louse and ixodid and argasid ticks. Since most species of RF Borrelia are transmitted by argasid ticks in the Ornithodoros genus, we developed this model. Unfortunately, we do not understand the molecular mechanisms driving RF spirochete transmission leading to an absence of preventative interventions that disrupt the pathogens’ life cycle. While RF- and Lyme disease-causing spirochetes are in the same family, their biology significantly differs indicating what is known for one system is not necessarily applicable to the other. One key difference is that populations of RF spirochetes persistently colonize Ornithodoros midguts and salivary glands. The salivary gland population is essential because those spirochetes are preadapted for entry into the vertebrate host and are transmitted within seconds of tick bite. Upon transmission, vector-specific genes are downregulated and the variable major protein (vmp) locus, which is responsible for antigenic variation and persistent mammalian infection, is upregulated. However, very little is known regarding which genes are expressed in the tick and vertebrate and the regulatory mechanisms controlling their expression. We are addressing this through advances in RF spirochete genomics. We utilized Oxford Nanopore Technology (ONT) to generate plasmid-resolved genomes needed for comprehensive transcriptional studies. Furthermore, since it is challenging to obtain enough spirochete RNA from the tick for transcriptional studies, we characterized salivary glands and found that they are highly oxidative. This allows us to grow the pathogen in in vitro conditions that better mimic the tick environment. We also identified essential RF Borrelia genes expressed in the tick (bta132 – bta136) and will build on the importance of vmp to delineate regulatory mechanisms. We hypothesize that RF spirochetes possess unique mechanisms to regulate genes differentially expressed during the tick-mammalian transmission cycle. In Aim 1, we will utilize the ONT platform for a comprehensive analysis of RF Borrelia genes and operons that are upregulated in the tick salivary glands versus murine blood and determine their transcriptional start sites. The objectives are: 1) perform long- read ONT-Cappable-seq using in vitro grown spirochetes; 2) analyze data and select candidates; and 3) validate findings in vivo. In Aim 2, we will investigate the regulatory mechanisms of important genes upregulated in the tick (bta132-bta136) and mammal (vmp locus) through the identification of promotor regions and DNA-binding proteins. The objectives are: 1) identify promoter sequences; and 2) identify DNA-binding proteins that interact with promoters of bta132 - bta136 and the vmp expression locus. Our findings will result in the identification of genes to target for the development of countermeasures against a significant yet neglected pathogen.

NIH Research Projects · FY 2026 · 2025-08

Venous thromboembolism (VTE) is the second-leading cause of non-cancer death in ambulatory cancer patients receiving chemotherapy. Despite evidence supporting the prescription of low dose direct oral anticoagulants (DOACs) in ambulatory patients with cancer who are high-risk for VTE and low-risk for bleeding, its implementation is almost nonexistent due to the absence of accurate hemostatic risk prediction. The central hypothesis is that we can leverage population science and data science methodologies while guided by clinical and ethical principles to ascertain and predict thrombotic and hemorrhagic outcomes in ~330,000 patients with cancer from three different healthcare systems in the US. These sites are selected for their significant differences in age, sex, race, ethnicity, and cancer type to ensure fairness in model development and application. Our two specific aims are: 1) To ascertain and validate incident VTE and CRB outcomes from clinical notes in patients with cancer across three healthcare institutions; and 2) To develop, externally validate, and deploy a multimodal, dynamic risk prediction model for incident VTE and CRB following the initiation of anticancer systemic therapy to individualize preventive recommendations. We will pursue these aims using several innovative methods including natural language processing (NLP) algorithms fine-tuned from pre-trained masked language models, retrieval augmented generation (RAG) in large language model (LLM), federated learning (FL) framework to allow for decentralized privacy-preserving data sharing, and multimodal dynamic risk prediction with longitudinal trajectories from both structured and unstructured data. The proposed research is significant because accurate thrombo-hemorrhagic risk prediction will lead to increased adoption of risk-adaptive thromboprophylaxis to reduce complications in patients undergoing anticancer therapy. The expected outcome of this proposal is the creation of validated VTE and CRB dynamic risk prediction models in patients with cancer starting systemic therapy that are applicable for all racial and ethnic groups. The success of our proposal will empower other clinical investigators to validate our work against their own datasets, integrate it into clinical care, or join our ongoing FL network to further improve accuracy and applicability of the multimodal individualized treatment effects model for thrombosis and bleeding.

NIH Research Projects · FY 2025 · 2025-08

Project Abstract: The number of patients worldwide with severe immune dysregulation associated with STAT1 gain of function (GOF) disease is increasing due to genetic testing and early identification. There is moderate success with using Janus kinase inhibitors (JAKi)s in balancing immune cell function. However, hematopoietic stem cell transplant (HSCT) outcomes are not favorable with a high incidence of secondary graft failure. The utility of treatment with JAKi pre-transplant to improve outcomes is not clearly established. The central hypothesis is that impaired cytokine signaling leads to secondary graft failure in HSCT in STAT1GOF and this can be mitigated by pre-transplant JAKi treatment. In the first aim, we will evaluate the efficacy of JAKi inhibition pre- and post-transplant using a murine model of STAT1 GOF. We will treat STAT1 GOF recipient animals with JAKi before or after transplantation with WT bone marrow. By comparing the outcomes of those treated before versus after transplant we will identify effects of inflammation in the radioresistant bone marrow milieu that may persist after transplant. In the second aim, we will xenotransplant primary CD34+ cells from STAT1 GOF patients into NSG mice and study whether JAKi therapies affects their radiosensitivity and mitigation of inflammation related consequences. Single cell transcriptomics performed on these cells will be compared to transcriptional changes induced by STAT1 signaling that are known to affect stem cell niche localization, quiescence, cell division, and differentiation. These studies will reveal mechanisms by which hematopoiesis is impaired in STAT1 GOF patients and may lead to discovery of critical disease biomarkers or new avenues for therapy and improved transplant outcomes.

NIH Research Projects · FY 2025 · 2025-08

ABSTRACT Studies aimed at the identification of cancer-related genes usually focus on the genes with an excess of somatic mutations. We hypothesized that genes with a lower-than-expected number of loss-of-function (LOF) mutations are also cancer-related. Indeed, genes whose function is essential for tumor cell survival and proliferation are expected to lack or have a deficit of LOF mutations since the loss of the function of an essential gene will lead to death of the tumor cell. As a result, genes essential for tumor cell survival are “prohibited” from having LOF somatic mutations and, therefore, can be identified through a deficit of LOF mutations. We tested this idea in a pan-cancer analysis. We applied a multiple regression model to predict how many LOF mutations one can expect in a given gene based on characteristics of the gene. Analysis of residuals was used to identify negative outliers—i.e., genes with a lower-than-expected number of mutations in them. After our pan-cancer analysis was published, the number of available mutations detected in tumors more than doubled, making it possible to conduct a lung cancer-specific analysis which is expected to be more powerful compared to the pan-cancer analysis. The cancer-essential genes identified in pan-cancer analysis fall into two categories: (1) genes that are essential in general - common housekeeping genes, and (2) genes that are nonessential in normal tissue but become essential after cells undergo malignant transformation. We will focus on the genes from the second category because they are expected to be a better therapeutic target than genes with housekeeping functions, as silencing the former is expected to have lower overall toxicity compared to the silencing of housekeeping genes. We propose the following specific aims: Aim 1: To identify genes with a significant deficit of loss-of-function mutations in lung tumors. Aim 2: To conduct pilot functional studies of the genes with a significant deficit of LOF mutations. To summarize, we will use existing somatic mutation data to identify genes in the human genome that are essential for survival of tumor cells in lung cancer. We will conduct pilot functional studies to demonstrate that silencing of the genes with a significant deficit of LOF mutations has antitumor effect. 1

NIH Research Projects · FY 2025 · 2025-08

Summary: New technologies that provide molecular-based cancer detection and tissue identification are highly desirable to improve treatment for patients with cancer. High-grade serous ovarian cancer (HGSC) is the most common and lethal type of ovarian carcinoma, as most patients present with metastasis and advanced disease. Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery has been increasingly used as the main treatment for patients. Yet, most patients do not achieve complete response to NACT and still have cancer at the time of surgery. Thus, gynecologic surgeons have the critical task of visually identifying and removing all residual tumor lesions during surgery— a task that can be very challenging due to the drastic changes that NACT causes to tumor tissue morphology. Inevitably, surgeons are faced with a difficult scenario: aggressively remove suspected tumor with surrounding healthy tissue; or leave suspected treated tumor behind. Moreover, many patients still present chemoresistant minimal residual disease (MRD) after NACT and surgery, leading to worse outcomes. These issues escalate health care costs, place patients at risk for morbidity, and negatively affect survival. To address these challenges, we developed the MasSpec Pen (MSPen) technology as an innovative approach for rapid and non-destructive intraoperative tissue analysis. The MSPen employs a droplet of water to directly extract lipids and metabolites from tissues, which are then immediately analyzed by mass spectrometry (MS) and statistical classifiers to identify tissues in seconds. In lab studies, we showed that the MSPen metabolic information allows identification of HGSC with 96% accuracy. In clinical studies, the MSPen was tested by surgeons intraoperatively for in vivo tissue identification and implemented in ovarian surgeries at MD Anderson Cancer Center (MDACC). Using MS imaging, we have further shown that metabolic data from ex vivo ovarian cancer tissues is related to NACT response. We hypothesize that the MSPen allows identification of pre- and post-NACT tumor tissue and MRD in vivo to guide surgical treatment, and reveals novel in vivo metabolic patterns related to NACT response and cancer persistence. Our aims are: Aim 1. Refine the MSPen technology for intraoperative HGSC detection in open surgeries. We will use a next-gen version of the MSPen to optimize performance for metastatic HGSC detection in primary (n=120) and interval debulking surgeries (n=200) and use the metabolic data from pre- and post-NACT HGSC tissues to refine statistical classifiers for metastatic HGSC detection; Aim 2. Develop the laparoscopic-MSPen for identification of MRD after NACT and surgery in second-look laparoscopies (n=100), in comparison to histopathology and circulating tumor DNA data from the same patients; Aim 3. Define metabolic markers of cancer persistence and response to NACT using the in vivo data obtained. We will also obtain ex vivo tissues from a subset of patients and leverage our expertise in MS imaging and spatial transcriptomics to further explore metabolic patterns of MRD. Our proposal has the potential to offer transformative benefits to surgeons in advancing the standard of care for patients with ovarian cancer.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Heart failure is the leading cause of morbidity and mortality in the United States, with many heart failure cases being the result of an ischemic insult such as coronary artery disease or myocardial infarction. As the adult heart lacks native regenerative repair mechanisms, most current heart failure therapies attempt to alleviate patient’s symptoms. However, recent studies have demonstrated that mammals do have endogenous cardiac repair mechanisms in early postnatal stages, but this endogenous regenerative ability wanes as postnatal maturation proceeds. This regenerative ability is lost as cardiomyocyte proliferation naturally decreases throughout cardiomyocyte maturation, as cardiomyocytes need to switch from hyperplastic growth to hypertrophic growth to adjust to the demands of pumping blood throughout the body. This switch to hypertrophic growth is accompanied by metabolic and sarcomere state changes, however the mechanistic underpinnings of these cardiomyocyte maturation changes are well characterized. Initial mechanistic examinations of cardiomyocyte maturation identified the Hippo signaling pathway due to how Hippo signaling could promote or inhibit CM proliferation depending on the activity of its transcriptional effector Yap1. My transcriptional activity analysis discovered major transcriptional landscape changes between induced-immature cardiomyocytes and controls, with high Yap activity defining immature cardiomyocytes while Notch activity defined mature cardiomyocytes. Interestingly, transitions between Yap and Notch activity are critical to cell type or state changes in various organ systems, however whether a Yap to Notch transition regulates cardiomyocyte maturation has not been investigated. Thus, I hypothesize that Notch activity is critical to promote and maintain mature cardiomyocytes, with a Yap to Notch transcriptional activity transition regulating cardiomyocyte maturation state. To address this hypothesis, I will utilize genomic techniques alongside mouse models to examine cardiomyocyte maturation in vivo. My first aim will define the role of Notch transcriptional activity in postnatal cardiomyocyte maturation state, defining whether Notch maintains a mature cardiomyocyte state (1A), is necessary for transition to a mature cardiomyocyte state (1B), or directly promotes a mature cardiomyocyte state (1C). As our preliminary data demonstrates a transition between Yap and Notch coinciding with cardiomyocyte maturation state, aim 2 will address possible mechanisms underlying the endogenous switch from Yap to Notch activity during postnatal maturation. First investigating how Yap activity may directly promote a transition to a Notch active state (2A), alongside how Notch activity may directly inhibit Yap activity to facilitate cardiomyocyte maturation (2B). In total, the proposed project aims would further our understanding of cardiomyocyte maturation along with the transcriptional regulatory programs that govern cardiomyocyte maturation. Providing knowledge that could be utilized to improve regenerative therapeutic development for heart failure.