Baylor College Of Medicine

NIH Research Projects · FY 2025 · 2025-03

Myocardial infarction (MI) causes irreversible loss of cardiomyocytes and often leads to ischemic heart failure. To date, there is no effective treatment for ischemic heart failure. The ultimate therapeutic for such disease should replace the lost cardiomyocytes, resolve the fibrotic scar, preferably transdifferentiate the fibroblasts into cardiomyocytes, and increase vascularization to the regenerated myocardium. Therefore, the most promising treatments currently within the experimental phases are induction of existing cardiomyocyte proliferation, direct cardiac reprogramming of the existing fibroblasts to induced cardiomyocytes (iCMs), and increasing angiogenesis. Each approach has been tested individually either in preclinical animal models or in Phase I/II clinical trials with proven efficacy. In this proposal, our central hypothesis is that combining the most powerful three modalities to regenerate the myocardium will synergize to provide a full regeneration of the myocardium to cure ischemic heart failure; therefore, we gathered a team of academic investigators and biotech industry partners to perform a full preclinical testing of the efficacy and toxicity of the triple therapy (Induction of cardiomyocyte proliferation (TNNT2-4F-NIL), direct cardiac reprogramming (TN1-006), and increasing vascularization (XC001)). One of the limiting factors for such gene therapies for heart failure is developing a noninvasive procedure that is suitable for clinical application. Therefore, in this proposal, we are aiming to make this triple therapy less invasive (and thus more clinically applicable) by injecting the viral cocktail into the heart muscle using a novel trans-endocardial injection catheter that was developed by Tenaya Therapeutics (NovoStar Endomyocardial Injection Catheter). Here, building on our published solid preliminary data demonstrating the high efficacy of each individual approach in treating ischemic heart failure in preclinical animal models and clinical trials, we will perform dose-response efficacy and initial toxicity testing in preclinical animal models of heart failure to determine the best dosage for this triple therapy. R61 phase Aim: Determine the optimal dosage and therapeutic window for best in vivo efficacy of the triple therapy in rats. Milestone: Achieve a significant improvement in cardiac ejection fraction by at least 10 points with minimal expression of the reprogramming and cell cycle factors in other tissues. R33 phase Aim: Demonstrate the efficacy and initial safety of the triple therapy injected with the NovoStar catheter in improving cardiac function and systemic congestion in other organs in a pig model of ischemic heart failure and human heart slices. Milestone: Achieve a significant improvement in cardiac ejection fraction by at least 10 points in pigs with no toxicity. Achieve improvement in human heart slice contractile function with no arrhythmia. This project will provide evidence of the efficacy and initial safety of a promising and novel triple therapeutic approach for ischemic heart failure, which combines the three most efficient modalities for cardiac regeneration.

NIH Research Projects · FY 2026 · 2025-03

Project Summary/Abstract: Breast cancer poses a significant burden on women's health, being the most commonly diagnosed cancer and a leading cause of cancer-related mortality in the United States. While progress has been made in treating primary breast cancer, the development of metastasis and multi-drug resistance remains a major challenge and accounts for the majority of breast cancer-related deaths. Dysregulation of calcium (Ca2+) homeostasis is prevalent in breast cancer cells, yet the precise role of Ca2+ signaling in breast cancer metastasis, its upstream regulatory mechanisms, and potential therapeutic vulnerabilities remain elusive. This knowledge gap stems largely from the absence of reliable breast cancer models with direct readouts of intracellular Ca2+ dynamics. However, our recent groundbreaking research has uncovered the involvement of noncanonical Wnt signaling and downstream integrin/focal adhesion pathways in regulating the invasion and dissemination of triple-negative breast cancer (TNBC). Noncanonical Wnt signaling is a known inducer of intracellular Ca2+ cascades, which play critical roles in cell adhesion and the cell cycle. In this proposed project, we aim to establish a robust mouse model capable of indicating intracellular Ca2+ levels to unravel the intricate Wnt/Ca2+ signaling pathway in TNBC metastasis and drug resistance. In specific Aim 1, we will employ a highly sensitive, genetically encoded Ca2+ indicator called GCaMP6s to directly measure Wnt-induced Ca2+ mobilization in three-dimensional tumor organoid cultures and genetically engineered mouse models of TNBC. Aim 2 focuses on understanding how Wnt/Ca2+ signaling modulates tumor cell-endothelium adhesion and invasion, thereby enhancing our understanding of tumor intravasation and extravasation processes. In Aim 3, we will explore the molecular mechanisms and therapeutic vulnerabilities associated with Ca2+ inhibition to overcome chemoresistance in TNBC. This comprehensive research proposal will not only shed light on the intricate mechanisms governing Wnt/Ca2+ signaling in TNBC metastasis but also provide novel insights into targeting TNBC progression and overcoming drug resistance from a fresh perspective. My strong background in Ca2+ signaling during my graduate studies at Texas A&M University, combined with my expertise in breast cancer metastasis gained through my postdoctoral training at Baylor College of Medicine, positions me well to undertake this proposed research. This project aligns with the mission of the National Cancer Institute (NCI) to advance scientific knowledge and improve the lives of individuals by leading, conducting, and supporting cancer research nationwide. With the guidance of experts as my mentors and collaborators, as well as access to cutting-edge facilities at Baylor College of Medicine, this proposed project will further enhance my training and contribute to the development of an independent career pathway in metastatic breast cancer research.

NIH Research Projects · FY 2026 · 2025-02

PD-L1 Modifications in Cancer Diagnosis and Treatment PROJECT SUMMARY Programmed death ligand 1 (PD-L1, also known as CD274 or B7-H1) is the principal ligand of programmed death 1 (PD-1), a coinhibitory receptor on activated T cells. In the tumor microenvironment, PD-L1 overexpression is an immune evasion mechanism exploited by tumor cells and is generally associated with a poor prognosis in cancer patients before the era of immunotherapy. PD-L1 is a type I transmembrane protein with immunoglobulin V-like and C-like structures in its extracellular domain. Interaction between PD-L1 and PD-1 is a key oncogenic process between tumors and the host system. Inhibiting antibodies to block PD-1 or PD-L1 has revolutionized cancer care, whereas PD-L1 detection is often used as a companion or complementary diagnostic biomarker. However, contradictory evidence exists as to its role across histotypes. PD-L1 detection in tumors is complex because of variable antibodies and platforms, the subjective nature of scoring, and non-interchangeable definitions of PD-L1 positivity. Our preliminary studies demonstrate that a E3 ligase mediates non-proteolytic ubiquitination of PD-L1, facilitating its translocation from the cytosol to the plasma membrane, where it binds PD-1 extrinsically to prevent tumor cell killing by T cells. In this application, we propose two specific aims to ascertain the pathobiological role and translational significance of the non- proteolytic ubiquitination of PD-L1 in evading tumoricidal T cells and cancer care using lung cancer as a model. Lung cancer is chosen because it causes over 100,000 deaths annually in the United States and most FDA- approved anti-PD-L1 or anti-PD-1 treatment antibodies can be used for lung cancer. More lung cancer patients benefit from immune checkpoint blockade (ICB) than patients with any other cancer type. ICB therapies are usually recommended for late-stage lung cancer. However, most lung cancer patients do not respond to ICB therapy. Aim 1 will evaluate the clinical significance of PD-L1 and the E3 ligase expression in lung cancer diagnosis and prognosis. Aim 2 will dissect the molecular mechanisms of PD-L1 protein modifications in immune suppression using lung cancer cells and mice. This project will reveal the interplay among ubiquitinated PD-L1, the E3 ligase, anti-PD-L1 antibodies, and PD-1, which represents critical tumor and immune cell interactions in the tumor microenvironment to promote or attenuate tumorigenesis and progression. We expect to provide new insights into the molecular regulation of PD-L1 endomembrane trafficking and the clinical values of membranous PD-L1 and the modifying enzyme for lung cancer diagnosis, prognosis, and treatment.

NIH Research Projects · FY 2026 · 2025-02

ABSTRACT: Autism spectrum disorder (ASD) is a common neurodevelopmental disorder that is highly comorbid with sleep disruptions. Although 40-80% of children diagnosed with ASD exhibit sleep disruptions, the etiology of this association remains largely unknown. However, through genome wide association studies, it is predicted that genes regulating neural stability including neurite outgrowth, synapse formation, and synaptic plasticity play an important role in ASD pathogenesis. One such family of genes that have previously been associated with ASD is the Neuroligin (NLGN) gene family. NLGNs are a family of postsynaptic cell adhesion molecules that interact trans-synaptically with neurexins to regulate synapse formation and maturation. Five NLGN genes have been identified in humans, but only NLGN2, 3, and 4 are classified as high confidence ASD associated genes. All five genes have unique expression patterns at either y-aminobutyric or glutamatergic synapses; however, only NLGN3 is expressed in both. Furthermore, individuals with variants in the NLGN3 gene have been identified to display both ASD and sleep disorders. Three variants of interest are the NLGN3 p.R175W, NLGN3 p.R451C, and NLGN3 p.R597W as all three variants are associated with ASD and the latter variant is also associated with sleep disorders. Previous studies have indicated that the NLGN3 p.R451C variant is a gain-of-function allele that causes mice to exhibit primary phenotypes of ASD and secondary phenotypes of sleep disruption suggesting that the variant may contribute to both disorders. However, the remaining two variants have yet to be functionally assessed in vivo. The goal of this proposal is to functionally characterize these variants and identify a molecular mechanism for the comorbidity between ASD and sleep using a Drosophila model organism. The Drosophila model organism has a simplified neural circuit, and it has extensively been used to study behaviors associated with ASD and sleep. Loss-of-function phenotypes associated with the loss of Nlg3, the Drosophila ortholog of NLGN3 have already been characterized. Nlg3 mutants display a reduction in locomotion, abnormal sleep consolidation, and an increase in the number of synaptic boutons found at the neuromuscular junction. Furthermore, Nlg3 mutants are thought to have impaired endocytic behaviors, providing a possible mechanism. I hypothesize that human NLGN3 variants associated with ASD impairs sleep and vesicle endocytosis. To accomplish this, we have used a humanization strategy to generate “humanized’ Drosophila lines that express NLGN3-Ref, NLGN3-R175W, NLGN3-R451C, and NLGN3-R597W cDNAs. We will first determine if human NLGN3-Reference and variant cDNAs can rescue the loss of fly Nlg3 using behavioral assays to assess for ASD-associated behaviors and sleep deficits. Then, we will determine if these variants impair endocytosis of vesicles. This will allow us to determine if NLGN3 variants inhibit endocytosis leading to behavioral deficits. Together these results can provide a functional link between ASD and sleep comorbidity and give insight into therapeutics for those suffering from sleep disorders.

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY Strongyloidiasis, caused by infection with the parasitic nematode Strongyloides stercoralis, remains an important public health problem in tropical and sub-tropical regions, with an estimated 30-100 million infected persons globally. Because S. stercoralis infection is acquired from contact with contaminated soil, those most at risk include the socioeconomically disadvantaged, those with agricultural occupations, and those living in areas with poor sewage control practices. S. stercoralis larval migration during chronic infection is limited to the gastrointestinal tract and lungs and causes few if any symptoms. However, larvae can disseminate and cause severe disease in immunosuppressed individuals. The importance of identifying S. stercoralis infection before immunosuppressive treatments are started has been highlighted by increased use of corticosteroids during the COVID-19 pandemic and related increases in disseminated strongyloidiasis diagnoses. Because disseminated strongyloidiasis is often diagnosed late, after larvae have caused significant and irreversible end-organ damage, the mortality rate of disseminated strongyloidiasis is near 90%. Regional studies and case reports indicate that strongyloidiasis is commonly diagnosed in tropical and sub- tropical regions of the US. We have found 4-10% seropositivity in a Houston solid organ transplant cohort and, more recently, even higher seropositivity (16.5%) in a central Texas community. Other small studies of US immigrants from low- and middle-income countries have indicated infection rates as high as 46.1%. Screening for strongyloidiasis is suboptimal due to poor knowledge of the disease among US healthcare providers and imperfect performance of available diagnostic tests. The clinical gold standard of strongyloidiasis diagnosis is microscopic evaluation of multiple stool specimens for S. stercoralis larva. Unfortunately, it is challenging for patients to submit even one stool specimen in a timely manner, and US clinical laboratory technicians may not have enough training and expertise to reliably identify larvae. Several serologic tests have been developed, but commercially available tests have imperfect test performance and are less sensitive in immunocompromised individuals who may not be able to mount a reliable humoral immune response. Newer serologic and molecular tests based on recombinant antigens have been developed but are not yet commercially available. We propose a prospective study of adult HHS patients undergoing a panel of parasitologic, serologic, and molecular Strongyloides assays, with the following specific aims: (1) to identify a high-performing strongyloidiasis screening strategy for at-risk individuals living in the US and (2) to evaluate each assay as a test-of-cure for strongyloidiasis. Improvement in Strongyloides testing would improve screening and management practices, thereby allowing for timely treatment and reduction of strongyloidiasis related morbidity.

NIH Research Projects · FY 2026 · 2025-02

Project Summary/Abstract Cardiovascular disease (CVD) is the leading cause of death in the United States, making it a promising disease for genetic testing to predict those at risk and prevent problems before they start. Indeed, genetic testing for CVD is now being implemented in clinic, but we are still far away from it being a first-line tool given existing gaps in accuracy. This reduction in accuracy is occurring in-part because many genetic tests are developed using data from only one population, posing a problem when these methods are applied more universally. Further, many human genetics tools are geared towards homogeneous data and are not optimized to work in populations that may have multiple or varying genetic patterns. To overcome these challenges and improve CVD genetic testing for the full US populace, I propose to study the genetics of CVD across a wide range of populations using novel and precise tools that evaluate genetic backgrounds appropriately. Specifically, I aim to improve genetic testing for CVD and lipoprotein a (Lp(a)), a lipoprotein that is resistant to commonly used CVD medications, can increase CVD risk by 2-4X when elevated, and is highly genetically-mediated. For Lp(a) in particular, I will evaluate the role of genetic structure and linkage disequilibrium in LPA, the key gene regulating this lipoprotein. I take this approach as there is compelling evidence that variation in recombination patterns affects the genetic architecture of LPA and thereby may influence the predictive capability of currently used genetic tests. I will pair this work with phenotypic analyses of Lp(a) and CVD through Genome-Wide Association Studies, and the development of a novel polygenic scoring model accounting for both a single locus of large effect and polygenic variation across the genome. This will provide me with the critical information needed to improve precision medicine approaches for CVD, giving potential to better identify high-risk individuals, prevent, and mitigate disease. To succeed in my goal to improve genetic testing for CVD and Lp(a), I will be developing skills across disciplines, especially in the domains of heart disease and computer science. This will not only advance my skills and increase my knowledge, but will also address existing challenges in precision medicine approaches to CVD. Better tools to predict those at risk of CVD and pathogenic levels of Lp(a) will benefit the American public, and will also help me further develop my role as a scientist and leader in the field of CVD and genetics now and for the years to come.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY/ABSTRACT Eukaryotic mRNAs typically have a 5’ cap and 3’ poly(A) tail that protect the ends from degradation. In addition, the cap and poly(A) tail are recognized by specific RNA binding proteins (eIF4E and poly(A) binding protein [PABP], respectively) that help the mRNA form a closed loop that promotes efficient translation. Many viruses analogously ensure their mRNAs end in poly(A) tails, but there are thousands of other viruses, including Flaviviridae, Bunyavirales, Reovirales, and Nodaviridae, that solely generate non-polyadenylated mRNAs. A handful of these non-poly(A) mRNAs are known to bind PABP, while others instead use viral proteins to bridge the non-poly(A) end to proteins bound to the cap, enabling the mRNA to adopt a closed loop. However, key molecular details of how the vast majority of viral non-poly(A) 3’ ends, including from Bunyavirales, enable mRNA stability and translation remain unknown. Addressing this gap will reveal critical insights into molecular mechanisms of pathogenesis and identify novel avenues for developing highly specific antivirals. Bunyavirales is a large order of single-stranded, segmented negative-sense RNA viruses that can cause serious human disease, yet there are no effective therapies or vaccines. They generate capped, non-poly(A) mRNAs and the exact 3’ ends of some of these transcripts were mapped decades ago. Their regulation is independent of PABP, but little else is known about how exactly these 3’ ends are stabilized or enable translation. This is in part due to a lack of efficient methods for generating and manipulating non- poly(A) mRNAs in cells. We have now overcome this major obstacle by repurposing a unique cellular process discovered in our lab (3’ end processing of the noncoding RNA MALAT1) into a novel expression method that efficiently and easily generates non-poly(A) mRNAs that precisely end in any sequence of interest. Here, we will take advantage of this new method to characterize the key minimal sequences and underlying molecular mechanisms of how select viral non-poly(A) mRNAs are stabilized and translated. We hypothesize that many of these non-poly(A) sequences fold into structures that enable interactions with RNA binding proteins distinct from PABP, thereby enabling the viral mRNAs to be subjected to unique regulatory strategies that may promote their own expression over host mRNAs and/or be targetable by therapeutics. In Aim 1, we will define in detail how non-poly(A) 3’ ends from exemplar bunyaviral mRNAs enable mRNA functionality. The minimal functional sequences and their protein binding partners will be identified, thereby revealing new paradigms of bunyaviral post-transcriptional gene regulation. In Aim 2, we will perform a novel massively parallel reporter assay to screen non-poly(A) sequences from the 3’ ends of a variety of viral mRNAs in order to rapidly identify those that most efficiently stabilize a reporter mRNA and enable robust translation. These collective efforts will reveal critical insights into how viruses ensure their mRNAs are hyper-stable and translated, which will help guide the development of novel antivirals and mRNA-based therapeutics with higher expression and efficacy.

NIH Research Projects · FY 2026 · 2025-01

Project Summary This R01 application will investigate a novel signaling pathway, the Hippo-YAP pathway, in mammalian heart injury. The long-term goal is to develop new treatments for patients with heart failure by generating treatments that promote a productive response to injury. The objectives of this application are to gain insights into gene therapy strategies that knock down Hippo signaling in cardiac tissue following myocardial infarction. The central hypothesis is that our Hippo knockdown gene therapy approaches can be modulated to improve cardiac function safely and efficiently in mice models of ischemic heart failure. The specific aims are to investigate the YAP-mediated mechanisms for induction of regenerative repair and to create a multi-omic map of the post-myocardial infarction heart. Further preclinical refinement of our gene therapy knockdown strategy is a required and important step to bring the approach to the clinic. The project is conceptually and technically innovative. Concepts to be tested include new ideas in cardiac biology and cutting-edge single-cell genomics technologies to address hypotheses. The significance is high because there are no treatments for heart failure, and devising ways to improve patient outcomes is highly significant.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY/ABSTRACT Genetic disruptions of the kynurenine pathway (KP) have been linked to congenital nicotinamide adenine dinucleotide (NAD) deficiencies in families with a history of birth defects and recurrent miscarriages. Mammals synthesize NAD from two pathways. The KP synthesizes NAD de novo from dietary tryptophan, whereas the Preiss-Handler pathway (PHP) bypasses the KP and utilizes dietary niacin. Birth defects associated with congenital NAD deficiency disorders (CNDD) include vertebral, anal, cardiac, tracheoesophageal, renal, and limb anomalies. Some individuals with CNDD also have global developmental delays, learning disorders, and autism. Through the Undiagnosed Diseases Network at Baylor College of Medicine (BCM), we identified a patient with biallelic variants in kynurenine 3-monooxygenase (KMO). KMO encodes an enzyme that catalyzes a key step in the KP and has not been previously associated with CNDD. The proband presents with congenital anomalies, short stature, neurodevelopmental delays, low plasma levels of NAD, and extremely elevated plasma levels of metabolites upstream of KMO (kynurenine and kynurenate). While indicative of a deficiency in KMO, the relative contribution of low NAD levels versus elevated upstream metabolites to her phenotypes is unclear. Moreover, it is not known which phenotypes associated with this disorder may be prevented by supplementing dietary niacin. I propose to use two mouse models of KMO deficiency and dietary manipulations to better understand the metabolic mechanisms underlying the phenotypes associated with KMO deficiency. My central hypothesis is that KMO deficiency is a novel CNDD that increases the risk for congenital anomalies and neurodevelopmental phenotypes, some of which are preventable with niacin supplementation. Overall, the findings from these studies will provide insights into strategies for preventing and treating the phenotypes associated with KMO deficiency and other CNDDs. To understand the risk for prenatal and postnatal phenotypes associated with CNDD and the role of NAD during embryonic development, I am utilizing a mouse model with a global KMO deficiency (Kmo-/-) and a mouse model with a liver-specific deletion of Kmo. My preliminary data show that Kmo-/- embryos are at a higher risk for developing congenital anomalies in the setting of a low niacin diet than their heterozygous littermates. In this proposal, I will analyze skeletal phenotypes in Kmo-/- and Kmo+/- embryos and assess metabolic alterations in these embryos. I will also investigate the role of kynurenine and kynurenate derived from the liver in causing neurodevelopmental phenotypes in Kmo-/- mice fed a niacin- sufficient diet. The long-term goal of these studies is to benefit individuals with CNDD as well as provide insights into the role of NAD and kynurenine metabolism in normal prenatal and postnatal development. The trainee’s environment is primed to accomplish these aims with mentorship from the sponsor and co-sponsor, and resources from the BCM CPMM, the BCM Advanced Technology Cores, and collaborators.

NIH Research Projects · FY 2026 · 2025-01

ABSTRACT Malignant glioma, the most common subtype of primary brain tumor in adults, causes high patient morbidity and mortality due to its aggressive nature and limited efficacious treatment options. To improve this prognosis, increasing studies have investigated a growing list of genetic factors that may contribute to glioma pathophysiology. These brain tumors are heterogeneous and generally arise sporadically; however, in 5-10% of cases, glioma stems from inherited genetic variations and are classified as familial glioma. Although there are many studies exploring mechanisms behind somatic mutations in glioma, less is known about hereditary variants that promote glioma susceptibility. Recently, germline mutations in Daam2 (Dishevelled associated activator of morphogenesis 2) were discovered in familial glioma patients. Daam2 is a formin protein known for its role in potentiating intracellular signaling during early development, regulating myelin structure, and influencing glial cell differentiation and morphology. Our research established the role of Daam2 in glioma in which its overexpression increases tumorigenesis by promoting the degradation of hypoxia-related tumor suppressor von Hippel-Lindau (VHL). While a handful of studies have linked Daam2 mutations to diseases such as lung cancer and renal disorder, the relationship between Daam2 mutations and glioma remains undefined. Moreover, whether and how Daam2 variants contribute to gliomagenesis, glioma growth, and progression remains unknown. To address this knowledge gap, I overexpressed these newly discovered Daam2 variants in patient-derived glioma stem-like cells and assessed their proliferation in vivo. In a patient-derived orthotopic xenograft immunodeficient mouse model, mice bearing tumors with Daam2 R414W overexpression showed a significant increase in tumor size and proliferation. These preliminary findings suggest that the Daam2 R414W germline variant promotes glioma growth. To study this variant in an immunocompetent model, I generated a Daam2 R414W knock-in mouse and discovered an expansion of proliferating glial progenitors in these Daam2 R414W mutant mice. Moreover, in search of a potential mechanism for this phenomenon, I found significant changes in cytoskeletal remodeling signatures in Daam2 R414W overexpression tumors from proteomic profiling gene ontology analysis. In this proposal, I propose to further define this mutation’s impact on glioma with three aims: (1) evaluate the capacity for this variant to promote glioma susceptibility and growth, (2) define the role of this variant in malignant progression, and (3) delineate a potential underlying mechanism of cytoskeletal dysregulation in glioma pathogenesis. When completed, this work will represent a significant advancement in our fundamental understanding of familial mutations and their role in glioma development. Moreover, the functional characterization and identification of familial mutations in Daam2 as potential early markers for glioma predisposition will have a far-reaching impact on patient survival.

NIH Research Projects · FY 2026 · 2025-01

Project Summary Congenital heart disease (CHD) is the most common birth defect and a leading cause of infant fatality in the United States. With improvements in techniques for medical intervention, more and more newborns with CHD live to adulthood. Severe CHDs often lead to heart failure (HF), which is a leading cause of death in children and adults with CHDs. High mortality and the cost of required treatment for CHD patients pose a tremendous burden to public health. Therefore, there’s an urgent need to develop novel and more efficient CHD therapies. Single Ventricle Disease (CVD) is a severe form of congenital heart disease in which neonates are born with a missing or underdeveloped left ventricle. Current treatment procedures are extremely invasive and introduce new risks of progressive HF. In addition to causes related to suboptimal surgeries, the reasons for CVD patients to develop HF remain unknown and difficult to predict. Genetic, epigenetic, and environmental factors have all been implicated as causative mechanisms underlying maladaptive features in the myocardium. This R01 application will investigate CVD in human and mouse cardiac fibroblasts (FBs). The objectives of this application are to gain insights into CVD with the long-term goal of generating treatments that promote productive heart repair in failing CVD hearts. The central hypothesis is that functional studies based on our published human profiling studies will develop datasets that can be used to predict HF patient clinical outcomes and uncover new therapeutic CVD targets. The specific aims are 1) To investigate FB intrinsic molecular mechanisms that promote senescence in CVD-HF patients, 2) To investigate the molecular mechanisms that lead to metabolic remodeling in CVD FBs, and 3) To determine if pathologic outgoing signaling from CVD FBs to CMs have deleterious functional effects on CVD CMs. The project is conceptually and technically innovative. Concepts to be tested include new ideas in cardiac biology and cutting-edge single-cell genomics technologies to address hypotheses. The significance is high because there are no treatments for heart failure, and devising ways to improve patient outcomes is highly significant.

NIH Research Projects · FY 2026 · 2025-01

Project Summary Disruption of the normal gut microbiota composition, termed gut dysbiosis, is an underlying cause of hypertension (HT). The pathway where dysbiosis leads to HT involves gut inflammation, neuroinflammation in the cardiovascular control centers in brain, and ultimately HT. This pathway from gut microbiota to HT requires communications via the microbiota-gut-brain axis (GBA), a multiple component system for the communication between the gut and the brain. Although a number of mechanisms have been described as messengers for GBA communications, our understanding of the GBA in the context of HT is lacking. Extracellular vesicles (EVs) released from bacteria represent a route for inter-kingdom communication through which the gut microbiota influences host. In this proposal, we will develop the idea that extracellular vesicles (EVs) derived from gut microbiota constitute an important component of the GBA communications involved with the development of HT. We now propose the overall hypothesis that the dysbiotic microbiota releases pro-inflammatory bacterial EVs that induce gut inflammation, neuroinflammation, and HT. In strong support of this hypothesis, we demonstrate that the cargo of bacterial EVs isolated from normotensive Wistar Kyoto (WKY) rats and spontaneously hypertensive stroke prone rats (SHRSP) gut is significantly different. Specifically, the pro- inflammatory bacterial components flagellin and lipopolysaccharide (LPS) are significantly elevated in SHRSP EVs. We show that bacterial EVs gain access to blood and brain. Finally, transplantation of bacterial EVs from SHRSP to WKY by oral gavage leads to increased blood pressure (BP). This proposal will interrogate the role of bacterial EVs as mediators of the GBA by examining the effects of EVs at the epithelial interface and in brain. In Aim 1 we will identify the bacterial origin of bacterial EVs involved in the development of HT and examine the mechanistic role of bacterial EV flagellin and LPS. Using a novel dilution scheme to simplify bacterial communities, we will determine the bacteria producing EVs that contribute to elevated BP. In Aim 2 we will elucidate the role of bacterial EVs on gut epithelial inflammation. Using gut enteroids derived from WKY and SHRSP we will determine the direct effects of bacterial EVs on epithelial inflammation and barrier function. In Aim 3 we will define the role of bacterial EVs on the development of neuroinflammation. Using single cell RNA sequencing we will determine the effects of bacterial EVs on microglia and neurons in the paraventricular nucleus. We will also deplete microglia to investigate the role of neuroinflammation in bacterial EV-induced HT. The focus of this proposal represents a novel area of investigation examining the role of bacterial EVs in the GBA and hypertension. These studies represent a translatable foundation for development of novel approaches for the prevention and treatment of HT.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY STXBP1 encodes syntaxin-binding protein 1, an essential protein for presynaptic neurotransmitter release. Patients with heterozygous pathogenic variants in STXBP1 are characterized by intellectual disability, epilepsy, movement, and psychiatric disorders, which are collectively termed STXBP1-encephalopathy (STXBP1-E). STXBP1-E is among the most common and severe forms of developmental and epileptic encephalopathy. The current treatments at best only alleviate individual symptoms without targeting the underlying genetic defect. Haploinsufficiency has been clearly identified as the disease mechanism for patients with truncating variants, which is supported by multiple in vivo mammalian models that recapitulate neurological phenotypes of patients. In contrast, the mechanism of action for missense variants, which make up 48% of the STXBP1-E patient population, remains unclear, in part due to the lack of in vivo mammalian models with construct and face validity. This leaves a critical knowledge gap in understanding the disease mechanism and developing mechanism-based genetic therapies. Thus, there is a critical need to establish a mouse model of STXBP1 missense variants to address this gap. To this end, the applicant focused on one of the most common and understudied missense variants in STXBP1 and has established a knock-in mouse model that recapitulates all key aspects of disease including epilepsy and impaired motor and cognitive functions. The goal of this project is to use this mouse model to understand the molecular and synaptic mechanisms (Aim 1) and determine the efficacy of an adeno- associated virus (AAV)-based gene therapy in rescuing the neurological dysfunctions (Aim 2). The applicant will use genetic manipulations in combination with various techniques including biochemistry, electrophysiology, optogenetics, behavioral assays, and electroencephalography (EEG) recordings. The proposed research is expected to elucidate how a common missense variant contributes to neurological phenotypes in a mouse model of STXBP1 encephalopathy and determine the potential of gene therapy as a therapeutic option. Furthermore, this project is designed to prepare the applicant for a career as an independent scientist in research and development and furthers the applicant’s long-term goal of performing gene therapy research to reduce the burden of neurological disease for all people. The Sponsor, Dr. Mingshan Xue, has a strong track-record of successful trainees and his lab conducts impactful research using mouse models of neurodevelopmental disorders to discover disease mechanisms and genetic therapies to treat the disease. Furthermore, the collaborative training environment of both Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute provides state-of-the-art technology cores, experts in the field of neurological disorders, and a central location in the Texas Medical Center that facilitates the success of the project and training of the applicant.

NIH Research Projects · FY 2026 · 2024-12

Project Summary / Abstract Accurately perceiving touch on our hands is essential to daily life. Discerning the source of sensory stimuli within the environment is referred to as Causal Inference (CI), and is vital in sensory processing. While principles of CI are well known, it is less known how the inferred causal structure of sensory stimuli modulates perception. Bayesian CI provides a probabalistic framework using Bayesian statistics to model how the perceived relationship between stimuli conditions stimulus perception. I hypothesize bimanual tactile processing can be understood within a Bayesian CI framework. To evaluate this hypothesis, I have developed a novel tactile paradigm that allows for the manipulation of inferred causal structure of touch across the hands. Using this tactile paradigm, I will characterize how concurrent visual feedback (Aim 1a) and previous visual feedback (Aim 1b) affect bimanual tactile sensitivity to timing differences. Additionally, I predict that Bayesian CI judgements and sensory percepts are represented within the brain. I will use functional Magnetic Resonance Imaging to identify human brain regions associated with CI judgements and evaluate to what extent brain activation reflects Bayesian CI computations (Aim 2). Completion of these aims will allow for better understanding of how bimanual touch is integrated and can shed light on broader principles of sensory integration. Understanding how touch is integrated across the hands can inform novel therapies for sensory- related disorders and advance development of haptics and brain-computer interfaces.

NIH Research Projects · FY 2025 · 2024-12

ABSTRACT Since the 1950s, integrated dual-degree MD/PhD training programs have enabled individuals with a passion for both science and medicine to pursue unique and impactful careers as physician scientists. These training programs empower individuals to play pivotal roles translating cutting-edge research into clinical applications that improve patient care by honing scientific rigor and transferrable skills and preparing students to become leaders in the biomedical research workforce. However, the number of physician scientist trainees has remained stagnant for more than a decade, challenging the objective to recruit and retain a large and diverse population of biomedical research leaders capable of addressing the nation’s evolving health care needs. Collaborative efforts by the National Institutes of Health, the Association of American Medical Colleges, and the National Association of MD-PhD Programs strive to increase support and foster the needs of aspiring physician scientists. More recently, the American Physician Scientists Association (APSA), a student-led national organization “by trainees, for trainees” has committed to addressing these obstacles by providing career development opportunities and serving as a voice for students of dual-degree training programs at all levels. To cultivate regional communities of physician scientist trainees, APSA empowers students in MD/PhD programs to organize and host regional meetings across the United States, spanning five regions: West, South, Midwest, Mid-Atlantic, and Northeast. The 2025 APSA South Regional Conference, hosted by the Baylor College of Medicine (BCM) Medical Scientist Training Program, aims to inspire and support early-career trainees from diverse backgrounds as they embark on the physician scientist career pathway. This one-day conference will feature scientific and career development sessions led by established physician scientists, panel discussions featuring regional academic leaders, oral and poster presentations by current MD/PhD trainees, and interactive educational workshops tailored to meet the specific needs of students at various stages of training. Focused outreach efforts will engage students from diverse backgrounds including those underrepresented in medicine and students with disabilities. By providing a platform for inter-institutional collaboration, longitudinal mentorship, and career development, the 2025 APSA South Region Conference will cultivate an inclusive community of physician scientists with an emphasis on the importance of diversity in the biomedical workforce.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY Clonal hematopoiesis (CH) is the expansion of peripheral blood cells derived from a single mutant hematopoietic stem cell (HSC) in the absence of hematological malignancy. CH is associated with increased risk of several age associated diseases however the disease manifestation and prognosis varies based on which gene is mutated, the variant, and the mutational burden. Most individuals over the age of 55 have at least one detectable clone, and of those, 25% have two or more mutant populations present. Despite this vast and variable health burden, little is known about how interactions between mutant clones influences clonal expansion. The top three genes mutated in CH are epigenetic modifiers DNA Methyltransferase 3A (Dnmt3a), Ten- Eleven Translocation Protein 2 (Tet2) and Additional Sex Comb like 1 (Asxl1). Several independent studies of each mutant clone in isolation have identified that these mutations provide HSCs with a survival advantage over wild type HSCs in the setting of inflammatory stressors, like infections. Additionally, these mutant clones not only respond to inflammatory stimuli, but are also potent produces of pro-inflammatory cytokines that aids in creating an environment that selects for the survival of the mutant clone. Transcriptionally, CH clones have a mutation- specific resistance to extinction by either attenuating the inflammatory stress response or preventing terminal differentiation. Collectively, these studies suggest Dnmt3a, Asxl1 and Tet2 deficient clones have a mutation- specific resistance to inflammatory pressures, and they perpetuate this selective advantage by inducing pro- inflammatory states. These studies also suggest that mutant clones and their progeny may impact the expansion of neighboring clones, but such clonal interactions and competition has not been studied. Preliminary experiments show Tet2 mutant clonal expansion is impaired when in the presence of Asxl1 and Dnmt3a-mutant cells. Interestingly, Asxl1 mutant clonal expansion is unaffected by other mutant clones and remains consistent with the presence or absence of other mutant clones. This unexpected finding suggests unexplored interactions between clones having a mutation-specific effect on clonal expansion. Based on published and preliminary data, I hypothesize that mutations influence the inflammatory microenvironment as well as the transcriptional response to stimuli such that clones behave differently in the presence or absence of other clones. In Aim 1, I will characterize clonal competition by measuring clonal expansion of Dnmt3a, Asxl1 and Tet2 deficient clones when in the presence and absence of other mutant clones following inflammatory challenge. In Aim 2, I will utilize single cell RNA sequence and ex vivo culturing experiments to identify interactions underlying clonal expansion between Dnmt3a, Asxl1 and Tet2 deficient HSCs and downstream immune cells. With the successful completion of these aims, I will be able to characterize mutation-specific expansion dynamics of each D-A-T clone and their interaction with other clones. I envision using this information to manipulate clonal dynamics as a future therapeutic modality for CH-associated diseases.

NIH Research Projects · FY 2026 · 2024-12

Project Summary Triple-negative breast cancer (TNBC), an aggressive breast cancer subtype that constitutes 10%–15% of all breast cancer cases in the United States, disproportionately affects Hispanic and African-American women. TNBC is associated with relatively poorer outcomes than other breast cancer subtypes due to the inherently invasive clinical behavior of TNBC and the lack of expression of molecules targeted by therapeutic agents that are effective for other breast cancer subtypes. TNBC displays molecular and transcriptomic heterogeneity, and both canonical (β-catenin–dependent) and noncanonical (β-catenin–independent) Wnt signaling dysfunction can mediate TNBC progression. Our group identified an inverse correlation between canonical and noncanonical Wnt signaling pathways, in which the noncanonical receptor, tyrosine kinase-like orphan receptor (Ror2), spatiotemporally regulates Wnt signaling in basal-like breast cancer. More recently, our lab identified that Wnt– Ror2 signaling can regulate tumor cell–driven extracellular matrix (ECM) modifications to support basal-like breast cancer invasion. However, the integration of Wnt signaling cues that drive ECM remodeling and promote colonization competence at distant sites remains unresolved. We hypothesize that Wnt signaling plasticity, influenced by the presence or absence of Ror2, fosters adhesion and matrix alterations in the lung metastatic niche to mediate micro-to-macrometastasis progression in TNBC. In Specific Aim 1, we will investigate how fluctuations in Wnt signaling modulate the ECM to bolster the ability of basal-like TNBC to colonize the lungs. Specifically, Aim 1.1 will map the dynamics of Wnt signaling transitions and monitor associated changes in ECM composition through various metastatic stages using models of lung metastasis. Aim 1.2 will focus on discerning alterations in the integrin–fibronectin relationship in response to genetic shifts in Wnt signaling. In Specific Aim 2, we will determine how Wnt signaling alterations influence tumor cell interactions with the lung endothelium, focusing on adhesion, extravasation, and macrometastatic progression post-colonization. Aim 2.1 will assess how perturbations in Wnt–Ror2 signaling impact interactions with the perivascular lung niche, potentially dictating patterns of basal-like TNBC tumor cell growth and arrest. Aim 2.2 will explore the role of Wnt signaling in regulating tumor dormancy cycles. Our overarching goal is to decode how Wnt signaling variations drive the metastatic journey of TNBC within the lungs. Utilizing both in vitro and in vivo methodologies, including genetically engineered mouse models of TNBC, we aim to unravel how Wnt–Ror2 signaling modifications affect metastatic aptitude in TNBC.

NIH Research Projects · FY 2026 · 2024-12

Project Summary/Abstract Many debilitating neurodevelopmental disorders (NDDs) are caused by a deficiency or excess of a specific gene product. Most of these disorders are treated at the symptomatic level, without targeting the underlying cause. Many efforts have been made to systematically find drugs that can modulate the responsible gene product and correct the imbalance. Artificial intelligence (AI) techniques, fueled by the vast amount of publicly available data, can prioritize the most promising treatments to test. There are tens of thousands of RNA-sequencing (RNA-seq) studies from the Gene Expression Omnibus (GEO) that give a quantitative readout of many gene and drug perturbations. If a chemical changes a cell’s transcriptome similarly or oppositely to the disruption of a specific gene, the drug might support or counteract the gene’s function. Large-scale analyses of discrete pathway data and transcriptomic studies have been used to discover novel protein regulators, and even successful NDD therapeutics. However, their ability to expedite screens for NDD therapies has not been quantitatively tested. This project will use AI to curate and analyze the literature and RNA-seq data, and predict the most likely genetic and pharmacologic regulators of single genes. Aim 1 will assess whether a fully automated prediction pipeline effectively prioritizes regulators of methyl-CpG- binding protein 2 (MeCP2). MeCP2 is an ideal target upon which to systematically validate predictions. It is a dosage-sensitive protein that is widely studied and perturbed. Patients with MeCP2 deficiency (Rett syndrome) and excess (MECP2 duplication syndrome) are given symptomatic therapies, and treatments for its imbalance are being developed, but there is no definitive remedy, and affected individuals continue to die in childhood or live with cognitive and motor defects. Drugs that correct the imbalance could help affected individuals, especially if given in their infancy, before all symptoms emerge and set in. This aim will involve using neuronal lines from an individual with Rett syndrome to test the top 20 predictions of MeCP2-regulating genes and drugs. Testing the top treatments without any manual filtering will determine whether this predictor effectively prioritizes successful MeCP2 regulators. Additionally, parts of a disease signature might be pathogenic, and others protective. There thus remains a need to find druggable subnetworks within a gene disruption signature. Aim 2 will establish a network analysis that can find separate network modules surrounding a given gene, and drugs that specifically target those modules. This study will identify promising treatments that can be repurposed to rescue developmental defects in individuals with Rett syndrome, as well as genes that serve as upstream regulators of MeCP2. On a larger scale, it will quantitatively assess the ability of AI-guided predictions to expedite the search for undiscovered drug-gene relationships. This will save a tremendous amount of time and resources in the search for therapeutics for monogenic NDDs, and pave the way to making more of these disorders treatable.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY Osteogenesis imperfecta (OI) is the most common osteodysplasia affecting between 1 in 15,000 and 1 in 20,000 live births. While variants in COL1A1 and COL1A2 are the most common causes of OI, up to 15% of OI cases are attributed to variants in other genes. Osteogenesis imperfecta type V (OI-V) is caused by a recurrent, heterozygous pathogenic variant (c.-14C>T) in the 5’ UTR of IFITM5, which encodes an osteoblast transmembrane protein. This point mutation creates a new in-frame start codon upstream of the endogenous start site which results in the addition of five amino acids to the intracellular N-terminus of IFITM5 that is hypothesized to prevent normal osteoblast differentiation in a neomorphic manner. Patients with OI-V may present with classic OI phenotypes like short stature, low bone mass, and recurrent fractures, in addition to OI- V specific phenotypes such as interosseous membrane calcification, hyperplastic callus formation, and radial head dislocation. The current standard of care for patients with OI-V is off-label use of bisphosphonates, which is ineffective at treating the complete phenotypic spectrum of OI-V. As such, the overall goal of this proposal is to develop targeted therapies that better address the underlying mechanism of OI-V. However, the temporal consequence of IFITM5(c.-14C>T) expression is not understood and further investigation has been limited by perinatal lethality of global Ifitm5(c.-14C>T) mouse models. Our lab has generated an OI-V conditional mouse model by inserting mutant Ifitm5(c.-14C>T) cDNA into the Rosa26 locus and induced expression of Ifitm5(c.-14C>T) in mesenchymal progenitor cells and mature osteoblasts using Prx1-Cre, and Ocn-Cre, respectively. Prx1- Cre;Ifitm5(c.-14C>T) mice demonstrate a severe skeletal phenotype including low bone mass, long bone deformities, and growth plate abnormalities that persist into skeletal maturity while the vertebrae and femora of Ocn- Cre;Ifitm5(c.-14C>T) mice do not show gross skeletal abnormalities, suggesting that early expression of Ifitm5(c.- 14C>T) disrupts normal osteoblast development. TGF-β is a known regulator of osteoblast differentiation, is a well- described pathogenic driver of other subtypes of OI, and anti-TGF-β therapies are in clinical trials to treat OI. Preliminary data from our lab suggests that downstream targets of TGF-β are upregulated in our OI-V animal models. We hypothesize that Ifitm5(c.-14C>T) results in increased TGF-β signaling which is a primary driver of the OI-V osteoblast differentiation defect and therapies that target either TGF-β signaling or the pathogenic point mutation early in development will improve OI-V phenotypes. This central hypothesis will be tested by the following two specific aims: 1) determine the role of TGF-β signaling in Ifitm5(c.-14C>T) mediated abnormal osteoblast differentiation and 2) determine the effect of IFITM5(c.-14C>T) targeting ASO therapy on osteoblast differentiation. By assessing these aims, we will gain important insight into the pathogenesis of OI-V that has the potential to directly impact preclinical development and testing of novel OI-V therapies.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY/ABSTRACT The overall objective of this study is to develop a novel imaging technology to directly observe and better understand multiple aspects of fertilization within the mouse fallopian tube in vivo. This study is aligned with the NIH mission in Woman’s Health Research established across all NIH Institutes and Centers “to advance rigorous research that is relevant to the health of women”. The ovulation, fertilization, and pre-implantation pregnancy are fundamental processes of clinical importance. However, because mammalian reproductive processes take place deep inside the body, our understanding of cellular and molecular mechanisms driving reproduction is based on the histology of extracted organs, low- resolution visualizations, and extrapolation from invertebrate animal models (e.g., sea urchin). The dynamic environment of the female reproductive tract is too complex to model, and understanding the interplay between the oviduct eggs, sperm, and the oviduct environment based on in vitro data without direct observation is not feasible. Therefore, much of our knowledge regarding the dynamics of fertilization and oocyte/embryo transfer in vivo is based on assumptions thereby limiting the development of infertility treatments and assisted reproductive technology (ART). By integrating expertise in live functional optical imaging and reproductive biology, we established a unique project investigating multiple aspects of fertilization in vivo within the mouse fallopian tube with functional optical coherence tomography (OCT). We performed the first in vivo tracking of oocytes and embryos within the fallopian tube and made discoveries that question current views in the reproductive field, setting a foundation for this proposal. This study is taking advantage of new technological developments in high-speed volumetric imaging and will allow for quantitative functional analysis of the natural fertilization process and fertilization failures in mouse models of human infertility. This project will provide new insight into the process of mammalian fertilization in its native state and lead to a better understanding of pathologies resulting in infertility. Mouse models provide an irreplaceable resource for healthcare, with thousands of genetic and epigenetic preclinical models available to study human diseases and an established pipeline for translating the knowledge from mouse models into clinical practice. This study will also enable the global international effort to inform human reproductive healthcare strategies through functional phenotyping of hundreds of mouse models linked to infertility.

NSF Awards · FY 2024 · 2024-11

The broader impact of this I-Corps project is based on the development of a surgical system that simplifies and optimizes various types of fetal surgeries. Fetal surgery, performed on a developing fetus during pregnancy, can be lifesaving or reduce the burden of congenital diseases. This technology may benefit the estimated 168,000 fetuses affected annually by conditions requiring fetal surgery. The absence of fetoscopes designed specifically for advanced fetal procedures means some fetal centers may avoid offering certain surgeries, or surgeons may rely on tools not optimized for fetal use. When centers do not offer comprehensive fetal therapies, families and communities face unnecessary expenses related to travel and support services. Additionally, the off-label use of pediatric instruments for fetal surgery often results in the use of larger diameter tools, and the need for additional uterine punctures, increasing the risk of maternal complications. These complications can undermine the medical and financial benefits of fetal surgery. This new technology has the potential to improve both maternal and fetal health outcomes and reduce unnecessary prenatal costs related to suboptimal instrumentation. This I-Corps project utilizes experiential learning coupled with a first-hand investigation of the industry ecosystem to assess the translation potential of the technology. The solution is based on the development of a surgical system designed to meet the unique demands of advanced fetal procedures, offering high-quality optics, advanced capabilities like dissection and suturing, and access to difficult-to-reach and hard-to-visualize areas. Currently, no commercially available fetoscopes are specifically designed to minimize risk and maximize functionality for these procedures. This system addresses multiple shortcomings of existing devices that are used off-label for advanced fetal surgeries. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY The cardiac conduction system (CCS) is specialized in the generation and propagation of electrical impulses from the atria to the ventricles to produce a highly coordinated muscle contraction. Cardiac conduction disorders (CCDs) including sick sinus syndrome, atrioventricular block (AVB), and bundle branch block are common arrhythmic disorders that impact the contraction of atria or ventricles. Cardiac pacing is the standard treatment for patients with symptomatic bradyarrhythmia resulting in implantation of over 600,000 pacemakers annually in US due to sinus node dysfunction (SND) or AVB. Currently, there is no alternative treatment for these patients. Thus, understanding the molecular and cellular mechanisms leading to CCD may provide a foundation for new therapeutic strategies. A nonsense mutation (c.C673>T, p.R225>X) in lamin A/C (LMNA) identified in a kindred, was associated progressive CCD and atrial arrhythmias, preceding the development of cardiomyopathy and heart failure. The mechanistic link between mutated lamin A/C and CCD is largely undetermined. Preliminary results suggest that the LMNA-R255X knockin mice develop CCD phenotype, similar to patient carriers of R225X mutation. The proposed work will elucidate the molecular mechanisms by which mutation in lamin A/C promote CCD. Our study will establish the pathological function of lamin A/C in CCD development. The molecular pathways uncovered from this study will likely have a broader impact on our understanding of the molecular mechanisms of CCD in the general population.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT The great advances made in genomic medicine that impact diagnoses and care of newborn babies in large academic centers in Texas are generally not available at most level III and level IV NICUs across the state. Major populations in El Paso, the Rio Grande Valley, and northwestern and central Texas lack local access to medical genetic expertise, capacity for genomic testing, and frontline practitioners with the knowledge to leverage personal genomic data to improve care. Residents in some of these regions must travel over 300 miles to reach the nearest in-state geneticist. Only twenty years ago, less than three percent of genetic conditions in newborns could be molecularly diagnosed. Today, with routine genomic tests at academic medical centers, over one third of these cases are diagnosed. Unfortunately, many babies born in regions far from academic medical centers lack access to genetic evaluation and testing, remain undiagnosed, and are unable to benefit from early personalized medical treatment. Here, we propose to dramatically improve the diagnosis, especially of rare diseases, in the sickest newborns in hospitals across under-resourced regions of Texas using a new generation of clinical assays (whole genome and RNA sequencing), leveraging a lower-cost sequencing technology and Consultagene, our established remote consultation service and platform. This combined approach (MAGNET) will improve access to care, help bridge gaps in health outcomes, increase the scale and quality of the genomic data generated, and advance personalized care. Moreover, we propose to make these diagnostic strategies available through a telehealth-based approach expanding access to medical genetics expertise while improving patient and provider engagement and education, at both academic and community neonatal intensive care units across Texas. This strategy will greatly democratize genome technology, enhancing access in geographically remote, poor, or under-resourced communities, and reaching a much larger proportion of hospitalized newborns. As such, our work will serve as a model for increasing genetic diagnoses among many communities in NICUs across the United States.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Obesity is a major risk factor for many chronic medical conditions, including diabetes, cardiovascular disease, depression, and cancer. Elucidating the neural mechanisms that regulate feeding behavior and body weight control is critically needed towards the development of effective strategies to combat obesity and its co- morbidities. We discovered that anoctamin 4 (Ano4, an ion channel) is abundantly expressed in the area postrema (AP) in the hindbrain. Activation of these APAno4 neurons increase food intake and blood glucose in mice. Importantly, a large-scale human genetic study established the association of the ANO4 gene mutation with human obesity, but the causality of this association has not been tested. The first objective is to determine physiological relevance of APAno4 neurons in energy/glucose balance. We will use both gain- and loss-of-function models to establish the function of the APAno4 neurons on feeding and valence behavior, as well as long-term regulation of body weight and glucose homeostasis. The second objective is to use a Cas9-mediated DNA editing to delete Ano4 only in AP neurons, and to determine physiological functions of the Ano4 channel on the excitability of AP neurons and on the whole-body energy/glucose balance. The third objective is to use a humanized Ano4 knock-in mouse model (mimicking the obesity-associated human ANO4 mutation) to determine whether this mutation causes obesity in mice and alters Ano4 channel functions. Completion of the proposed research will identify a novel target that regulates body weight balance in mice and humans, and provide the necessary framework to develop therapeutic strategies towards treating obesity.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY Historically largely focused on the demise of neurons, a wealth of literature in the neurodegeneration field has provided strong evidence for a critical role of neuroinflammation. It is now well established that both astro- and microgliosis contribute to disease onset and/or progression. These glial cells can directly respond to the aggregate/condensate pathology that characterizes these conditions and this has been suggested to underlie their hyperinflammation. Yet, why this happens has been puzzling as humans never experienced selective pressure to evolve the ability to detect age-related pathology. Why do glia respond to something they have never been trained to respond to? The immune system did evolve detection systems for infection, and the evolutionary arms race between humans and their pathogens has shaped a plethora of receptors and signaling cascades that are involved in the sensing of and immediate response to infection. This is the innate immune system. Recently, I unexpectedly discovered that some of these neuropathological proteins mimic the biophysical behavior of innate immune signals. Antimicrobial peptides—mostly known for their killer activity towards pathogens—also moonlight as pro-inflammatory signals. More specifically, these cationic peptides can promote the immunogenicity of nucleic acids towards their Toll-like receptors, in a process that is dependent on the electrostatic condensation of such peptides with the anionic nucleic acids. Condensing these immunogens concentrates them, protects them from degradation, and drives their trafficking to their corresponding receptor— hereby dramatically boosting the inflammatory response. Neuropathological proteins from many diseases condense or aggregate with nucleic acids, suggesting that such potent immune triggers are commonly found in the diseased brain. We show that the pathology associated with the most common genetic form of amyotrophic lateral sclerosis and frontotemporal dementia indeed signals to the innate immune system via this condensation- dependent mechanism. Thus, I propose the provocative idea that neuropathology in general must hijack such ancient immune signaling cascades to trigger the immune system. This hypothesis provides and elegant explanation of the decades-old question of the molecular origins of neuroinflammation. In this proposal, my lab will set out to rigorously test this hypothesis using a multidisciplinary approach that spans from biophysics to in vivo disease modeling. By leveraging our expertise in condensate biology, building on preliminary data from our genetics- and proteomics-based approaches, and using in vitro and in vivo models, we will uncover the biophysical rules and signaling cascades underlying this molecular mimicry. Neuroinflammation is a key modifier of disease progression. If successful, we will identify promising new candidates and compounds for therapeutic neuro-immunomodulation in these devastating diseases.