Baylor College Of Medicine

NIH Research Projects · FY 2026 · 2026-04

Preterm birth (PTB) affects 10% of pregnancies globally, with rates rising 12% between 2014-2022, incurring healthcare costs exceeding $25 billion annually in the US alone. While inflammation is a known trigger of PTB, the environmental factors driving this inflammatory response remain poorly understood. A critical knowledge gap exists in understanding how emerging environmental contaminants, particularly micro- and nanoplastic (MNP) particles, associate with PTB and alter placental immune function. Our preliminary data provide compelling evidence that MNPs bioaccumulate in human placentae at concentrations 23.9 times higher than in blood. Using pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS), we found significantly elevated MNP levels in preterm versus term placentae (224.7 vs 175.5 µg/g tissue; p=0.0032), with specific polymers showing 17-157% higher concentrations in preterm cases. The long-term objective of this research is to establish how environmental MNP exposure correlates with adverse pregnancy outcomes and identify modifiable risk factors for PTB prevention. Leveraging our completed longitudinal pregnancy cohort study (the Bacteria and Birth Study; BaBs Trial, n=585; PTB=103, term=367) with comprehensive maternal-infant biospecimens collected from first trimester through 6 weeks postpartum (>93,000 samples), we will: Aim 1) Define temporal patterns of MNP accumulation by quantifying 12 environmentally relevant polymers in maternal blood, urine, placental tissue, and cord blood (n=3,500 specimens) using Py- GC/MS, while integrating data on other environmental toxicants to establish exposure signatures that predict PTB risk; and Aim 2) Characterize the pathophysiology of MNP-associated placental dysfunction through systematic analysis of inflammatory markers (n=1,200 samples), histopathological changes (n=351 placentae), and immune cell distributions mapped by spatial transcriptomics (n=30 placentae). This comprehensive molecular and cellular characterization will establish the foundation for future mechanistic studies using animal models and in vitro systems. This research is innovative in challenging current paradigms of PTB etiology while introducing state-of-the- art methods to track environmental exposures during pregnancy. Our unique approach combines advanced analytical capabilities (Py-GC/MS- submicron plastics detection) with high-resolution spatial profiling to reveal how MNP exposure correlates with altered maternal-fetal immune balance. Success will establish: 1) The first longitudinal assessment of MNP accumulation patterns during pregnancy; 2) Novel biomarkers for identifying at- risk pregnancies; and 3) Key molecular and cellular changes associated with MNP accumulation in human placentae. These findings will directly inform the design of future mechanistic studies while directly providing evidence-based guidance for reducing harmful exposures during pregnancy, particularly benefiting vulnerable populations disproportionately affected by PTB.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Our long-term goal is to understand how rotaviruses (RVs) cause life-threatening diarrhea and to develop vaccines to combat this pathogen. Despite the global introduction of vaccines for RV over a decade ago, RV infections still cause >200,000 deaths annually, mostly in low-income countries, creating an urgent need for better vaccines to overcome this mortality. The structure of this large icosahedral virus is complex, consisting of three concentric capsid layers (triple-layered particles, TLPs) that encapsidate 11 genomic dsRNA segments. TLP assembly is unique and requires the viral nonstructural protein 4 (NSP4). NSP4, initially synthesized as an endoplasmic reticulum transmembrane 175 amino acid glycoprotein, serves as an intracellular receptor for nascent immature double layered particles (DLPs). DLPs bind to the cytoplasmic C-terminus of NSP4 and bud through NSP4-containing membranes and acquire a transient membrane. Through a poorly understood mechanism, the transient membrane is lost and the outer capsid proteins, the glycoprotein VP7 and the spike protein VP4, are assembled forming the infectious TLP. We previously characterized a domain of NSP4 that interacts with the stalk domain of VP4, which may be instrumental in outer capsid protein assembly onto TLPs. Unexpectedly, more recently, we discovered a domain of NSP4 is part of infectious animal and human RV TLPs but not DLPs. Immuno-electron microscopy clearly shows NSP4 associates with TLPs as detected by rabbit polyclonal anti-NSP4 antibody. Rabbits parenterally immunized with CsCl and sucrose gradient purified, psoralen-inactivated RV TLPs develop antibodies against NSP4 but not against any other known RV nonstructural proteins. Importantly, we previously demonstrated NSP4 interacts with integrins that have been implicated as RV receptors. Integrins are primarily located on the basolateral surface of intestinal epithelial cells where human RVs infect. Preliminary data shows NSP4 antibodies neutralize RV infectivity. Together, these data indicate a domain of NSP4 is a previously unrecognized component of virus particles. Our central hypotheses are a domain of NSP4 is retained on TLPs, NSP4 mediates the basolateral infection of human epithelial cells and NSP4 antibodies will neutralize RV infectivity. We propose experiments to answer: (1) Which domain of NSP4 is retained on RV, and where is NSP4 located on the TLP? (2) Do NSP4 antibodies neutralize human RV basolateral infection of human intestinal enteroids? While a correlate of protection against RV has not been determined, NSP4 antibodies ameliorate NSP4 induced diarrhea, and studies indicate NSP4 antibodies acquired by natural RV infection are associated with reduced RV diarrhea and seizures. NSP4 may become a new component of non-replicating injectable vaccines, either inactivated RV or subunit vaccines. Such vaccines that bypass the gut could be more effective than oral vaccines in low-income settings by avoiding factors that may limit immune responses in the intestine, such as gut inflammation, malnutrition, or co-infections.

NIH Research Projects · FY 2026 · 2026-04

Project Summary Relapsing fever (RF) Borrelia are vector-borne pathogens that cause severe clinical manifestations. While RF Borrelia can be transmitted by lice and hard ticks, soft ticks transmit most RF Borrelia species. The unique biology of soft ticks causes concerns for future RF outbreaks. While soft ticks have three developmental stages, which is similar to hard ticks, they also have 2-7 instar nymphal stages and can feed multiple times as adults resulting in a 10–20-year life span. RF Borrelia are maintained in the tick through the molt to each new life stage and can be transovarially transmitted from mother to offspring creating >10 opportunities for a single tick to transmit a RF Borrelia infection. In humans, RF Borrelia repeatedly reach high densities in the blood (spirochetemia) and cause recurring febrile illness, neurologic complications, and perinatal death. Upon initiation of antibiotic treatment, 30-50% of patients experience an acute exacerbation of symptoms known as Jarisch- Herxheimer reaction (JHR). Unfortunately, due to the lack of a cost-effective animal model that mimics human RF disease, we do not understand the mechanisms leading the severe clinical manifestations caused by RF Borrelia. Mice are the most commonly used animals to study RF Borrelia infection and pathogenesis, but mice are a limited disease model because they do not become hyperthermic during RF Borrelia infection. Nonhuman primates develop fever during periods of spirochetemia, but are too expensive to routinely use for rigorous studies. In this R03 application, we propose to develop the Guinea pig model to study RF disease. A historical study described Guinea pigs as viable hosts for Borrelia hermsii and Borrelia turicatae, the two Borrelia species that cause the most RF disease in North America. Both B. hermsii and B. turicatae repeatedly reached high densities in Guinea pig blood, and Guinea pigs become hyperthermic during spirochetemic episodes. Due to a lack of follow-up studies, the RF Borrelia-Guinea pig model remains largely uncharacterized in terms of pathogenesis, disease pathology, and JHR development. We hypothesize Guinea pigs will model human RF disease by inducing hyperthermia during spirochetemic episodes, producing pro-inflammatory cytokines during infection, and developing signs of JHR following antibiotic administration. To test this, we will assess B. hermsii and B. turicatae pathogenesis in Guinea pigs through quantification of spirochetemia, asses clinical signs of RF disease by measuring weight loss and body temperature of Guinea pigs and quantify cytokine production and tissue damage caused by B. hermsii and B. turicatae infection (Aim 1). We will also evaluate the development of JHR in Guinea pigs by measuring body temperature and quantifying cytokine levels after antibiotic treatment (Aim 2). Our thorough characterization of the RF Borrelia-Guinea pig model is critical to finding a relevant animal model to perform mechanistic and intervention studies to help mitigate the severe clinical manifestations cause by RF Borrelia.

NIH Research Projects · FY 2026 · 2026-03

1 Malignant gliomas are the most common and deadly form of primary brain tumors in adults. Despite decades of 2 research, their formation and progression mechanisms remain poorly understood, and survival rates have 3 remained unchanged over the past 30 years. These glial tumors include isocitrate dehydrogenase (IDH1) mutant 4 (IDH1mut) and IDH wild-type (IDH1WT) subtypes, each of which presents with unique clinical and histopathological 5 correlates. Prognostic outcomes for IDH1WT tumors are poor, conferring a median survival of less than 14 6 months. In contrast, IDH1mut tumors confer significantly better prognoses, with a median survival of 31–65 7 months after diagnosis. Molecular and genomic studies have revealed that the disparity in survival outcomes 8 between glioma subtypes is primarily attributed to differences in tumor cell proliferation and invasiveness. 9 Emerging evidence, including our own studies, suggests that glioma progression is closely linked to neuronal 10 activity, where interactions between glioma cells and neurons create a vicious cycle that drives tumorigenesis. 11 Despite recent findings on tumor-neuron interactions, there remains a key knowledge gap in glioma biology 12 regarding the electrophysiological profiles of tumor cells and their role in tumor progression. Therefore, the 13 overarching goal of this proposal is to develop computational methods to integrate multi-modal data and 14 systematically link the molecular and electrophysiological states of glioma cells, enabling a deeper understanding 15 of the mechanisms underlying electrophysiological function that contribute to tumor progression. 16 Patch-sequencing (Patch-seq), which couples electrophysiological recordings, morphological analysis, 17 and single-cell RNA-sequencing (scRNA-seq), has unveiled various neuronal subtypes that feature distinct 18 properties. In our preliminary studies, in situ Patch-seq on surgically resected human gliomas to 19 ascertain whether glioma cells exhibit neuronal features. We have identified a unique subset of glioma cells, 20 termed neuronal-like tumor (NLT) cells, which exhibit partial neuronal characteristics. These cells are capable of 21 firing action potentials, mimicking the electrophysiological behavior of neurons, while retaining the morphological 22 features of glial cells. While Patch-seq provides paired electrophysiological and transcriptomic data, technical 23 limitations restrict profiling to hundreds of cells. In contrast, scRNA-seq alone allows the sequencing of millions 24 of cells but lacks corresponding electrophysiological profiles. To bridge this gap, we aim to develop computational 25 models to predict electrophysiological profiles within large scRNA-seq datasets. These models will identify cell 26 types and gene programs underlying electrophysiological function, uncover postsynaptic partners, and reveal 27 spatially colocalized cells of electrophysiologically active NLT cells. Collectively, our preliminary findings have 28 led us to our central hypothesis that understanding how glioma cells disrupt normal brain physiology by mimicking 29 neuronal functions will provide critical insights into their contribution to tumor progression and guide the 30 repurposing of approved neurological and psychiatric drugs that target neural-cancer signaling. we performed

NIH Research Projects · FY 2026 · 2026-03

Abstract Despite improved human genome references, like the T2T and Human Pangenome References, limitations of short-read sequencing and inadequate tools preclude routine characterization of medically relevant complex regions like LPA, HLA, and GBA. This includes ‘graph genome’ methods, which have not yet been effectively applied to the characterization of clinically important, complex genes. We will develop a novel user-friendly and intuitive local graph approach that will be applied to resolve these critical genomic regions and yet accessible to non-specialists who wish to study complex regions of the human genome. A graph genome will be built from ~15,000 long-read genome assemblies from existing data from NIH Programs (All of Us, HPRC) and 50 locally generated long-read assemblies from a Cardiovascular Risk study (HeartCare) and then benchmarked and validated against existing references and methods. This graph will allow us to utilize existing short-read data to deepen our insights into the variation in LPA and its complex hypervariable Kringle IV type 2 (KIV-2) region, where additional variants potentially impact cardiovascular disease (CVD) risk. Newly assessed LPA variants will be analyzed for association with deep phenotypic measurements across 30,000 WGS and positive findings will greatly impact the application of LPA testing outside European populations. We will also apply our graph genome methods across larger data sets from TOPMed and All of US to assess around 1000 challenging but medically significant genes, including the American College of Medical Genetics Secondary Findings Gene List (73 genes), 132 HLA genes, and a further 395 clinically relevant genes, providing the most comprehensive annotated variant catalog of its kind. We will work with individual investigators (ARIC, SOL, All of US, GREGOR, TOPMed) to further validate the pathogenicity of newly identified variants, across multiple genetic diseases. We will also work with the TOPMed IRC to include these variants in imputation servers (BRAVO). Overall, this proposal will enable the use of graph genomes at scale and demonstrate their utility, impacting both the assessment of CVD risk across different populations and providing new information for multiple other diseases.

NIH Research Projects · FY 2026 · 2026-03

ABSTRACT Vascular dementia (VaD), the second most common subtype of dementia, is a neurological brain disorder in which cognitive deficits are attributed to cerebrovascular pathologies. Cognitive impairment and neuronal dysfunction are two of the major hallmarks of VaD. Throughout disease progression, vascular pathologies change the integrity of the neurovascular unit (NVU), a complex environment of cells that regulate brain homeostasis such as blood-brain barrier (BBB) and pH regulation. Astrocytes are glial cells within the NVU that serve a variety of functions, including the maintenance of the BBB and ion balance. Studies have shown that an astrocyte-enriched gene, Slc4a4, encoding for a sodium-bicarbonate cotransporter, has a role in regulating BBB integrity in both physiological and stroke conditions, as well as participating in pH buffering to mediate neuronal activity. This raises the question of whether astrocytes function in the progression of cellular pathologies and cognitive impairments seen in VaD. To investigate this, I combined our Slc4a4 conditional knockout mouse with an established VaD injury model to recapitulate and study the pathology of this disease. My preliminary data indicate a decrease of mature neuronal cells, elevated cell counts and morphological complexity of microglia, and a reduction of astrocytes, with severe cognitive deficits upon VaD injury in Slc4a4-depleted mice. When astrocytic Slc4a4 is overexpressed after VaD injury, I observed alleviation glial activation. Furthermore, bulk RNA sequencing of Slc4a4-cKO mice post VaD injury highlights an enrichment of genes associated with cognitive deficits and neurotransmitter dysfunction; however, the underlying mechanisms remains unknown. To bridge this knowledge gap, I propose three aims to investigate the role of astrocytic Slc4a4 in VaD progression. First, I will characterize Slc4a4 expression in human VaD tissue and in my VaD mouse model, additionally, assess cognitive and NVU VaD pathology in Slc4a4-cKO mice after VaD injury. Next, I will explore whether overexpression of astrocytic Slc4a4 rescues detrimental phenotypes in VaD. Finally, I will examine the functional correlation of Slc1a3, a candidate gene upregulated in Slc4a4-cKO mice in human VaD and during VaD in Slc4a4-cKO mice, in Slc4a4-dependent synaptic dysregulation. Additionally, I will test the synaptic and NVU changes upon pharmacological inhibition and overexpression of Slc1a3 in VaD-injured Slc4a4-cKO mice. Altogether, these studies will aid our understanding of the influence of Slc4a4 in VaD, paving the way for the development of essential therapeutic targeted strategies.

NIH Research Projects · FY 2025 · 2026-03

PROJECT SUMMARY Hematopoietic stem cells (HSCs) maintain blood production throughout an organism’s lifespan. Thus, HSCs must balance differentiation with self-renewal to protect stemness. To this end, HSCs are largely quiescent. Quiescence protects HSCs from genotoxic insults and functional exhaustion. Understanding the molecular mechanisms controlling HSC quiescence will yield valuable insights into mechanisms underlying hematopoietic disorders. While post-transcriptional regulation is increasingly recognized as important for hematopoietic cell fate specification, its role in HSC quiescence remains poorly understood. Preliminary data indicate that the post- transcriptional regulator DDX6 is important to maintain HSC quiescence. DDX6, an RNA helicase, orchestrates translational suppression and mRNA sequestration in cytoplasmic condensates known as P-bodies. Notably, Ddx6 knockout mice have normal mature blood cell populations but exhibit loss of HSC quiescence. Accordingly, Ddx6−⁄− HSCs exhibit increased proliferation and mitochondrial numbers, which results in diminished fitness during serial, competitive transplants. Mechanistically, initial analysis of DDX6-targeted transcripts in P-bodies revealed an enrichment for untranslated mRNAs encoding crucial regulators involved in exiting quiescence. Together, these data lead to our central hypothesis that Ddx6-mediated RNA processing is pivotal in protecting HSC quiescence and function. Aim 1 will test the hypothesis that Ddx6 is required for in situ stress hematopoiesis by challenging Ddx6−⁄− HSCs in vivo using regenerative and infectious stressors. Aim 2 will elucidate the mRNAs translationally suppressed by Ddx6 in HSCs and characterize the HSC translatome in situ both with and without Ddx6 deletion. Additionally, we will investigate the functional role of Ddx6 targeted transcripts in vivo, specifically Myc. The overall goal of this project is to elucidate a new mechanism controlling HSC function at the molecular and cellular levels and to advance strategies for treating hematologic diseases. This fellowship application is sponsored by Bruno Di Stefano, Ph.D., an expert in post-transcriptional gene regulation in stem cells, and Katherine King, M.D., Ph.D., a physician-scientist and expert in hematopoietic stem cells, who will provide close guidance throughout the fellowship period. The training plan includes strategies to 1) Learn from accomplished scientists and physician-scientists that will advise the applicant through her training goals; 2) Undergo rigorous scientific training in hematopoiesis and gene regulation; 3) Experience opportunities to improve scientific communication skills and expand professional networks; 4) Advance the applicant’s clinical training, especially in hematology. The clinical and scientific training environment at Baylor College of Medicine is within the Texas Medical Center, the largest medical research complex in the world. This environment is ideal to foster the applicant’s scientific and clinical growth toward a career as a physician-scientist investigating the role of post-transcriptional regulation in hemopoietic stem cell function and dysfunction.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY The NIH and other sponsors are investing heavily in translational research on new neural, brain, and pain relief devices. Many translational studies involve first in human subjects and include the implantation of brain devices in study participants. Translational neurodevice research raises many important ethical issues. One area that has received comparatively little empirical investigation and attention involves the ethics of decision-making about participation in early translational first-in human (FIH) neuro device research. This gap is concerning given that patients who decide whether to participate in FIH neuro device research are vulnerable due to refractory medical conditions, last resort options, trust and power dynamics with their team, and documented decisional biases such as optimism bias and “translational misconception”. At the same time, we must avoid unjustified paternalism—the belief that patients cannot provide true informed consent to participate in such research or that they should not be allowed to do so. What is essential is patient-centered perspectives on the vulnerabilities and value of participating in FIH neuro device research, their decisional and informational needs, accompanied by tools and approaches to improve decision making. The objective of this proposal is to identify and to address pressing ethical issues related to decision making about enrollment and participation in first-in-human translational research. In Aim 1, we will examine clinician- researchers’ and patient-subjects’ views on the value, vulnerabilities, and decisional and informational needs associated with participation in translational first-in human neuro device research. We will collaborate with and draw upon NIH-funded early and FIH translational research that represent growing areas of translational research with broad application and significance to patient populations: closed loop deep brain stimulation for a.) refractory and chronic pain and b.) treatment resistant mood disorders. In each case study will interview 1) patients with experience participating in first in human translational neuro-device research and patients who are potential future research subjects, 2) their family members and caregivers, 3) clinician researchers (e.g., neurosurgeons) who design the research studies, care for these patients, and implant translational neuro- devices, 4) other care team members including nurses, and 5) study coordinators with experience enrolling patients. In Aim 2 of the project, we will translate our findings from Aim 1 into a communication-decision tool for clinician researchers to use with patients considering participation in translational neurodevice research. We will alpha test this tool and disseminate it to key stakeholders.

NIH Research Projects · FY 2026 · 2026-03

ABSTRACT This project will generate tool compounds and chemical probes for putative therapeutic targets in Alzheimer’s Disease (AD) and AD-related dementias (ADRD) using DNA encoded libraries (DELs) and machine learning (ML). DELs are combinatorial small molecule libraries in which the identity of each small molecule is encoded in a unique, covalently attached DNA tag. We will use our pre-existing DELs at the Baylor College of Medicine Center for Drug Discovery to identify hits against dozens of AD/ADRD targets and to produce data sets with which we will train DEL-ML models to predict binders to these targets. We will share the compounds we make and a subset of the selection data to encourage ML method development and AD drug discovery by others. In Aim 1, we will perform DEL selections on putative AD/ADRD targets selected in consultation with our Target Advisory Board. We will share the selection input of 12 DELs (907 million structures: our OpenDEL) and the output (sequencing counts for tens of thousands of hits per target) as public data sets. We will synthesize high- ly enriched DEL hits off DNA, test them for activity, and share the data publicly. We will use focused DELs, as described in Aim 3, to optimize biochemically validated scaffolds and share these tool compounds. We will train DEL-MLs to identify hits in virtual re-purposing libraries composed of investigational small-molecule drugs that have passed a Phase I clinical trial, purchase hits, and test them biochemically. True positives in this drug re-purposing could be tested in animals and immediately go into clinical trials. In Aim 2, we will pursue in greater depth a few targets chosen with our Target Advisory Board from our Aim 1 portfolio. We will synthesize hits, test these for biochemical activity or binding, and pursue hit to lead optimi- zation. If our hits show toxicity or fail to cross the blood-brain barrier, we will use our DEL-MLs to identify unrelated hits in a compound virtual library curated for drug-like molecular properties and brain penetrance. We will purchase dozens of these compounds and test them for binding or biochemical activity. We will increase the potency of validated novel binders by constructing new DELs that incorporate the novel scaffolds. We will optimize the molecular properties of potent, selective hits, including the ability to pass the BBB, and test the efficacy of promising leads in animal models via collaboration. Aim 3 outlines how we will design and synthesize focused DELs or novel DELs that explore chemical space around a novel scaffold. We will use the predictive power of our DEL-MLs to assess our designs before implementing them synthetically. Selections performed using these DELs will provide potent hits to be tested in Aims 1 and 2, and large amounts of data to better train our DEL-MLs.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT Group B Streptococcus (GBS) is commonly associated with neonatal infections and can also cause a variety of soft tissue infections, including urinary tract infections (UTI) in non-pregnant adults. However, patients suffering from type 2 diabetes have a significantly higher incidence of GBS UTIs. Additionally, diabetics are more likely to develop complications from UTIs, such as pyelonephritis, urosepsis, and recurrent UTIs. Due to the metabolic/hormonal imbalance that characterizes diabetes, the disease can result in significant urinary tract alterations, including the presence of glucose and fructose in the urine (glycosuria). As metabolism is a significant regulator of both bacterial virulence and host response, I seek to examine glycosuria as a key contributor to the unique susceptibility of diabetic patients to GBS UTI. To discover how the diabetic urinary environment is shaping GBS adaptation, I conducted an RNA-sequencing (RNA-seq) screen on GBS cultured in urine from diabetic, pre- diabetic, and non-diabetic donors under microoxic conditions. The screen identified numerous genes that connect metabolism to virulence regulation. These results are further supported by my preliminary data showing that glycosuria increases GBS survival against reactive oxygen species and neutrophils. Based on these findings, I hypothesize that diabetic glycosuria modulates GBS virulence and host immune responses to promote urogenital colonization and infection. Testing of this hypothesis will be split into two aims: 1) characterize the fitness and virulence impact of candidate GBS genes in the diabetic urinary environment, and 2) evaluate the role of diabetic-associated urinary carbohydrates on immune response to GBS. I will use diabetic urine and healthy urine supplemented with carbohydrates to delineate the broad effects of diabetes from glycosuria on GBS survival against host factors and host epithelial response using complex in vitro urine-tolerant host models. Additionally, I will employ two mouse models, one of type 2 diabetes and one of glycosuria alone, to assess GBS virulence and the host immune response in vivo. This project will provide me with training in mammalian tissue culture and organoid model systems, mouse models of diabetes and UTI, and approaches to assessing host responses to pathogens while also expanding on my background in microbial pathogenesis. Training will take place at Baylor College of Medicine under the mentorship of experts in GBS, UTIs, and the immune response of bladders to infection. Together, this work will provide critical insights into GBS adaptation in diabetic hosts and inform the development of targeted, non-antibiotic interventions for this high-risk population, with potential implications for other pathogens affecting metabolically dysregulated individuals.

NIH Research Projects · FY 2026 · 2026-02

The Baylor College of Medicine node of the NHGRI GREGoR program (BCM-GREGoR) has built on the extensive discoveries and infrastructure established in previous programs. The research program is nested within the Department of Molecular and Human Genetics at BCM and engages the Human Genome Sequencing Center along with other BCM-research activities. Collaborators at the University of Texas and Columbia University Medical Center also participate. Overall, BCM-GREGoR has enrolled a cohort of ~18,000 individuals and families with challenging-to-diagnose rare disease conditions (those unsolved by routine clinical studies such as exome sequencing). Individual cases have been ‘solved’ through the integration of novel methods of genomic data analysis, data sharing across networks, new genomic sequencing technologies, and methods for molecular and organismal phenotypic interrogation of prioritized candidate disease genes and variants. Data have been shared with the GREGoR network via the GREGoR Data Coordinating Center (DCC) and AnVIL, including genomic and phenotypic data, case metadata, and BCM-GREGoR developed genomic tools. This supplement request to support the Baylor College of Medicine GREGoR program will enable completion of the original stated GREGoR goals, including a limited amount of data gathering for participant samples that remain unprocessed and consolidation of all data accrued during the course of the program to support analysis and final conclusions.

NIH Research Projects · FY 2026 · 2026-02

Project Summary Acari (mite and tick)-borne illnesses severely impact human health, and it is essential to understand the mechanisms maintaining the pathogens within their vectors for the development of countermeasures. Transovarial transmission (ToT) is used by mites and ticks to keep vector populations persistently colonized, but virtually nothing is known about the mechanisms of vertical transmission. While most work focuses on ixodid ticks, mites and argasids are understudied vectors most likely because of their complex biology. We developed the argasid–relapsing fever (RF) spirochete model (Ornithodoros turicata–Borrelia turicatae), which is one of the most comprehensive systems to study reproduction and ToT. We reported O. turicata vertically transmits B. turicatae by autogenous reproduction (laying of eggs without a blood meal), a unique aspect of argasid reproduction. This means that endemic foci of RF spirochete-infected ticks can be established quickly without needing a blood meal host. We have also identified an isolate of B. turicatae that is infectious by tick bite but fails to be vertically transmitted to offspring ticks. This phenotype enables us to study the mechanisms of ToT in this complex non-model system through comparative genomics. Also, our work in O. turicata genomics identified vitellogenins and the vitellogenin receptor, proteins that can be targeted by plant and veterinary microbial pathogens for ToT. Building on prior work and our developed entomological, bacterial, genomics, and genetics resources, we can now identify the molecular players involved in ToT. This application implements a functional genomics approach to test the hypothesis that ToT of RF Borrelia occurs throughout the reproductive cycles of female ticks and is driven by B. turicatae binding to vitellogenins and/or the vitellogenin receptor. The first aim will define the reproductive cycles of O. turicata and assess the dynamics of ToT for B. turicatae. This will be accomplished through the utilization of developed in vitro and in vivo tick feeding systems, tick colonies, and a diverse collection of B. turicatae isolates. The second aim will identify the molecular constituents of ToT. We identified gene loci and plasmids associated with a vertical transmission phenotype. We will build on these findings through comparative genomics and transcriptomics and identify B. turicatae surface proteins that bind to vitellogenins and/or the vitellogenin receptor. Using our developed genetics, we will transform the non- vertically transmitted B. turicatae isolate with plasmid and/or gene candidates to restore a ToT phenotype. While rickettsial, viral, parasitic, and RF Borrelia undergo ToT in mites and ticks, the molecular mechanisms are unknown. The completion of this project will result in the first identification of the molecular constituents involved with ToT of an Acari-borne pathogen. These findings will likely be broadly applicable and move the field closer to finding interventions that disrupt the life cycle of pathogen and vector.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY/ABSTRACT Lysinuric protein intolerance (LPI) is an inborn error of metabolism associated with multiple life-threatening complications in children. LPI results from biallelic loss of function variants in SLC7A7, which encodes a subunit of the y+L transporter (y+LAT-1). Dysfunction of this transporter impairs absorption of arginine, ornithine, and lysine by renal and intestinal epithelial cells as these amino acids may be intracellularly trapped. Low circulating levels of arginine and ornithine result in urea cycle (UC) dysfunction and the risk of hyperammonemia. These complications are managed with protein restriction and citrulline supplementation. However, children with LPI also develop other potentially fatal complications that do not respond to protein restriction and citrulline supplementation such as pulmonary alveolar proteinosis, hemophagocytic lymphohistiocytosis, early-onset autoimmunity, and juvenile osteoporosis. The underlying mechanisms of these complications in LPI are unknown, and there are no therapies specifically targeting these non-UC phenotypes. Myeloid cells have high levels of Slc7a7 expression, suggesting that dysfunction of myeloid cells may cause the non-UC phenotypes. Our lab has created a tissue specific conditional knockout mouse model that recapitulates LPI complications seen in children including osteopenia. I propose to use this mouse model to understand the metabolic and cellular mechanisms that underlie reduced bone mass in LPI. My central hypothesis is that juvenile osteoporosis in LPI is the result of arginine retention in cells of the hematopoietic lineage, which promotes inflammation and drives osteoclastogenesis. I will address this hypothesis with two aims. Aim 1 will demonstrate osteoporosis in our mouse model and determine if bisphosphonates are a suitable therapy for treating juvenile osteoporosis in LPI. Aim 2 will identify the metabolic mechanisms that explain how osteoclast progenitors contribute to the reduced bone mass phenotype in LPI. Together, these aims will demonstrate osteoclast dysfunction as the mechanism underlying juvenile osteoporosis in LPI. The long-term goal of these studies is to identify targeted therapies of osteoporosis that benefit children with LPI in addition to broadening our understanding of osteoimmunity and metabolism. With the clinical and scientific training environments offered at the Baylor College of Medicine and Texas Medical Center, the applicant is primed to accomplish these aims while working towards a future career as a pediatric physician-scientist.

NIH Research Projects · FY 2026 · 2026-02

The population of older adults (OA) is rapidly rising and anticipated to exceed 2 billion by 2050 causing an exponential rise in age-related comorbidities and healthcare costs. Age-related defects include mitochondrial dysfunction, inflammation, oxidative stress (OxS), insulin resistance (IR), genomic damage and endothelial dysfunction and result in declining physical function (gait speed and muscle strength), elevated blood pressure (BP) and higher waist circumferences. Via studies in OA and old mice (OM), we identified that deficiency of the body’s most abundant antioxidant Glutathione (GSH) plays a key contributory role for these defects in aging. GSH is an intracellular tripeptide composed of glycine, cysteine and glutamic acid, and declines with age. We found that GSH deficiency in OA occurs due to diminished synthesis caused by deficiency of glycine and cysteine (and not glutamic acid), and that GSH deficiency can be corrected by supplementing GlyNAC (combination of oral glycine, and N-acetyl-cysteine (NAC) as a cysteine donor because oral cysteine is absorbed poorly). In OM and OA, we discovered that GSH adequacy is critically necessary for efficient mitochondrial fuel (fatty-acid) oxidation (MFO) and for lowering OxS. In a small NIH-funded double-blinded, placebo-controlled, proof-of-concept pilot randomized clinical trial (RCT) in 24 highly selected, healthy OA and 12 young adults (YA) we reported that OA had (a) GSH deficiency in muscle and red blood cells; (b) impaired mitochondrial function; (c) deficient nutrient sensing; (d) increased inflammation; (e) elevated IR; (f) endothelial dysfunction; (g) genomic damage; (h) stem cell fatigue; and (i) cellular senescence. These abnormalities were associated with: (i) physical decline in gait speed, strength and exercise capacity; (ii) increased waist circumference; and (iii) higher blood pressure. GlyNAC (and not placebo) supplementation: (a) normalized RBC GSH concentrations, mitochondrial fuel oxidation, molecular regulators of energy metabolism, nutrient sensors, genomic damage, stem cells and cellular senescence; (b) lowered OxS, proinflammatory cytokines (IL6, TNFa, hsCRP); IR; endothelial dysfunction; (c) improved gait speed, strength, exercise capacity, body composition and systolic BP. GlyNAC supplementation in young humans had no impact. These data provide proof-of-concept that supplementing GlyNAC in OA corrects GSH deficiency and improves 7 aging hallmarks, and was not associated with any adverse effects. Could GlyNAC supplementation introduce a transformational change to improve the health of aging humans by promoting healthy aging? Although our completed RCT provides proof-of-concept for this, the sample size was small. Critically, the RCT was conducted in a rigorously screened cohort of healthy OA, using a high dose of GlyNAC. Therefore, it is important to definitively establish the validity and effectiveness of GlyNAC supplementation in a larger RCT conducted in a more typical population of OA, and also determine whether a lower GlyNAC dose, with lesser pill burden, could be effective. We propose a less invasive, less restrictive RCT in 150 more typical OA to determine the effects of supplementing GlyNAC on intracellular GSH, OxS, mitochondrial function, inflammation, IR, endothelial function, genomic damage, physical function, body composition and QoL. The proposed RCT will also test and compare two doses of GlyNAC to determine whether a lower dose of GlyNAC can be as effective as a higher dose on measured outcomes after 24-weeks.

NIH Research Projects · FY 2026 · 2026-02

Eukaryotic cells coordinate numerous biochemical reactions within specialized liquid-like compartments known as condensates. The largest of these, the nucleolus, has been proposed to orchestrate ribosome biogenesis by enhancing and regulating the dynamics of relevant molecules and their reactions. Consequently, nucleolar form (size, shape, and fluidity) and ribosome biogenesis are frequently disrupted in human diseases like developmental and neurodegenerative disorders, cancer, and aging. More generally, a persistent issue is the physical principles that govern the structure and function of condensates in cells and their relationship to liquid-liquid phase separation, akin to how oil droplets form in water. Indeed, nucleoli are complex structures formed through the interactions of numerous proteins and RNA, regulated by various aspects of cellular biology, which recent models must adequately address. My laboratory aims to develop new quantitative methods to clarify the physical properties and principles of condensates in cells, thereby enhancing our understanding of their role in cellular processes. We are investigating the hypothesis that phase separation and the formation of a nucleolar meshwork affect biomolecular transport and the rate of ribosome biogenesis, which the cell can subsequently regulate and may be compromised in disease. Recently, we have developed a novel quantitative microscopy method to determine the local meshwork and structure within condensates on the nanometer scale. Here, we seek to determine if there are changes in the composition of the nucleolus and nucleolar-derived condensates in response to cellular stimuli and during cellular transitions. We anticipate that addressing this question will uncover new biophysical principles underlying nucleolar form and the relationship between form and function, which may have broad implications for understanding and investigating the molecular mechanisms of condensate action in human physiology and disease.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Proper cerebellar function is important for many aspects of mental health, as evidenced by the wide range of neurological and neuropsychiatric disorders that have been associated with impaired neural processing in the cerebellum, from ataxia and dystonia to schizophrenia, autism and attention-deficit/hyperactivity disorder (ADHD). To understand how the cerebellum contributes to both motor control and cognitive functions it is necessary to define what kind of inputs it receives, particularly via the massive mossy fiber system, which carries the bulk of all sensory, motor and cognitive signals sent to the cerebellum from the rest of the brain. Furthermore, variations in brain state are likely to alter the information content of mossy fiber inputs and have a major impact on how well and reliably the cerebellum can perform its function. Unfortunately, conventional extracellular recording methods do not offer enough stability and often fail to distinguish signals of mossy fibers from other cell types in the cerebellar cortex. As a result, there is very limited knowledge about mossy fiber activity in cerebellar tasks, and no information at all about state-dependent modulation of mossy fiber responses or which mossy fiber states may be associated with enhanced cerebellar function. The experiments in this application take advantage of Neuropixels probes and a recent semi-supervised deep learning algorithm to overcome previous technical limitations and record for the first time from identified mossy fiber populations while mice perform a cerebellar-dependent eyeblink conditioning task. The analysis of mossy fiber activity, both before and during conditioning trials, is meant to achieve the following goals: (1) to provide new biological insight into the moment-to-moment variability of mossy fiber states, (2) to help define which mossy fiber states are associated with ‘faulty’ vs ‘reliable’ cerebellar function and, (3) to reveal how locomotion and non-invasive stimulation of the prefrontal cortex can be used to steer mossy fibers toward favorable states that are linked to improved performance of cerebellar-driven motor responses. Thus, the findings will have important implications for enhancing cerebellar function, both in health and disease, by developing new therapeutic interventions that can be used to promote beneficial mossy fiber states. Given the well-established role of the cerebellum in the control of movement, it is expected that the findings will impact patients with motor problems most directly. However, cerebellar dysfunction has also been associated with impairments in executive function, abstract reasoning, working memory, high-level language processing and attentional control. To the extent that the neural signature of ‘faulty’ and ‘reliable’ mossy fiber states is similar in regions of the cerebellum involved in these cognitive functions, the aims of this application and the implications for future treatments may apply to them as well.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Sepsis-induced coagulopathy (SIC) is a common problem of sepsis, occurring in up to 60% of patients with severe sepsis. It is characterized by widespread fibrin-rich clot formation in small blood vessels, impeding perfusion to vital organs, resulting in organ dysfunction and death in sepsis patients. Interleukin -1β (IL-1β) is a pro-inflammatory protein implicated in the pathogenesis of SIC. Interestingly, IL-1β can also directly bind to fibrin(ogen) (Fg), which may enhance its biological effects. IL-1β bound to Fg may play a significant role in the pathogenesis of SIC. To investigate this, I propose to study how IL-1β bound to Fg alters clot characteristics and neutrophil engagement in SIC in pediatric patients with sepsis and our swine SIC models. Aim 1: Investigate the effects of IL-1β bound to Fg on clot characteristics in SIC. Hypothesis: IL-1 bound to Fg increases clot formation and density while reducing clot lysis in SIC. I will use biochemical and cellular biology techniques to determine how IL-1β bound to Fg alters clot characteristics (i.e., clot formation, clot lysis, and structure) and clot function (i.e., clot stability and permeability) in septic human and swine plasma. This aim will reveal alteration in the clot characteristics due to IL-1 bound to Fg in SIC. Aim 2: Determine the impact of IL-1β bound to Fg on neutrophil activation in SIC. Hypothesis: IL-1β bound to Fg potentiates neutrophil activation and release of neutrophil extracellular traps (NETs) in SIC. I will isolate neutrophils from patients with and without SIC to study IL-1β bound Fg potentiates neutrophil activation and release of NETs. I will systematically block neutrophil receptor pathways to determine which pathway is critical for the IL-1β bound to Fg effects. The aim will clarify the path involved in the activation of neutrophils and the release of NETs mediated by the interaction between IL-1β and Fg. Aim 3: Compare thromboinflammatory signatures between septic patients with and without SIC. Hypothesis: Septic patients with SIC have a distinct thromboinflammatory endotype compared to those without. I will define and validate thromboinflammatory endotypes by generating and integrating data on disease severity, clot characteristics, IL1-β, Fg, proteomics, and immune profiling using unbiased clustering approach. This aim will identify thromboinflammatory endotypes in patients with SIC in relation to IL-1β bound to Fg. Impact of this proposal: I will determine how IL-1β bound to Fg contributes to SIC and identify septic patients who may benefit from treatments targeting this interaction to reduce their morbidity and mortality. Moreover, I will acquire technical skills (i.e., analyzing clot characteristics, protein-protein interactions, immune profiling, and advanced statistical methodology) and professional skills, which will aid my growth as a physician-scientist in conducting patient-oriented translational research into the mechanisms behind coagulopathy in SIC.

NIH Research Projects · FY 2025 · 2025-12

Abstract Keratinocyte Differentiation Factor 1 (KDF1) is an ectodermal dysplasia (ED) disease gene with a wide range in phenotype severity. Individuals with putatively damaging heterozygous variants in KDF1 present with ED and severe tooth agenesis, or milder non-syndromic tooth agenesis. Identifying KDF1 genotype-phenotype correlations that will predict the severity of oral phenotypes will result in earlier intervention with dental implants and improved prognosis for affected families. Our work has broad future applications, as five other ED disease genes display the same range in severity of syndromic and non-syndromic tooth agenesis (NSTA) phenotypes, yet the mechanism driving this variable expression remains unclear. Investigating the mechanism underlying the range in phenotype expression in KDF1-disease biology will have a profound impact on diagnostic variant interpretation in the clinic and individualized treatment plans for individuals with pathogenic variants in KDF1. Preliminary analyses suggest that individuals with pathogenic missense variants within the central domain (CD) of the KDF1 protein develop ED and severe tooth agenesis, while patients with missense variants outside the CD develop the attenuated NSTA phenotype with milder tooth agenesis. The CD is critical for KDF1 to bind and deubiquitinate IKKα, resulting in IKKα stabilization and downstream transcriptional regulation of keratinocyte and tooth germ development. Understanding the functional consequences of KDF1 variation is critical to inform disease management and potential therapeutic development. My central hypothesis is that the position of variants within KDF1 mediates the phenotype of ED or NSTA through impacts on IKKα stability. To address this hypothesis, I will first determine if severe tooth agenesis and the presence of ED phenotypes are dependent upon variant position within KDF1 by statistically interrogating well-characterized cohorts of severe and more tolerated KDF1 variation. I will then quantify the effects of KDF1 variants associated with syndromic tooth agenesis on keratinocyte differentiation and IKKα stability and abundance by creating and characterizing CRISPR/Cas9-edited cell lines and performing co-immunoprecipitation assays and western blot analysis. The findings of these studies will elucidate the mechanism driving severe KDF1-disease, advance our understanding of ED pathogenesis, and inform predictive disease management practices. The research proposed in this application aims to foster my development in becoming a successful independent researcher and clinical molecular geneticist. My research environment within the Posey laboratory, the Texas Medical Center, and the Baylor College of Medicine GREGoR Consortium research center offers an exceptional foundation for achieving these aims.

NIH Research Projects · FY 2025 · 2025-11

PROJECT SUMMARY/ABSTRACT Heart failure (HF) remains a leading cause of morbidity and mortality worldwide. Despite the availability of various therapies, preventing the maladaptive changes associated with HF continues to be a challenge. This R01 project will elucidate the mechanistic aspects of how cardiac tissue-resident macrophages (TRMs) contribute to adverse remodeling in the heart during HF. Our long-term goal is to target innate immune response in the heart to pause and even prevent HF progression. Over the past decade, the PI's lab and others have demonstrated that cardiac TRMs play cardioprotective roles in various cardiac diseases and HF conditions. However, preliminary studies on human failing hearts and mouse HF models showed that in HF conditions, cardiac TRMs transitioned into a pathologically senescent state (SenTRM), which correlates with cardiomyocyte (CM) stress and inflammation. Interestingly, this transition is reversible with interventions that can unload the failing heart, suggesting the therapeutic significance of SenTRM modulation in HF. The central hypothesis is that macrophage senescence promotes CM dysfunction in HF involving chronic inflammation and impaired clearance of CM debris, the mechanisms of which will be dissected in the following three aims. Aim 1 will determine whether TRM senescence contributes to CM inflammation through both the loss of steady-state TRMs and the rise of senescent TRMs. Aim 2 will determine whether SenTRMs have an impaired clearance function, specifically their role in removing CM mitochondrial debris—a key factor in heart function deterioration. Aim 3 will address the upstream mechanisms leading to TRM senescence, focusing on whether blocking Interleukin-6 signal reverses macrophage senescence. This project is conceptually and technically innovative, involving cutting-edge single-nucleus profiling, human patient-derived cell-based models, and mouse genetic tools to test the hypothesis and elucidate the underlying mechanisms of macrophage senescence in HF. The mechanistic insights gained from these studies will enable the development of novel therapeutic strategies that specifically target macrophage senescence to prevent adverse cardiac remodeling during HF. Thus, this project has a solid translational impact, opening new avenues for improving treatment outcomes in patients with HF, an area of high significance to NIH/NHLBI.

NSF Awards · FY 2025 · 2025-10

The project aims to serve the national need of preparing the workforce to use data and advanced technologies such as artificial intelligence (AI) to solve problems. Data skills are important in science, technology, engineering, and math (STEM) careers, but all children will need to learn how to create, interpret, and apply data to be informed citizens. Unfortunately, many teachers lack experience with these topics or tools. They also lack opportunities to learn how these skills are applied in real STEM jobs. This means they may not be able to teach their students these skills or tell them about the jobs in these fields. This project is designed to teach prospective and practicing STEM teachers to use data and advanced technology in real science research. Teachers will learn to use the software Orange, which does not require a background in coding or analysis. Because it is easy to use, teachers can learn basic data skills quickly. After learning data and AI skills, teachers will use them in real bioscience research. They will also create classroom lessons and participate in activities to help build their confidence as members of the science community. By building their own skills and confidence in data and technology, teachers may be able to better prepare their students for future careers. This project at Baylor College of Medicine includes partnerships with Prairie View A&M University, Texas Southern University, Houston Christian University, St. Thomas University, the University of Houston Clear Lake UHCL) Teach program, and the Houston Independent School District. Project goals include developing data analytics competencies – understanding of authentic applications of data analytics, machine learning, and AI in STEM; ability to incorporate into teaching – and deepening identities as members of the scientific community of 20 preservice and 20 in-service STEM teachers over five years by engaging them in mentored bioscience research and professional development. The theoretical Collaborative Around Research Experiences for Teachers model supports the translation of research experiences into classroom instruction through the inclusion of community building, awareness of research and careers, etc. Research experiences can improve teachers’ understanding of the nature of scientific inquiry and their ability to communicate concepts and the value of science to students. Given the dearth of experiences explicitly aligned with data analytics and AI, we anticipate that participants could impact the workforce preparation of approximately 20,000 students by five years post-program. Surveys, artifacts, and rubrics will be used to evaluate impacts on skills, self-efficacy, identity and teaching practices. Curriculum, including training on the easy-to-use, visual data analysis software Orange, will be freely disseminated via our website, BioEd Online. Outcomes will be presented in conferences and peer-reviewed manuscripts. This Research Experiences in STEM Setting project is supported through the Robert Noyce Teacher Scholarship Program (Noyce). The Noyce program supports talented STEM undergraduate majors and professionals to become effective K-12 STEM teachers and experienced, exemplary K-12 teachers to become STEM master teachers in high-need school districts. It also supports research on the effectiveness and retention of K-12 STEM teachers in high-need school districts. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-09

Retinal diseases such as glaucoma, macular degeneration, and diabetic retinopathy, as well as traumatic injury, result in loss of retinal neurons and thus sight, depriving many worldwide of one of our most valued senses. Thus, there is a critical need to devise strategies to restore lost retinal neurons, leading to vision recovery. Current efforts in retinal regenerative medicine are heavily invested in cell replacement approaches. However, it may also be possible to induce the mammalian retinae to undergo an intrinsic self-repair mechanism to regenerate neurons. The retinae of non-mammalian vertebrates, such as zebrafish, are known to exhibit the remarkable ability of retinal regeneration. Here, Müller glial cells (MGs) reprogram to proliferative, retinal progenitor-like cells that, in turn, differentiate into new photoreceptors, leading to restoration of vision. Unfortunately, for unknown reasons, mammalian MGs have lost this ability, or it is dormant. Our long-term goal is to identify the cellular and molecular mechanisms blocking mammalian MG-mediated retinal regeneration. By doing so, we may be able to devise strategies to bypass this system and thereby reawaken the regenerative potential of the mammalian retina. In this proposal, we will test the overarching hypothesis that transient modulation of the Hippo signaling pathway drives MGs into a progenitor-like state capable of generating new retinal neurons and MGs. To test this hypothesis, we will employ a multi-disciplinary approach using genetic loss- and gain-of-function experiments, fate mapping, and single-cell transcriptomics. Our specific aims will precisely determine the fate of proliferative MGs, which are non-responsive to Hippo pathway regulation, as being neurons and/or MGs. We will also determine how retinal damage triggers MG cell cycle entry prior to repression by Hippo. These data will provide an essential molecular entry point for further investigating novel methods to promote Müller glial cell-mediated retinal regeneration, and are likely to have a significant impact on the field of retinal regenerative medicine. We anticipate subsequent investigation into more translational, therapeutic methods to modulate Hippo pathway activity to promote retinal regeneration.

NIH Research Projects · FY 2025 · 2025-09

Abstract This project will develop a robust and transparent framework for the validation and replication of autism data science models through a multi-modal, cross-institutional approach. The initiative will employ comprehensive datasets from various sources, including clinical, genomic, environmental, and physiological data from Texas Children’s Hospital (TCH) and other prominent research repositories. By leveraging advanced AI/ML methods, we will rigorously assess model performance across different pediatric populations, ensuring generalizability and fairness in clinical settings. We will implement a two-pronged validation strategy, including intact model testing and code-blinded replication. This methodology will rigorously evaluate the accuracy, reproducibility, and population-specific calibration needs of predictive models. Key to this effort will be a large-scale integration of structured clinical data from TCH's Research Data Warehouse, combined with genomic data from the SPARK (Simons Powering Autism Research for Knowledge) genetic cohort and metabolomics data from the BaBS (Bacteria and Birth Study). Additionally, environmental exposure models will be validated with placental biomarkers linked to neurodevelopmental outcomes. The project will provide essential insights into the limitations and strengths of autism-related AI models in real-world applications, guiding their future clinical deployment. Through a commitment to transparency, reproducibility, and stakeholder engagement, the project will deliver high-impact validation reports, including community-accessible tools that ensure models are utilized effectively across a broad range of patient populations. The outcomes of this work will enhance autism care and set a new standard for multi- modal, multi-institutional model validation in pediatric health research.

NIH Research Projects · FY 2025 · 2025-09

Acute lymphoblastic leukemia (ALL) is the most common cancer in children and, although cure rates have improved over the past 50 years, population-based disparities persist. In particular, Latinos have the highest incidence and among the lowest survival rates for leukemia in the U.S. The underlying causes of this disparity are multi-factorial, including differences in disease biology, host factors related to susceptibility and treatment response, and exposure to a broad spectrum of social determinants of health (SDoH). Host pharmacogenomics and epigenetics, and other biological factors resulting in increased treatment-related toxicities are key and under-studied causes of population-based disparities in outcomes. Adverse outcomes result both from direct treatment-associated morbidity and mortality, and from compromised ability to deliver sufficiently intensive anti-leukemic therapy. The overall goals of this U54 program are to reduce outcome disparities among Latino children and adolescents with ALL by identifying biological and SDoH factors that result in adverse outcomes. Notably, this program will constitute the first Specialized Programs of Research Excellence (SPORE) devoted to pediatric leukemia. The four Research Projects will identify multifactorial etiologies of disparities in outcomes in Latinos, including factors associated two key treatment-related toxicities, hepatotoxicity (Project 1) and methotrexate-associated neurotoxicity (Project 2); pharmacogenomics (Project 3); and patient-reported outcomes, epigenetics, and SDoH (Project 4). The ultimate goal of this SPORE is to pursue prevention and treatment strategies aimed at reducing population-based disparities in all these areas. The Program will be administered through the Administrative Core (Core A). Biospecimens will be processed by Core B, and statistical analysis will be provided by Core C. Core D will facilitate community outreach and engagement. A Developmental Research Program will foster development of innovative pilot projects that aim to understand and/or reduce population-based disparities in ALL outcomes, and a Career Enhancement Program will recruit, train, and guide an unselected, population-based group of physicians and scientists to become successful translational investigators focusing on population-based disparities in outcomes in pediatric ALL. We will leverage the REducing Disparities in Acute Leukemia (REDIAL) Consortium, comprising 6 cancer centers in the southwestern U.S., to generate a rich population-based dataset derived from over 7,000 children and adolescents with de novo ALL (over 6,000 existing and 1,000 to be added during the current study), and a biorepository of bone marrow, blood, buccal cells, and cerebrospinal fluid samples from nearly 2,000 subjects. This invaluable resource will also serve as an important asset for current and future investigations of factors associated with disparities in ALL toxicities and outcomes. This work will form the foundation for development of effective risk prediction and intervention strategies to reduce outcome disparities in Latino children and adolescents with ALL.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Atherosclerotic risk factors, including disturbed flow (d-flow), induce endothelial cell (EC) DNA damage and the subsequent EC death, compromise the integrity of the endothelial barrier, and ultimately lead to the formation of atherosclerotic lesions. Metabolism such as glycolysis and fatty acid metabolism are reprogrammed to accommodate ECs to the atherosclerotic environment. Nucleotide metabolism, including purine and pyrimidine synthesis, has been reported to regulate DNA repair and cell proliferation in cancer cells. However, the role of endothelial purine and pyrimidine synthesis in atherosclerosis has not been investigated. 5-aminoimidazole-4- carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC) and Carbamoyl- phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) are critical enzymes for de novo purine synthesis (DNPS) and de novo pyrimidine synthesis, respectively. Recently, I have demonstrated the pivotal role of ATIC in vascular smooth muscle cells in proliferative arterial disease in rodent models. However, it remains unclear in the role of ATIC or CAD-mediated de novo nucleotide metabolism in ECs in the development of atherosclerosis. My preliminary data show that (1) DNA damage response was increased in ECs exposed to disturbed flow, and this was accompanied by increased ATIC-mediated DNPS and CAD-mediated de novo pyrimidine synthesis; (2) Knockdown of ATIC with siRNA aggravated EC DNA damage and apoptosis induced by d-flow; (3) The atherosclerotic lesion size was markedly increased in EC-specific Atic deficient mice in d-flow-induced mouse atherosclerosis. These data allow me to hypothesize that ATIC-mediated DNPS and CAD-mediated de novo pyrimidine synthesis in ECs supply nucleotides to repair DNA damage and preserve EC barrier integrity in vulnerable atheroprone regions and ultimately protect against the development and progression of atherosclerosis. To test my hypothesis, I have generated endothelial Atic or Cad deficient mice (AticΔVEC and CadΔVEC) and crossed the mice with ApoE-/- mice to generate ApoE-/-;AticΔVEC and ApoE-/-;CadΔVEC mice. I will investigate the effect of endothelial Atic or Cad deficiency in the formation of atherosclerotic lesions using specific genetic tools with an integrated approach of in vivo and in vitro models. The results of this study will provide insights into how metabolic reprogramming of purine and pyrimidine synthesis in endothelial cells is involved in the development of atherosclerosis, offering new strategies for its prevention and treatment. This grant will be critical for me to achieve the following short- and long-term objectives: 1) to acquire additional scientific training both methodologically and conceptually; 2) to merge the yet distinct metabolism and atherosclerosis fields with the goals toward opening up new avenues of discovery; 3) to establish an independent research program; 4) publish high-impact corresponding author articles and develop a highly competitive R01 grant application. I have assembled a multidisciplinary team to guide my career toward independence and assist with the completion of the proposed research study.

NIH Research Projects · FY 2025 · 2025-09

Acute kidney injury (AKI) is the most frequent complication after cardiac surgery and is associated with a multitude of adverse outcomes including increased short- and long-term mortality, length of stay, and hospital cost. Early prediction of AKI can enable targeted interventions involving volume, inotrope, and pressor management that have been shown to improve outcomes and mitigate injury. Presently, AKI is identified via clinical parameters such as urine output and serum creatinine, however these represent late findings often manifesting after the treatment window. Furthermore, current methods for estimating AKI risk provide static predictions that are of limited clinical value in the dynamic postcardiac surgery critical care environment. In our preliminary work, our team recently demonstrated that ensemble machine learning (ML) analysis of electronic medical record (EMR) intensive care unit (ICU) data enables the early and accurate prediction of AKI after cardiac surgery. The objective of this proposal is to leverage ML based analysis of EMR data to develop new clinical decision support (CDS) tools to monitor AKI risk and suggest personalized, timely, data-driven interventions that prevent or mitigate morbidity. Our central hypothesis is that ML models can facilitate clinical decision making by accurately and dynamically predict AKI from routinely collected EMR data and enhancing clinical decision making by quantifying risk reduction of therapeutic interventions. The rationale underling this proposal is that completion will yield a clinically translatable ML-enabled CDS tool that can identify AKI earlier than clinical detection and effectively support clinical decision making to mitigate AKI after cardiac surgery. The central hypothesis will be tested by pursuing three specific aims: 1) develop personalized ML algorithms for real-time early detection of AKI; 2) develop interpretable ML algorithms for therapeutic interventions to mitigate AKI; 3) prospectively validate model predictive performance and efficacy as CDS tool. The proposed project is innovative in the application of novel ensemble ML techniques to analyze our unique Baylor College of Medicine Cardiac Surgery Database that combines validated clinical registry data with time series EMR data (hemodynamic, medication, and laboratory) during the pre-, intra- and post-operative phases of care. The proposed project is significant because early identification and optimized management of AKI will improve outcomes for patients with this highly prevalent and morbid complication. Furthermore, successful measurement of model efficacy in clinical practice will legitimize ML-enabled CDS systems thereby improving clinician buy in, as heretofore few ML-enabled CDS tools have been evaluated in real-world conditions and even fewer clinically implemented. This work will provide a framework for development and translation of ML-enabled digital health solutions that can be applied to a variety of clinical scenarios. The expected outcomes of this work are 1) the early and accurate identification of AKI; 2) the data-driven identification of optimal management strategies to mitigate AKI; 3) validation of ML-enabled clinical decision support systems in the clinical environment.