University Of Miami School Of Medicine

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY Efficient glycemic control relies on the ability of the pancreatic islet to enhance its function after a meal. An islet solely reacting to elevated glucose levels will address hyperglycemia after it occurs, whereas an islet that receives advance sensory cues about impending nutrient intake can proactively prevent glucose spikes. This anticipatory regulation is driven by sensory inputs relayed from the gastrointestinal tract, enabling the islets to fine-tune their function based on forthcoming dietary intake. In the current view, nutrients in the gut lumen trigger incretin secretion that act directly on beta cells or signal through the central nervous system, influencing both glucoregulation and appetite. By contrast, the entero-pancreatic neuronal pathway did not get traction after its discovery in the 1990s, most likely because of technological roadblocks. Major goals of this proposal are to (A) investigate the glucoregulatory role of the entero-pancreatic neuronal pathway in detail, and (B) elucidate the mechanisms by which signals from the gut lumen are transmitted to the pancreatic islets via enteric nerves. We hypothesize that the neuronal entero-pancreatic reflex plays a major physiological role in glucose metabolism, with an impact on insulin secretion comparable to that of hormonal incretins. The rationale for the proposed research is that if we want to develop therapies it is imperative to elucidate the mutual interactions and mechanism between the gut and the pancreas that promote beta cell function. The proposed research is therefore relevant to the mission of the NIH that pertains to the pursuit of fundamental knowledge about beta cell function and its demise in diabetes. Guided by strong preliminary data, our hypothesis will be tested by pursuing three specific aims (1) uncover the mechanisms coupling gut sensing to entero-pancreatic neurons, (2) elucidate the neurotransmission mechanisms from enteric neurons to pancreatic islet cells, and (3) define the functional role of the entero-pancreatic neural plexus in glucose metabolism. We will leverage advanced in vivo genetic and imaging technologies to delineate the specific mechanisms involved. We have developed an innovative intravital imaging platform that enables Ca2+ imaging in pancreatic cells while perfusing the duodenum with various stimuli, allowing us to investigate how different luminal contents impact pancreatic activity. Additionally, single nuclei sequencing will be employed to uncover the transcriptional signatures of entero-pancreatic neurons. Pharmacogenetic manipulation of this pathway will help us understand its role in glucose metabolism under normal conditions and in diet-induced obesity. The proposed research is significant because it could generate mechanistic insight into how the enteric nervous system primes the beta to respond appropriately to an upcoming surge in glucose. By identifying the effectors and principles governing this inter-organ regulation, we will not only be complete our model of the regulation of blood sugar levels but also find potential targets in the entero-pancreatic nervous system for novel therapeutic strategies for the treatment of type 2 diabetes, a condition that globally affects 462 million individuals.

NIH Research Projects · FY 2026 · 2026-06

Attenuating neuronal cell death during the secondary phase of spinal cord injury (SCI) is critical for reducing long-term neurological dysfunction. Recent studies have identified protein arginylation—a posttranslational modification mediated by arginyltransferase 1 (ATE1), as a key driver of neuronal death following SCI. While genetic or pharmacologic suppression of ATE1 confers neuroprotection in both cellular and animal models, the lack of potent, specific, and in vivo-compatible small-molecule ATE1 modulators has hindered progress toward therapeutic development. Building on our prior work in ATE1 biology and assay development, we have established a novel dual- fluorescence, cell-based reporter platform capable of monitoring ATE1 activity in live cells with high sensitivity and compatibility for high-throughput screening (HTS). In this project, we aim to optimize this platform for large- scale compound screening at the R61 phase, and apply it to a ~645,000-compound small-molecule library to identify candidate ATE1 inhibitors at the R33 phase. Lead compounds will be validated through orthogonal biochemical assays, binding specificity studies, and pharmacologic profiling in SCI-relevant cell models, including mouse and human motor neurons. Our goal is to identify small-molecule ATE1 inhibitors with favorable drug-like properties that can serve as lead candidates for therapeutic intervention in SCI, first in animal models and ultimately in human patients. Our multi-PI team brings a unique and complementary set of expertise to this effort. The contact PI, Dr. Fangliang Zhang, a recognized leader in the ATE1/arginylation field, will lead assay development and validation. The multi-PI, Dr. Timothy Spicer, supported by co-investigators Drs. Louis Scampavia and Michael Cameron, brings extensive expertise in HTS and medicinal chemistry. Dr. Aaron Smith will contribute to protein characterization, while Dr. Mousumi Ghosh, an expert in neuronal models and SCI pathophysiology, will lead the pharmacologic evaluation of lead compounds. Together, this interdisciplinary team is well-positioned to advance the discovery of the first pharmacologically viable ATE1 modulators for the treatment of SCI.

NIH Research Projects · FY 2026 · 2026-06

Abstract Polycomb group (PcG) complexes are multi-protein, evolutionarily conserved epigenetic machineries that regulate stem cell fate decisions, cell identity and early development. The PcG machinery can be divided into two major complexes: Polycomb Repressive Complex 1 and 2 (PRC1 and PRC2). Traditionally, PcG complexes are associated with gene repression mainly via histone-modifying activities. While PRC2 catalyzes methylation on lysine 27 of histone H3 (H3K27me1/2/3) via EZH1/2, PRC1 deposits a ubiquitin group at lysine 119 of histone H2A (H2AK119ub1) via the E3-ligases RING1A/B. Interestingly, several PcG encoding genes are found to be mutated in individuals with developmental disorders. Specifically, de novo missense mutations in the genes encoding for RING1A (RING1), and RING1B (RNF2), have been found in pediatric patients with neurodevelopmental disorders. How mutations at PcG genes impair development in humans is completely unexplored. Additionally, we have discovered novel missense mutations in both genes in children with intellectual disabilities. We conducted predictive analyses using crystal structures to start understanding how these mutations affect PRC1's stability and interaction with nucleosomes. In this proposal, we will focus our efforts in one of the RNF2 mutations, which is associated with intellectual disabilities using novel knock-in ESC lines as well a new mouse model carrying a monoallelic missense mutation on RNF2. Preliminary data reveal that mutant RING1B disrupts Polycomb complex assembly, induces derepression of PRC1 and PRC2 target genes, and impaired differentiation into neurons. By ChIP-seq and mass spectrometry we will investigate chromatin occupancy and recruitment mechanisms and potential rescue strategies. Additionally, this proposal will examine how Rnf2 mutations impact hippocampal structure, and behavioral outcomes in mice. Immunohistochemistry, RNA-seq, and ATAC-seq will determine the cellular diversity and regulatory dynamics in the hippocampus, providing insights into the mutation's molecular and behavioral consequences. Overall, our proposed research aims to define the role of missense mutations in Polycomb genes in neurodevelopment in vitro and in vivo, examining epigenetic mechanisms, behavior, and neuronal architecture. This work will enhance our understanding of how missense mutations influence PRC1 function and their contribution to neurodevelopmental disorders, shedding light on the complex relationship between epigenetics and neurodevelopment. Finally, our findings could pave the way for therapeutic strategies for neurodevelopmental disorders associated with PcG mutations.

NIH Research Projects · FY 2026 · 2026-05

Project Summary My laboratory investigates epigenetic mechanisms in health and disease. In 1R01GM141349-01A1, we proposed to investigate the mechanisms by which the E3-ligase RING1B, a core member of the Polycomb Repressive Complex 1 (PRC1), positively regulates the expression of oncogenic pathways in breast cancer. In 1R01GM146409-01, we proposed to study how the epigenome is remodeled, and genome instability is regulated, by the loss of H3K36me and Polycomb complexes (PRC1/2) in head and neck squamous cell carcinoma (HNSCC). By converting both R01s to a MIRA-R35 under the unifying umbrella of “Non-canonical functions of Polycomb complexes,” we intend to continue working on the aims we proposed in both grants and expand our research program. New research programs include to determine the role of the RING1B paralog RING1A in gene regulation in breast cancer (both in the settings of sensitive and resistance to current therapies) and the identification and characterization of the first set of non-histone substrates of RING1A and RING1B. To address these questions, we will use multiple model systems including new and established breast and HNSCC cellular models, knock-in (KI) and knock-out (KO) cell lines, patient-derived organoids (PDO), xenografts (PDX), and orthotopic xenograft models, biochemistry and mass spectrometry assays. These efforts aim to unravel novel epigenetic mechanisms deregulated in cancer to develop novel targeted therapeutic strategies, encompassing potential combinations with anti-epigenetic compounds. We also propose another original research program aiming to decode the role of novel de novo missense mutations on PRC1 genes that drive neurodevelopmental disorders. This is particularly significant because the prevalence of neurodevelopmental disabilities in children has risen sharply in recent years, while their underlying causes remain largely unknown and insufficiently studied. To address this, we generated the first set of mouse models, along with human and mouse embryonic stem cells, engineered to carry PRC1 variants newly identified by us in individuals with neurodevelopmental disorders. Our research into genetic disorders not only will provide clinical insights but also reveal fundamental mechanisms by which chromatin regulates brain development and neuronal networks underlying cognition. Overall, our program will uncover fundamental mechanisms of gene regulation that profoundly influence cell identity, differentiation, and oncogenesis, while paving the way for precision medicine and enhanced interventions for cancer and developmental disabilities.

NIH Research Projects · FY 2026 · 2026-05

ABSTRACT HIV latency constitutes a formidable problem marked by the virus integration into host DNA. While limited penetration and accumulation of antiretroviral drugs in the brain contribute to the generation of CNS reservoirs, the mechanisms that regulate the formation and maintenance of these reservoirs are poorly understood. This represents a substantial gap of knowledge, hindering progress toward an HIV cure and effective treatment of HIV-associated neurological disorders. Moreover, the impact of psychostimulants, such as methamphetamine (METH), on the formation and maintenance of HIV reservoirs is largely unknown. The central hypothesis is that molecular synergy between METH and HIV drives infection and influences HIV latency. We will explore this hypothesis using experimental models based on i) cell culture systems of primary human brain pericytes and ii) brain microvessels isolated from people living with HIV (PWH) with substance use disorder/METH use disorder (SUD/MUD) and a history of viral suppression. We have identified brain pericytes as the only blood-brain barrier (BBB)-related cell type that is susceptible to productive HIV infection. Moreover, our novel results indicated that brain pericytes can harbor latent HIV infection and may serve as a previously unrecognized HIV reservoir. In order to evaluate the central hypothesis, our transdisciplinary study will focus on the modulatory impact of METH on: (i) innate immune dysregulation and mitochondrial dysfunction in HIV infection (Aim 1), (ii) epigenetic regulations of HIV latency (Aim 2), and (iii) estrogen receptor signaling in HIV infection (Aim 3). Overall, the proposed study will evaluate the mechanisms underlying the formation and maintenance of latent HIV infection in brain pericytes, with a specific focus on the impact of METH on these events. This focus is an innovative and cutting-edge conceptual approach, consistent with the current RFA. Deeper knowledge of how brain pericytes respond to METH exposure and HIV infection, and how METH can modulate the processes of virus hijacking the host innate immunity and epigenetic machinery has paradigm-changing potential and may drive new discoveries in the field. Moreover, estrogen receptor- dependent mechanisms influencing molecular synergy between METH and HIV latency are novel and have not been explored in the literature. The planned experiments will help us to better characterize the influence of psychoactive substances, such as METH, on HIV infection in the brain in order to design future therapies for HIV cure, especially for PWH who experience SUD.

NIH Research Projects · FY 2026 · 2026-05

Human pluripotent stem cells (hPSCs) have been demonstrated to be powerful tools to study human biology and diseases, especially for which human tissue is difficult to access to and biopsy is challenged to obtain. Inner ear is one of organs that is nearly impossible to access without causing damages. Moreover, it is rare to obtain human inner ear biopsy. However, inner ear disorders, including hearing loss and vestibular dysfunction, are one of the most common sensory disorders. Although animal studies have advanced our understanding in hair cells, the underlying cellular processes may differ from those of human. A human cell-based model is therefore needed to progress our understanding of inner ear and the development of therapeutic strategies. Recently, stem cell-derived three-dimensional (3D) inner ear organoids have been reported to mimic certain aspects of inner ear development and disease pathologies in vivo. Despite this potential, there are limitations in the 3D inner ear organoid system to faithfully recapitulate some developmental processes, e.g., morphogen gradients that are critical for proper patterning. Therefore, we first propose to develop an innovative microphysiological system featuring a microfluidic chip that can precisely establish desired morphogen concentration gradients to which large size, 3D organoids are subjected on-chip (Aim 1). We will mediate BMP, WNT, and SHH signaling pathways to model dorso-ventral patterning in otic vesicles as a proof of concept. Results will assist us to understand how to induce the proper dorso-ventral patterning such that a similar strategy can be applied to effectively induce ventralization in the hPSC-based inner ear organoid system. As many inner ear disorders stem from malfunction of or damages in hair cells, we then propose to understand regulatory processes for the hair cell formation with special focus on epigenetic regulatory mechanisms, which is poorly understood, using the hiPSC-derived 3D inner ear organoid system (Aim 2). We propose to generate comprehensive epigenetic and transcriptomic regulatory networks for nature occurring hair cell differentiation and post-damage-induced hair cell regeneration using single cell (sc) muti-‘Omic approaches. Furthermore, we will validate the findings from sc multi-‘Omic approaches by testing the effects of the identified regulatory enhancer regions and genes in hair cell regeneration using CRISPR/dCas9-based assays (Aim 3). This will allow us to mimic epigenetic regulation of gene expression during hair cell formation. This project is not only improving the technology for the organoid system, but also providing the first step towards systematically advancing our knowledge of the role of epigenetics in human hair cell formation and, ultimately, developing therapeutic strategies for damaged hair cells.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY The long-term goal of the proposed research is to advance our knowledge of the optics of childhood myopia, with a focus on the role of the lens. In the period of childhood when myopia develops, the evolution of the refractive state of the eye is determined primarily by the combined effects of lens remodeling and ocular elongation. However, our understanding of this mechanism remains very limited. To address this gap, the project will produce new technologies to measure the full three-dimensional lens shape, ocular biometry, central and peripheral refraction, and their changes with accommodation in children. These new technologies will be used to discover how lens remodeling and ocular elongation combine to regulate ocular defocus in children in the age range of myopia onset. This new knowledge will help develop more targeted optical strategies to control myopia progression. There are three aims: Aim 1: To characterize the lens compensatory mechanism and its role in myopia development and control. A longitudinal study will be conducted to quantify full lens shape, ocular distances and refraction in children before and during the development of myopia. The data will be used to verify that a) there is a coupling of lens remodeling with ocular elongation that helps regulate ocular defocus through a compensatory effect, and b) this coupling and compensatory effect are different in emmetropic, myopic, and myopia control groups. Aim 2: To characterize changes in peripheral defocus with accommodation during the phase of lens remodeling in children. A novel instrument will be developed to enable simultaneous measurements of lens shape, ocular biometry, and defocus across a wide range of field angles and accommodative demands in children. The instrument will be used in a longitudinal study to quantify the age- and accommodation dependence of lens and ocular biometry and peripheral defocus. The data will be used to assess the role of the crystalline lens on ocular peripheral defocus, particularly during accommodation, which is highly relevant given the expected role of peripheral defocus and near work in myopia development. Aim 3: To generate a database of computational models that replicate eye growth, lens remodeling, accommodation, and their effect on central and peripheral defocus. The critical need for better models of the eye in childhood was highlighted in the recent report on myopia published by the National Academies. The goal of this aim is to develop the first database of anatomically accurate longitudinal eye models that replicate the real eyes of individual children before and during myopia development. It is envisioned that the database will be a resource that will enable designers of optical corrections for myopia control to simulate their designs on computerized replicates of real eyes.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY The advancements in genomic medicine have significantly accelerated over the past decade. However, their translation into clinical practice have been slow, and the precise treatment options are essentially nonexistent. The formulation of effective therapies is obstructed by the vast diversity of genetic diseases and the limited number of patients diagnosed with any specific genetic condition. Furthermore, the inefficiency often encountered in diagnostic workups leads to delayed diagnoses for children, rendering it difficult to test interventions effectively at an appropriate stage of their condition. There exists an urgent necessity to bridge the disparities between the prompt identification of patients who are likely to have a genetic disease, the delineation of a precise genetic diagnosis, and the development of effective precision therapies. This project is centered on the Neonatal Intensive Care Unit (NICU) and establishes a framework for an innovative approach to addressing its challenges by integrating rapid turnaround diagnostics with expedited gene-targeted therapies. Within this model, we will provide rapid genome sequencing to patients in the NICU, where many severe childhood genetic conditions initially present—approximately 20% of all admissions—thus offering the opportunity for early diagnosis, prior to irreversible disease progression. Furthermore, we will leverage our VIGOR network and collaborate with comprehensive sequencing facilities, such as GeneDx, to identify NICU cases that exhibit specific types of mutations and conditions that qualify them for patient- customized antisense oligonucleotides (ASOs) therapies. These ASOs are modular therapeutic agents composed of snippets of synthetic DNA or RNA, ranging from 15-30 nucleotides, which can be flexibly tailored to modulate specific gene-splicing patterns or target genes for degradation. Our previous work has demonstrated the feasibility of developing ASOs as a platform for precision treatment in several genetic conditions. This proposal lays the groundwork for the implementation of precision medicine within the NICU. We will focus on identifying opportunities to use ASOs to treat NICU infants with various rare genetic disorders due to the pharmacological advantages conferred by ASOs. In Aim 1, we will conduct rapid genome sequencing on a cohort of NICU infants with rare genetic conditions and implement a systematic algorithm to identify pathogenic variants amenable to ASO intervention sourced from diverse resources. In Aim 2, we will establish a biorepository to preserve biospecimens and assess their ASO amenability through RNA sequencing, subsequently referring them to laboratories and non-profit organizations for the advancement of ASO-based therapeutic modalities. In Aim 3, we will survey the families and healthcare providers regarding this precision NICU care model. This initiative will address the pressing necessity for translational genomic medicine for infants suffering from severe genetic disorders and will provide a widely applicable framework for linking rapid genetic diagnosis to rapid precision therapy across other populations as well.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Public health in the US is facing two overlapping epidemics, namely, substance use disorder (SUD) and HIV infection. Methamphetamine (METH) use is steadily rising in the U.S., with one study reporting a 43% increase in past-year usage between 2016 and 2019. Clinically, amphetamines, including METH, are associated with cognitive decline and a variety of psychiatric disorders, including depression, psychosis, and anxiety. METH use is a prominent risk factor for HIV infection and correlates with poor adherence to antiretrovirals and, in turn, with worse response to therapy. HIV infection is associated with neurocognitive and neuropsychiatric deficits, loss of dopaminergic neurons, neuroinflammation, and increased neural oxidative stress. The loss of dopaminergic neurons in HIV infection may play a critical role in interactions with METH, as METH’s biological and psychostimulatory effects are primarily mediated through dopamine. Given the public health impact of the METH use and HIV epidemics, there is a critical need to understand the mechanisms driving concomitant HIV and METH-associated neuropsychiatric disorders. The central hypothesis of this proposal is that METH and HIV infection, individually and in combination, contribute to the development of neuropsychiatric disorders in a sex-specific manner. Mechanistically, we propose that an increase in dopamine-induced neuroexcitation, oxidative stress, and mitochondrial damage are responsible for these effects. To address this hypothesis, we will administer quetiapine to mice infected with ecoHIV, a murine tropic HIV, and/or receiving METH. Quetiapine is an atypical antipsychotic that blocks dopamine D1 and D2 receptors while agonizing serotonin receptors. We will evaluate the effect of quetiapine on the neurocognitive deficits and depressive symptoms (Aim 1), and pro-inflammatory and oxidative changes (Aim 2) observed in my preliminary studies on mice receiving METH and/ or infected with HIV. We anticipate that quetiapine will block the excitotoxic effects of dopaminergic neurons and reduce inflammation and oxidative stress, ameliorating the neurocognitive symptoms induced by HIV and /or METH. Additionally, we anticipate improvement of depressive symptoms through both the reduction of neuroinflammation and quetiapine-induced serotonin agonism. My overarching goal is to address a gap of knowledge in the mechanism of HIV and METH induced neuropsychiatric disorders and neurotoxicity by providing proof of concept that quetiapine, an FDA-approved antipsychotic, can prevent or ameliorate HIV and METH induced neurotoxicity and neuropsychiatric disorders. The data generated from Aims 1 and 2 would provide new insights into the treatment of HIV- and METH-induced neuropsychiatric disorders while also playing a crucial role in my development as a physician-scientist with hopes of working in SUD and infectious diseases.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY The population of preterm survivors has significantly increased due to advancements in neonatal care. However, these individuals are later at risk for cardiovascular morbidities such as hypertension, ischemic heart disease, and heart failure, which poses a global public health concern. Preterm infants often receive supraphysiological levels of oxygen or hyperoxia to ensure adequate oxygen saturation, which can lead to neonatal inflammation- a strong predictor of vascular injury. This neonatal hyperoxia negatively impacts the immature vascular system, causing inflammation and vascular dysfunction later in life; however, the underlying mechanisms are essentially unknown. Currently, there are no therapies to prevent vascular consequences of preterm birth. Gasdermin D (GSDMD) is a cytosolic protein that plays a key role in the vascular inflammatory response and mediates pyroptosis, a form of programmed inflammatory cell death, forming pores in the cell membrane to release pro- inflammatory cytokines. Our preliminary data using a neonatal hyperoxia mouse model that mimics preterm- related neonatal morbidities indicate that neonatal hyperoxia increases vascular inflammation by upregulating pro-inflammatory GSDMD. In contrast, downregulating GSDMD decreases vascular inflammation and improves cardiovascular outcomes such as vascular stiffness, remodeling and elevated blood pressure in adult mice exposed to neonatal hyperoxia, suggesting an important mechanistic link. Based on our preliminary data, we hypothesize that the downregulation of GSDMD protects against neonatal hyperoxia-induced vascular remodeling and cardiac dysfunction. The primary goal of this proposal is to target GSDMD in neonatal hyperoxia-induced vascular dysfunction and identify how endothelial GSDMD downregulation improves neonatal hyperoxia-induced vascular outcomes. We test our hypothesis in two specific aims (SA): SA1: Test the hypothesis that GSDMD deficiency improves neonatal hyperoxia-induced short-term and long-term systemic vascular remodeling and cardiac function. Here, we will investigate whether genetic deletion and pharmacological inhibition of GSDMD in room air or hyperoxia-exposed neonatal mice will improve vascular remodeling and cardiac function in neonatal and adult mice. We will assess vascular stiffness, remodeling, blood pressure, cardiac function, angiogenesis, and perform molecular studies. SA2: Test the hypothesis that loss of GSDMD, specifically in endothelial cells, ameliorates neonatal hyperoxia-induced vascular outcomes. Here, we assess whether endothelial-specific deletion of GSDMD will ameliorate hyperoxia-induced vascular inflammation, pyroptosis, vascular remodeling, fibrosis and cardiac function in neonatal and adult mice. This study will bring new insight into the role of GSDMD in neonatal hyperoxia-induced vascular dysfunction and translate these findings into a new therapeutic approach to treat vascular consequences of preterm birth.

NIH Research Projects · FY 2026 · 2026-04

Abstract. Bacterial infection and antibiotic resistance are major healthcare issues facing the world. Designing rapid tests to tackle these challenges is critical. For example, urinary tract Infections, UTIs, approximately affect 150 million people worldwide annually. A bacterial load ≥ 100,000 cfu/mL in urine is a clinical indication of a patient suffering from a UTI. Current gold standard diagnosis is largely based on urine analysis and urine culture to verify the presence of bacteria. This requires a clinical lab and takes 1-3 days to get the final diagnosis. Existing point-of- care (POC) platforms such as those based on leukocyte esterase reagent strips and nitrite testing, which form part of urine analysis are an indirect measurement of infection, have low sensitivity and specificity, and do not provide any information about the bacterial load, which could be critical in the treatment decision. Gold standard treatment for UTIs involves antibiotics, which are in general very effective in resolving the infection. However, the misuse and abuse of antibiotics has led to a growing number of cases of antibiotic resistance in patients with UTI. Thus, hand in hand with the need for better UTI tests, there is also a growing need for tests which can screen for the presence of antimicrobial resistant (AMR) bacteria in patients suffering from UTI. For example, a bacterial load of <100,000 cfu/mL and without a prior history of UTI does not warrant antibiotic treatment whereas with a prior history of UTI and any co-morbidities does warrant an antibiotic treatment. Therefore, companion tests that would give information on bacterial load and rapidly screen for AMR bacteria present in the urine sample of patients, which would be critical for diagnosis, therapy decision, and follow-up culture test is ideal. To address this need we have formulated the following hypothesis: The development of a rapid test that will diagnose UTI specifically by measuring bacterial load in urine as well as screen for the presence of AMR bacteria will aid in making accurate clinical diagnosis and treatment decisions. In this work, we propose the development of two distinct diagnostic tests, both utilizing bioluminescent Photobacterium. To achieve our goal, we will pursue three specific aims, namely Specific Aim 1: Develop a bioluminescence-based test for quantitative detection of UTI-causing pathogens in urine using a microtiter plate reader and handheld luminometer; Specific Aim 2: Develop a bioluminescence-based test to screen for AMR bacteria in urine samples from UTI-diagnosed patients; and Specific Aim 3: Perform Pilot Studies with Clinical Samples. Our proposed non-culture, non- amplification, non-molecular approach will result in advances in the rapid diagnosis of UTI and the choosing of a therapeutic antibiotic regimen. Currently, this kind of technology does not yet exist.

NIH Research Projects · FY 2026 · 2026-03

ABSTRACT The X chromosome constitutes about ~5% of the human genome and harbors approximately 800 protein-coding genes, many of which have important immune and brain-related functions. Recently, we and others have demonstrated that the X chromosome is involved in Alzheimer’s disease (AD) risk. However, X chromosome genetics have not been comprehensively studies in large heterogeneous populations representative of the U.S. Furthermore, the process of X chromosome inactivation (XCI) balances gene expression across sexes. However, about 15% of genes on the inactive X chromosome consistently escaping inactivation and an additional 10% show variable escape patterns among individuals. The complexity in X chromosome requires careful analytical strategies that integrates epigenetics and multi-omics data. Unfortunately, large-scale population-based genetic and epigenetic studies in AD often ignore the X chromosome because of the analytical complexity, leaving a gap in our understanding of its influence on AD. This proposal seeks to fill this knowledge gap by conducting integrative analyses focused on the X chromosome and its relationship with AD, by leveraging a large number of genetic, DNA methylation and multi-omics population cohorts datasets. Specifically, in Aim 1, we will expand and confirm our knowledge of X chromosome genetic architecture in relation to risk and protection for AD in heterogenous large cohort studies. In Aim 2, we will identify DNA methylation (DNAm) differences on the X chromosome that are associated with AD in both brain and blood. In Aim 3, we will perform integrative multi- omics analysis to decipher the functional basis of X chr variants associated with AD. Our study will substantially improve the current understanding of the contribution of X chromosome genetics and epigenetics to AD, thus facilitating more targeted prevention, diagnostic, and treatment strategies.

NIH Research Projects · FY 2026 · 2026-03

Homelessness and housing instability represent critical public health challenges in the US with more than 650,000 people experiencing homelessness (PEH) nightly. PEH experience differential health effects across various conditions, including chronic disease, substance use, and HIV, compared to their housed counterparts. An astounding 65% of PEH report having used illicit drugs regularly in their lifetime with 37% reporting regular drug use in previous 6 months. Homelessness and illicit substance use, in isolation and in combination, continue to be significant drivers of poor HIV outcomes and are highlighted as key priority targets under the Ending the HIV Epidemic (EHE) Initiative. EHE has identified evidence-based interventions, including rapid HIV testing, antiretroviral therapy (ART), low barrier clinics, and PrEP that need to be implemented, scaled, and sustained within communities most affected by HIV. To maximize the effectiveness of these interventions among PEH who use drugs and to address the HIV, overdose and homelessness syndemic, comprehensive healthcare models need to be developed, tested, and deployed where they are in comfortable environments that simultaneously address a key driver of HIV, namely untreated substance use disorders (SUD). The HIV Medicine Association has called for the scale-up of street medicine (delivering health services directly to unsheltered individuals where they are), counseling and differentiated service delivery to end the HIV epidemic. We developed, refined, and pilot tested Status Neutral Tele-Health ConcieRge (SN-THR), a telehealth-based, multicomponent care model originally designed for people with who inject drugs (PWID) with HIV then adapted it to include PWID without HIV for prevention via PrEP and MOUD. We hypothesize that SN-THR will increase access to HIV care (testing, prevention, treatment), SUD services, and mental health services through telehealth to augment street-based primary care (i.e. street medicine). We propose to test the efficacy, cost-effectiveness, and implementation of an innovative integrated HIV, addiction, and primary care model—SN-THR—in a street-based setting using a hybrid type I effectiveness-implementation approach. The specific aims are 1) Evaluate the efficacy of SN-THR vs. standard of care (patient navigation to off-site clinic) on HIV treatment and prevention adherence; 2) Perform an economic evaluation of SN-THR and estimate the cost-effectiveness of SN-THR; and 3) Assess the drivers of SN-THR implementation and their impact on implementation outcomes. We hypothesize that more participants in the SN-THR intervention condition will be adherent to ART for treatment or prevention than those in the control condition across 12-month follow-up This application is directly responsive to the priorities of NIDA’s RFA-DA-25-072 by testing a novel telehealth-based, status-neutral care model for integrating HIV and SUD services into street-based primary care for PEH who use drugs.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Sex differences in immune responses underly variation in physiological processes and disease susceptibilities. However, there is limited insight into the sex-specific mechanisms that inform immune activation in the context of health and disease. Monocytes and polymorphonuclear neutrophils are the first line of defense against pathogenic insults and tissue damage, and also mediators of the homeostatic resolution process. Dysregulation of inflammatory vs immunosuppressive function of these myeloid cells is closely linked to disease pathogenesis. Our recent work identified metabolic and epigenetic signatures linked to the distinct function of monocytes and neutrophils in females versus males as well as sex differences in their response to the neurotransmitters γ- aminobutyric acid (GABA) and glutamate. Neurotransmitters are abundant chemical messengers with the potential to modulate immune cell activity. While neurotransmitter levels are altered in (patho)physiological states, their effects on innate immune response remain poorly defined. Building on these preliminary observations, we hypothesize that GABA and glutamate regulate monocyte and neutrophil activity in a sex- dependent manner through epigenetic, transcriptional, and metabolic programming. Here we will use mouse models, functional assays, and high-dimensional approaches to answer two central questions: (i) what the contributions of sex hormones versus chromosomes are in establishing myeloid cell programs and defining immunomodulatory effects of GABA/glutamate, and (ii) which transcriptomic, epigenetic, and metabolic mechanisms inform functional and sex-dependent GABA/glutamate response of monocytes and neutrophils. Unveiling the sex-specific roles of neurotransmitters and linked signaling pathways is important not only for improving the fundamental understanding of myeloid cell function but also for advancing therapeutic strategies by repurposing neurotransmitter modulators or targeting downstream signaling cascades in diseases characterized by innate immune dysregulation or exhibiting sex-bias. Upon successful completion of the proposal, we anticipate having identified (i) baseline sex differences in monocyte and neutrophil functionality, and the relative role of the sex steroids versus chromosomes in defining myeloid cell responses, and (iii) sex- specific transcriptional, metabolic, and epigenetic metaprograms that underlie the heterogenous monocyte and neutrophil activity. My lab is uniquely positioned to pursue this groundbreaking project and generate metadata that will drive future hypothesis-driven basic and translational research focused on the fine-tuning of myeloid cell activity through the modulation of neurotransmitter signaling.

NIH Research Projects · FY 2026 · 2026-02

Abstract The number of Americans living with end-stage renal disease (ESRD) who will eventually need a functional vascular access to receive hemodialysis and extend their lives is increasing. The arteriovenous (AV) fistula created by anastomosing an arm vein to a nearby artery is the preferred vascular access because, if it matures, it poses fewer complications than central venous catheters and arteriovenous grafts. AV fistulas fail because postoperative venous stenosis (narrowing) frequently compromises blood flow, demanding additional endovascular and surgical interventions to extend the life of the access. The failure of this vascular access is one of the most important causes of morbidity and hospitalization in the hemodialysis (HD) population. This highlights the need for in-depth research initiatives to investigate the cellular and molecular mechanisms leading to venous stenosis after anastomosis. This retro translational research (from clinical to basic science) finds preliminary premises supporting the association of type VIII collagen accumulation by endothelial cells (EC) with non-maturation of AV fistulas in hemodialysis patients. Our fundamental hypothesis is that IL-1b mediated endothelial inflammation promotes type VIII collagen biosynthesis to enhance monocyte recruitment and exacerbates the proliferative and pro-fibrotic vascular response that leads to failure. We will challenge the hypothesis with an integrated molecular/cellular approach, encompassing in vivo and in vitro models. In Aim 1, we will demonstrate the causality of endothelial type VIII collagen in fistula remodeling. In Aim 2, we will dissect the mechanisms controlling the transcriptional activation of COL8A1 in EC after AV anastomosis. We will reveal the first spatial transcriptomic cellular atlas of human stenotic and nearby non-stenotic venous segments obtained at the time of transposition. In line with the NIH-NCATS drug repurposing initiative, in Aim 3 we will demonstrate the clinical potential of IL-1b signaling inhibitors in a preclinical model of AV fistula failure in swine. We expect to demonstrate that we can improve AV fistula maturation by targeting the harmful effects of endothelial type VIII collagen after surgery.

NIH Research Projects · FY 2025 · 2025-12

PROJECT SUMMARY/ ABSTRACT Amyloid precursor protein (APP) represents a complex therapeutic target in Alzheimer's disease (AD), as its processing generates both toxic amyloid-beta (Aβ) peptides and neuroprotective fragments like soluble APP-α (sAPPα)1. While reducing APP through RNA interference shows preclinical and clinical promise for decreasing Aβ burden2,3, the broader impacts of APP knockdown on essential cellular functions, particularly DNA repair, remain unclear. In this proposal, I aim to investigate the dose dependent and region specific effects of APP reduction on AD pathology and DNA damage in the AppSAA mouse model. My study will utilize chemically modified APP-targeting siRNA administered via intracerebroventricular injection at a low and high dose to examine how varying levels of APP knockdown affect AD pathology and DNA damage in different brain regions. Through innovative techniques including Single-Strand Break mapping using Next-Generation Sequencing (SSiNGLe) and MERSCOPE FISH spatial transcriptomics, I will map DNA damage patterns and gene expression changes across different brain regions. This comprehensive approach will be complemented by behavioral testing and molecular analyses to assess cognitive outcomes and inflammatory responses. I hypothesize that the effects of APP knockdown on DNA damage and AD pathology are dose dependent and region specific, mediated by a balance between Aβ, APP, and sAPPα reduction. While reducing Aβ through APP knockdown may decrease some aspects of AD pathology, the concurrent loss of APP and sAPPα will worsen DNA damage and exacerbate AD pathology, particularly in vulnerable brain regions. The findings from this study will advance our understanding of APP's role in AD pathology and normal brain function, potentially leading to more nuanced therapeutic approaches that consider regional brain vulnerability and the importance of maintaining essential APP functions while reducing toxic Aβ accumulation.

NIH Research Projects · FY 2025 · 2025-12

Abstract Spinal cord injury (SCI) results in a persistently debris-ridden and scarred lesion site. This environment results in a scar that is non-permissive to wound repair, axon regeneration, and full functional recovery. Astrocytes are a main component of the injury site border that begin to rapidly proliferate 3 days after injury and slow by 7 days. By 28 days post-injury, a prominent gliotic region is present where reactive astrocytes densely surround the lesion. It has been previously shown that macrophages become oversaturated by up taking excessive lipid debris and become inflammatory “foamy” cells that fill the injury site – possibly blocking regeneration across the injury. After injury, reactive astrocytes also observably become lipid laden cells that chronically border the injury site. It is unknown if reactive astrocytes become foamy and if reducing this lipid accumulation will yield a more growth permissive gliotic region and promote recovery after SCI. The first aim of this proposal is to identify the time course of lipid accumulation in astrocytes after SCI in vivo and characterize the unique genetic signatures of foamy astrocytes by developing an in vitro model. The mechanism of lipid accumulation in astrocytes has not been previously identified. However, the PI3K pathway has been shown in macrophages as a regulator of lipid accumulation and the pro inflammatory phenotype. Therefore, the second aim of this proposal is to identify pathways, including PI3K, for foamy astrocyte formation using compound and lentiviral knockdowns in an in vitro model of the SCI environment. Together, these studies aim to address the hypothesis that reducing lipid-laden or foamy astrocytes is beneficial for functional recovery and regeneration after SCI. The proposed research will take place at the University of Miami Miller School of Medicine with the Miami Project to Cure Paralysis, where I will be in close contact with peers and mentors with specialized knowledge on my project. Along with my research, my training will consist of attending multiple seminar series within the neuroscience program and university, presenting at conferences and symposiums, participating in responsible conduct of research lessons, and broadening my scientific perspective in translational research with extracurriculars.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Air pollution is a significant global public health challenge, particularly in low- and middle-income countries (LMICs), where populations face substantial dual exposure to ambient and indoor air pollution, primarily from biomass fuel combustion. Fine particulate matter ≤2.5 microns in diameter (PM2.5) is a major contributor to morbidity and mortality. Previous studies have demonstrated associations between PM2.5 exposure, a higher prevalence of sleep-disordered breathing (SDB), and increased autonomic dysfunction. However, most of these studies have been conducted in high-income countries, limiting their applicability to resource-limited settings where PM2.5 exposure is substantially higher. As a result, the interaction between PM2.5 exposure and SDB and their effects of autonomic dysfunction remains poorly understood in LMICs. This knowledge gap is particularly concerning given the downstream effects of autonomic instability, including heightened cardiac repolarization lability which is a key risk factor for sudden cardiac death (SCD). The interplay between SDB-related intermittent hypoxemia and elevated PM2.5 exposure may amplify cardiac risks, as reflected by the QT Variability Index (QTVI), a validated electrocardiographic (ECG) biomarker of SCD. To address these critical gaps, this study has two specific aims: (1) evaluate the association between elevated PM2.5 exposure and the prevalence of SDB, defined as an apnea-hypopnea index (AHI) ≥5 events per hour, in a Ugandan cohort; and (2) investigate whether elevated PM2.5 exposure is associated with ECG biomarkers of SCD, independent of SDB severity and other cardiovascular risk factors, in the same cohort. This cross-sectional study leverages over a decade of epidemiological research experience in urban and rural Uganda. To achieve these aims, the study will deploy personal air pollution monitoring devices and home-based polysomnography, including single-lead ECG tracings, to collect granular data on PM2.5 exposure, SDB severity, and ECG biomarkers (e.g., QTVI). We hypothesize that elevated PM2.5 exposure will be associated with increased SDB prevalence and higher QTVI values through a dose-dependent mechanism linking air pollution to heightened cardiac risk. By integrating rigorous statistical modeling and sensitivity analyses, this research will provide critical insights into the interactions between poor air quality, SDB, and cardiac repolarization lability. The findings will inform public health policies, guide the design of targeted interventions to improve air quality, and mitigate risks for SCD in LMIC settings.

NIH Research Projects · FY 2025 · 2025-09

The Vascular Fibroblast: An Understudied Culprit in Postoperative Venous Stenosis ABSTRACT Creating a stenosis-free arteriovenous fistula (AVF) is a significant challenge even for highly skilled vascular surgeons. The surgery involves anastomosing a vein to a nearby artery in the arm of patients with end-stage kidney disease (ESKD). However, approximately 40% of newly created AVFs are never usable for dialysis without subsequent salvage procedures due to significant narrowing in the venous limb of the access (maturation failure). A major concern is that therapies designed to enhance reendothelialization or inhibit cellular proliferation have not succeeded in improving surgical outcomes. Consequently, the success of future anti-stenotic therapies will depend on our ability to update the existing theoretical framework by incorporating evidence emerging from human observational studies and clinical trials. This translational proposal utilizes emerging transcriptomic data from individual cells within the human vein and AVF to investigate the mechanisms by which fibroblasts and myofibroblasts control postoperative inflammation, medial fibrosis, and expansion of the intima that combined lead to constrictive remodeling and stenosis. Our fundamental hypothesis is that genetic and pharmacological inhibition of collagen VIII biosynthesis in venous fibroblasts decreases postoperative inflammation, myofibroblast accumulation, and stiffness in the venous wall, thereby improving AVF maturation. We will test this hypothesis using an integrated molecular and cellular approach, encompassing in vivo and in vitro models. Aim 1 will demonstrate the central role of venous fibroblasts in stenotic remodeling of human and murine AVFs. We will trace the contribution of fibroblasts to the myofibroblast population responsible for the remodeling of experimental fistulas created in transgenic mice. Additionally, we will investigate the clonal expansion, pro-fibrotic activation, and fate of human venous fibroblasts after fistula creation using genomic tracing. Aim 2 will demonstrate the causality of fibroblast-derived type VIII collagen on AVF failure. We will elucidate the upstream mechanisms responsible for the transcriptional activation of COL8A1 in fibroblasts. We will then demonstrate the role of collagen VIII as the link between inflammation, fibroblast activation, and excessive extracellular matrix (ECM) deposition in AVF failure. Mechanistically, we hypothesize that collagen VIII activates the complement C1 complex and Wnt/b-catenin signaling, ultimately leading to exacerbation of both pro-fibrotic and inflammatory pathways. Lastly, Aim 3 will test the benefits of COL8A1-targeted gene therapy and the anti-fibrotic drug pirfenidone, which also inhibits COL8A1 deposition, in a preclinical model of AVF failure in swine. We expect to show that both approaches are feasible and can enhance AVF maturation. We anticipate that these investigations will provide a comprehensive understanding of the cellular and molecular processes underlying AVF failure in humans and pave the way for novel therapeutic strategies to enhance maturation and durability of hemodialysis accesses.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY African American (AA) women have 40% higher breast cancer mortality and are more likely to be diagnosed with aggressive subtypes, such as triple negative breast cancer, than European American (EA) women. Exact reasons for these disparities remain unclear – but genetics and lifestyle may both play a role. However, it is unclear how genetic and lifestyle factors contribute to racial differences in molecular profiles of breast cancer. Our recent collaboration with Zambian cancer researchers presents a unique opportunity to include African Zambian (AZ) breast cancer patients in research to help reveal the underlying mechanisms for breast cancer racial disparity. Given the drastic differences in lifestyle and environmental exposures, yet relatively small genetic differences between AA and AZ, including AZ, AA, and EA breast cancer patients in one study will offer an excellent opportunity to disentangle the contribution of genetic predispositions from lifestyle exposures on the molecular profiles and tumor characteristics of breast cancer. We propose to recruit 250 incident AZ breast cancer patients, collect clinical and lifestyle data, obtain tumor tissues, and performing RNA sequencing (RNA-Seq). These data will be compared with existing data from the Southern Community Cohort Study. Specially, our study has the following aims: 1) to recruit 250 African Zambian women with pathologically confirmed breast cancer at the Cancer Disease Hospital in Lusaka, Zambia; 2) to derive molecular profiles of breast cancer in AZ women and compare with those from AA and EA women. We will perform RNA-Seq on breast tumor tissue samples from AZ patients to derive gene expression levels, molecular intrinsic subtypes of breast cancer, and PAM50-based risk of recurrence scores (ROR-S). The demographic, clinical, and molecular data will be summarized and compared across these three racial/ethnic groups. Expression levels of known breast cancer susceptibility genes, molecular intrinsic subtypes, and ROR-S derived in Aim 2 will be utilized to distinguish the differential effects of genetic ancestry versus lifestyle on breast cancer molecular phenotype among the three racial/ethnic groups. This will be the first epidemiological study to compare molecular profiles of breast cancer across AZ, AA, and EA women, shedding light on the underlying genetic and lifestyle factors that contribute to racial disparities in molecular profiles of breast cancer. This study will generate important preliminary data informing a full-scale investigation to delineate variances in genetic predispositions and lifestyle factors in association with breast cancer risk. This will also be the first molecular epidemiology study of breast cancer in Zambia, laying the foundation for conducting etiological research on breast cancer in the country.

NIH Research Projects · FY 2026 · 2025-09

Deaths due to extreme heat are projected to increase by 370% by mid-century, and at the same time, over 13 million Americans will be affected by Alzheimer’s disease and related dementias (ADRD). Our living environments need to adapt to extreme temperatures and protect against urban heat islands—built environments with reduced vegetation and more paved surfaces associated with greater surface temperatures and greater risk of heat-related health effects. This study will bridge significant scientific gaps by investigating ADRD-related impacts from cumulative urban heat island exposure; providing evidence on whether the provision of more greenspaces (offering shade and cooling) may buffer against urban heat island exposure; and investigating the mechanisms linking cumulative urban heat island exposure to ADRD outcomes. Our aims are to: (1) investigate whether recent urban heat island exposure is associated with cognitive function, (2) determine whether cumulative urban heat island exposure is associated with structural MRI biomarkers and longitudinal cognitive decline; and (3) evaluate whether (i) urban heat island exposures are associated with ADRD risk factors (physical inactivity, social isolation, inflammation) (i.e., mechanisms), and (ii) living in greener neighborhoods is associated with lower urban heat exposures and better ADRD outcomes (e.g., slower cognitive decline) (i.e., mitigation). We will create Geographic Information System (GIS) measures of recent and cumulative urban heat island exposure by linking geocoded addresses to land surface temperatures from satellite imagery. These measures will be developed for 500 participants in the Healthy Brain Initiative (HBI), a longitudinal cohort of ≥50-year-olds with no/subjective/mild cognitive impairment from the South Florida region. A subset (n=200) will wear smartwatches to derive GPS/travel behavior and heat exposure data for two 3-week periods (May-October) over a one-year period. Data on older adults (n=9,673) from the Health and Retirement Study will be used to externally validate HBI findings to a national setting (Aims 1-3). This will be the first known study to determine associations between cumulative urban heat island exposure and ADRD risk factors, brain imaging biomarkers, and cognitive outcomes. Providing evidence that supports causal associations between urban heat island exposures and ADRD outcomes and evidencing that greenspaces reduce the harmful influence of heat on ADRD risk would support targeted interventions for heat exposure reduction for ADRD prevention in populations most susceptible to extreme heat.

NIH Research Projects · FY 2025 · 2025-09

One-fifth of the 1.1 million individuals living with HIV in the US are women, and there is a disproportionate impact on in the Southern US. Reproductive age women with HIV are highly affected by worse HIV, reproductive, and chronic diseases outcomes, likely due to non-medical and biological factors that manifest differently across the reproductive life course. Despite experiencing poor outcomes and facing unique challenges, reproductive age women are underrepresented in HIV research. To address this gap, STAR became the largest cohort of reproductive age women with HIV and demographically similar women without HIV in the US since its inaugural funding in 2019, and now serves as a robust platform to support high impact research and the development of early-stage investigators. In this U19 application, we propose to continue and expand STAR in this program project application to address the overarching goal of advancing high priority science in HIV, reproductive health, and chronic diseases for reproductive age women through research, mentoring, and community engagement. This program project will provide the structure for expanded recruitment, participant retention, longitudinal data collection, scientific and community engagement, and development of the next generation of HIV scientists – all components needed to optimally address science for this population. Through the Scientific Administrative Core (SAC), Data Management and Analysis Core (DMAC), and Community Engagement Core (CEC), coupled with cohort-linked, synergistic research projects (RP1 focused on cardiovascular health and RP2 focused on sexual and reproductive health), we propose to address the intersecting effects of HIV, medical and non-medical factors, and reproductive transitions on health. We will accomplish our goals by: (Aim 1) expanding the STAR cohort as a platform for HIV science for reproductive age women; (Aim 2) leveraging the resources of the STAR Cores to promote rigorous patient-centered science; and (Aim 3), testing a unifying hypothesis on the intersecting effects of HIV and reproductive transitions on two major health challenges – comorbidities and coinfections – via interlinked projects that leverage the STAR Cores and utilize a shared framework, measures, and outcomes. Through the outstanding collaborative team assembled during the inaugural funding cycle, and by expanding based on lessons learned, the cohort will be rapidly established, effectively maintained, and will generate high quality longitudinal data with validated surveys, specimen procedures, and data management tools. This study is therefore poised to effectively engage, enable, and mentor scientists in a vast range of scientific areas aligned with NIH/OAR/ORWH priorities, and to ultimately ameliorate the effects of the epidemic across populations. NARRATIVE: HIV severely affects women of in the Southern US and reproductive aged women with HIV have poor HIV and other health outcomes. The overarching goal of the Study of Treatment And Reproductive outcomes (STAR) is to build upon our prior successes to advance high priority HIV science for reproductive age women with and without HIV through research, mentoring, and community engagement. In this application, we propose the establishment of a Scientific Administrative Core, a Data Management and Analysis Core, and a Community Engagement Core, to support the longitudinal STAR cohort and research projects that address the intersecting effects of HIV, and reproductive transitions on cardiovascular health (Research Project 1) and reproductive health and coinfections (Research Project 2).

NIH Research Projects · FY 2025 · 2025-09

In the US, anal cancer (AC) and cervical cancer (CC) disproportionately affect the most vulnerable—those who must navigate complex, cumulative intersectionality that further constrains access to disease prevention. In South Florida and Georgia, the catchment areas for the Sylvester Comprehensive Cancer Center (Sylvester), and Winship Cancer Institute (Winship), AC and CC incidence remains high among Blacks and Hispanics of a variety of ancestries, particularly those in groups at high risk of poor outcome. The proposed PeRsonalized Outreach and Multifaceted Interventions for Screening Enhancement (PROMISE) for Anal and Cervical Cancer Prevention and Treatment SPORE will address differences in cancer incidence and outcome across different population groups by leveraging, via horizontal and vertical engagement, the robust infrastructure and capacity of three, top-tier research institutions, with an established history of collaboration. Sylvester, Winship, and Morehouse School of Medicine, individually and collectively, have been at the forefront of high-impact, translational science in AC and CC through validating screening modalities that circumvent multilevel impediments to disease prevention and early detection, as well as examining critical heterogeneity in disease etiology, onset, and progression. PROMISE will expand upon this work via three innovative, high-impact Research Projects, as well as pilot studies that seek to understand and/or address observed variability in disease outcomes across the cancer control continuum through our Developmental Research Program (DRP). Our commitment to community-engaged, translational science will inform the proposed activities of our Career Enhancement Program (CEP). All Projects and Programs will leverage the shared expertise of three proposed Cores: The Community Outreach and Engagement Core (COE), Biospecimen and Pathology Core, and Biostatistics and Bioinformatics Core. PROMISE partners are committed to 1) translating lessons learned from our work in AC and CC into a framework that addresses differences in cancer outcomes; and, 2) deepening the longstanding connections between our academic and community partners to meaningfully modify the landscape of anal and cervical cancer prevention, early detection, diagnosis, and treatment.

NIH Research Projects · FY 2025 · 2025-09

Research supports a role for reduced cholesterol efflux and lipid droplet (LD) accumulation in mitochondrial dysfunction (MD) and podocyte injury in the pathogenesis of glomerular diseases of metabolic and non-metabolic origin, including Alport Syndrome (AS). Less is known about the contribution of triglyceride (TG) accumulation in LDs to MD and podocyte injury. LDs regulate the storage and homeostasis of intracellular TGs and regulate the availability of free fatty acids (FFAs), which can be oxidized in mitochondria and used as an energy source. Proper contact of LDs with mitochondria is mediated by LD-associated proteins, such as perilipin 5 (PLIN5), and is instrumental for FA synthesis and breakdown. PLIN5 is a protein that regulates TG metabolic pathways and cellular energy homeostasis through its role in the lipolysis of TGs stored in LDs, mediates LD-mitochondrial contact formation, and serves as a substrate for chaperone-mediated autophagy (CMA). However, little is known about the function of PLIN5 in podocytes. In preliminary data, we demonstrate decreased PLIN5 expression in glomeruli of patients with AS, in kidneys of Col4a3 KO (AS mice) and AS podocytes, and in a zebrafish model of AS when compared to controls. In AS podocytes, PLIN5 deficiency is associated with increased lipolysis, FFA accumulation, and reduced LD- mitochondrial contact formation and mitochondrial membrane potential, which was restored by PLIN5 overexpression. AS podocytes have an increased autophagosome number compared to WT, often in proximity of mitochondria, suggesting increased mitophagy. PLIN5 expression is restored by Ezetimibe (EZ), a compound that we found to partially protect AS mice from the development of proteinuria. Our results suggest an important role for PLIN5 deficiency in lipotoxicity-induced MD and podocyte injury and renal disease progression in AS. The overall goal of this proposal is to investigate a novel mechanism linking PLIN5 deficiency to lipotoxicity- mediated MD, CMA and podocyte injury in AS. We hypothesize that PLIN5 deficiency in AS causes TG-rich LD accumulation due to impaired CMA, FFA accumulation due to increased TG lipolysis and impaired LD-mitochondrial contact formation, resulting in lipotoxicity-induced mitochondrial dysfunction. We propose a combined in vitro and in vivo approach to investigate the mechanism by which PLIN5 deficiency causes lipotoxicity-induced MD and podocyte injury (aim 1), and in renal failure (aim 2) in AS. If successful, this innovative study will link PLIN5 deficiency to a novel pathway of lipotoxicity-induced MD and podocyte injury and may lead to the identification of new drug targets for the treatment of patients with proteinuric kidney diseases associated with altered GBM, such as AS.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Diffuse midline glioma (DMG) is the most aggressive primary brain tumor in children with a 5-year survival rate of <1%. DMG characteristically has an "immunologically cold" tumor microenvironment (TME) leading to poor clinical responses and resistance to immunotherapy. To overcome scarce lymphocyte infiltration and limited immune checkpoint (IC) expression in cold TMEs, our team and others have established novel viral mimicry activating therapies that leverage the accumulation of immunogenic dsRNAs and anti-viral innate immune response to change the TME and sensitize tumors to immunotherapies. Traditionally, drugs that modulate the epigenome have been used to activate the viral mimicry response in tumors. Unfortunately, these drugs have lacked efficacy in DMG clinical trials amid dosing limitations secondary to systemic toxicities and poor neuropenetrance. Thus, novel targets to activate viral mimicry and potentiate the immune response against DMG are critically needed. We propose a paradigm shift to focus on targeting epi-transcriptomic (RNA modifications) regulators, which promise to be more effective with less off-target effects in DMG. Via an unbiased screen, we have found that the RNA editor ADAR is significantly upregulated in DMG. Interestingly, ADAR-mediated RNA editing has been shown to help some cancer cells escape antitumor immune responses. In patient-derived DMG cell lines, our preliminary results show that ADAR knockdown (KD) increases immunogenic RNA species, activates an IFN response, reduces cell proliferation, and increases MHC-I and IC ligand levels on the tumor cell surface. The objective of this proposal will be to determine the mechanism for the observed ADAR-dependency in DMG cell lines, and to assess if this promising epitranscriptomic target activates viral mimicry to synergize with immunotherapies against DMG in vivo. To determine modulators of ADAR-dependency, I will perform a genome-wide CRISPR screen in DMG cells with a doxycycline-inducibleADAR KD background. This will inform us what genes cause sensitization or resistance to ADAR-modulation in DMG. Next, I will assess if ADAR knockdown synergistically enhances immune checkpoint inhibition (ICI, aPD-1) in a novel syngeneic orthotopic immunocompetent murine DMG model. Utilizing a previously validated panel to characterize the DMG TME by flow cytometry, we will assess the viral mimicry response by intracellular markers such as dsRNA levels and cell surface markers such as CD45 and CD3 to determine immune cell infiltration, namely tumor-infiltrating lymphocytes. This project seeks to understand the role of upregulated epitranscriptomic regulators in DMG from an immunologic perspective and assess their efficacy as targets for viral mimicry therapy. The results of these studies will open the doors to novel multi-modal regimens involving epitranscriptomic reprogramming and inform potential clinical trials for immune modulation in DMG.