University Of Houston

NIH Research Projects · FY 2026 · 2019-07

PROJECT SUMMARY/ABSTRACT Myopia, or nearsightedness, is an epidemic, with up to 90% of the population in some urbanized countries affected. Efforts have increased to understand the regulatory mechanisms underlying myopic eye growth due to the potentially blinding complications and socioeconomic burden associated with myopia. The long term goal of this work is to provide the scientific basis for effective environmental and behavioral treatment options to slow myopia onset and progression in children and to better understand structural changes in the myopic eye that render it more susceptible to ocular pathologies. Our central hypothesis is that reduced high intensity light exposure and increased time engaged in near work contribute to myopia onset and progression. We also hypothesize that the choroid, inner retinal vasculature, retinal morphology, and optic nerve head undergo significant remodeling during myopia development, which contribute to associated pathologies later in life. Refractive development is regulated by a complex interaction between genetic, environmental, and behavioral factors. Evidence suggests that outdoor time is protective against myopia onset, with some studies also showing that outdoor time decreases myopia progression. Numerous studies strongly support a role of near work in myopia onset and progression. However, there are conflicting findings, with some studies reporting no association. Inconsistent results are due to the variable and subjective nature by which light exposure and near work have traditionally been assessed. Based on gaps in the existing literature and our preliminary work, we will carry out the following studies to quantify the effects of environment and behavior on eye growth and the effects of eye growth on ocular structure in children; each aim will follow children for a two-year period. 1) Longitudinal objective and continuous measurement of personal light exposure over five one-week periods to determine its influence on refraction and axial length change; 2) Longitudinal objective measurement of near work over five one-week periods, paired with a visual activity questionnaire, to determine the influence of near viewing behaviors and electronic device use on refraction and axial length change; 3) Optical coherence tomography (OCT) imaging, OCT angiography (OCTA), and adaptive optics scanning laser ophthalmoscopy (AOSLO) imaging at one year intervals to investigate changes in foveal cone photoreceptor density, foveal pit morphology, foveal avascular zone characteristics, choroidal thickness, inner retinal vascular perfusion, and optic nerve head parameters in association with refraction and axial length change. The proposed studies are intended to fill a critical void in our understanding of the precise influence of environmental and behavioral factors on eye growth and myopia and how the eye remodels in myopia. This work will contribute to the development of evidence- based therapies, thereby reducing ocular complications and socioeconomic burden related to myopia.

NIH Research Projects · FY 2025 · 2019-03

Systemic Lupus Erythematosus (SLE) is a systemic, autoimmune connective tissue disease affecting multiple organ systems, marked by arthritis, dermatitis, nephritis (LN) as well as neurological involvement. The prevalence of LN varies depending on age, sex, and ethnicity, and is estimated to be 40–70%. Despite advancements in the understanding of the pathophysiology of end-organ involvement in lupus, and novel therapeutics, only 50–70% of patients achieve remission. There is clearly a need for identifying easily measurable biomarkers for diagnosing and monitoring this autoimmune disease, predicting response to therapy and prognosticating long term outcome in lupus. Our project focuses on identifying proteins in body fluids that may help identify and subset lupus more effectively. In the past cycle of funding, we have reported serum biomarkers for systemic disease in lupus, cerebrospinal fluid proteins for neuropsychiatric lupus, as well as excreted proteins for renal disease, using a variety of different proteomic approaches. In this renewal proposal, we will focus on ten proteins that have been independently validated across multiple patient cohorts, using orthogonal approaches, as being highly reflective of disease activity in lupus. Together, these 10 proteins constitute LN-10-plex. We will perform extended clinical validation of the LN-10-plex proteins in larger patient cohorts of different ethnic origins to confirm their association and correlation with clinical disease activity, using training and validation cohorts. Using longitudinal cohorts, we will examine if the LN-10-plex proteins at baseline can be used to predict oncoming disease flares. In lupus patients undergoing induction therapy, we will ascertain if baseline levels of LN-10-plex proteins can predict response to therapy. We will also assess if easily measurable biomarkers can be used to track tissue pathology, as this will avoid the need for repeat biopsies. Thus, the broad, over-arching goal of our research is to be able to identify easily measurable biomarkers of disease in lupus, and harness them for improved clinical utility.

NIH Research Projects · FY 2025 · 2019-01

Relating Structure to Function in Optic Neuropathies Glaucoma is a progressive optic neuropathy, marked by characteristic losses of retinal ganglion cells and connective tissue remodeling, that leads to irreversible vision loss. The exact etiology and pathophysiology of the disease remains unclear. Hence, the clinical diagnosis and monitoring are dependent on measures of intraocular pressure, and an indirect assessment of retinal ganglion cells using in vivo imaging and assessment of visual function. The current clinical standards for glaucoma evaluation are effective for detecting and monitoring disease. However, current clinical testing is ineffective for determining an eye’s susceptibility to disease, and current vision testing does not completely represent functional vision. The lab's long-term goals are to refine in vivo structure and function measures to determine; 1. An eye's susceptibility to disease, 2. Its retinal ganglion cell (RGC) content, and 3. Functional changes with RGC damage/loss. This proposal has two aims, which build on our previous findings and are designed for the non-human primate, which has similar ocular anatomy and visual function as humans. Relevant to aim 1, we previously reported that the risk of retinal ganglion cell loss in experimental glaucoma was related to the viscoelastic properties of the neuroretinal rim tissue, and the extent of axial elongation following chronic pressure elevation. Myopia or nearsightedness occurs when the optics of the anterior segment focus light from a distant object in front of the retina, and axial elongation is the main contributing factor. Myopia is an independent risk factor for glaucoma. Further, like glaucoma, there is significant variability in experimental models of myopia. We hypothesize that accelerated axial elongation, with form deprivation myopia, results in connective and neural tissue remodeling, as reflected in pressure challenge experiments, both increasing the risk of ganglion cell loss. In this aim, we will also determine if eyes with greater axial elongation with form deprivation myopia or their control eyes, are eyes that develop more severe experimental glaucoma. Relevant to aim 2, we previously reported that the relationship between visual thresholds, with standard automated perimetry, and retinal ganglion cell content follows that predicted by spatial summation. Further, data from experimental glaucoma eyes were shifted up and have a larger critical area. Spatial summation can be modeled to represent the cortical pooling of spatial filters of specific spatial frequencies. Our preliminary data suggest that there are disease stage-specific losses in spatial frequency contrast, and that eyes with experimental glaucoma have either non-functional or dysfunctional cells. We hypothesize that with progressive retinal ganglion cell loss, contrast sensitivity at higher spatial frequencies is reduced before that at peak contrast, and thresholds for standard size III stimuli. Further, we will test the hypothesis that eyes that are faster progressors with experimental glaucoma will have increased neural noise, determined using the equivalent noise paradigm, indicative of dysfunctional retinal ganglion cells.

NIH Research Projects · FY 2025 · 2018-09

SUMMARY Limbal epithelial stem cells (LESCs) produce transient amplifying cells (TACs) that move centripetally into the cornea and differentiate into corneal epithelial cells (CECs). Thus, TACs represent a transition state between LESCs and CECs. Studies have suggested some TACs retain stem cell-like characteristics. We have recently shown that the LSCN is composed of a hyaluronan (HA)-rich matrix that is essential for maintaining LESCs, and a loss of HA triggers LESC differentiation into CECs. Our unpublished data shows that clusters of cells expressing an HA-rich matrix (HA-clusters) break away from the limbus and move into the cornea containing LESC progenies with progenitor-like properties. Aim 1 will establish whether TACs retaining progenitor-like characteristics are located within HA-clusters, and verify whether these TACs can dedifferentiate into bona fide LESCs. The mechanism by which the HA-rich LSCN maintains LESCs remains unknown. Our group recently characterized the composition of the HA-rich matrix within the LSCN, identifying that heavy chains 2 and 5 (HC2 and 5) are transferred from inter-alpha-inhibitor onto HA by TSG- 6 to form specific HA/HC and HA/HC-TSG-6 complexes, and LESCs express CD44 and RHAMM, major cell surface receptors for HA. Aim 2 will investigate whether HA/HC5(-TSG-6) complexes within the LSCN are essential for maintaining LESCs, and whether the effects of HA on LESCs are mediated through CD44 and/or RHAMM cell surface receptors. Corneal injuries that decrease the overall number of LESCs may lead to limbal stem cell deficiency (LSCD), a serious medical condition that leads to impaired vision and severe pain, and, in more severe cases, complete loss of vision. Currently, treatment options for LSCD include LESC transplantation or corneal transplantation, for which human donor corneas are required. A major challenge for treating LSCD is the efficient preservation of LESCs in human donor corneas while stored at eye banks. The composition of storage medium used by eye banks worldwide is determined by the survival of corneal endothelial cells, without taking into consideration LESCs. Studies have reported that limited LESCs are detected in human donor corneas after 4 days in storage, and we have found that there is a significant loss of HA within the LSCN that occurs concomitantly with the loss of LESCs. Aim 3 will investigate how the composition of the HA-matrix within the LSCN of human donor corneas changes over time in storage and correlate the loss of HA with a loss of LESCs, and to improve the composition of storage media to better support LESCs. Clinical impact: Corneal diseases, including LSCD, are the third leading cause of blindness worldwide. Corneal blindness is ultimately treated with corneal or LESC transplantation, for which human donor corneas with viable LESCs are essential. This proposal will establish how the LSCN maintains LESCs, unveiling fundamental biological mechanisms underlying LESC survival and LSCD pathogenesis.

NIH Research Projects · FY 2025 · 2018-08

Abstract The prevalence of multidrug resistance in Gram-negative bacteria (e.g., Pseudomonas aeruginosa, Acinetobacter baumannii) is rising at an alarming rate, rendering many (if not all) antibiotics ineffective when used alone. The rate of new drug development is unlikely to keep pace with the increase in multidrug resistance. Combination therapy is often used clinically as a last resort. However, considering the numerous possibilities, combination therapy are selected by clinicians mostly based on anecdotal experience and intuition. A robust method to guide rational selection of combination therapy would be crucial to delay returning to the pre-antibiotic era. Our long-term goal is to optimize clinical use of antibiotics to combat the emergence of resistance. The objective of this application is to refine a novel precision medicine platform (monitoring device and data processing algorithm) that will guide the design of combination therapy. If short-term experimental data can be used to predict the response of patient-specific bacteria to clinically relevant antibiotic exposures, effective treatment strategies could be formulated rationally by identifying the best possible combination. Clinicians could be guided in the selection of combination therapy, without comprehensively knowledge of the resistance mechanism(s) involved. We plan to accomplish the objective of the application as follows: (1) identify useful antibiotic combinations against multidrug resistant bacteria; and (2) validate the mathematical model predictions with clinical outcomes. In this application, the proposed approach will be illustrated by experimental data with P. aeruginosa, A. baumannii and Klebsiella pneumoniae. However, the proposed model-based system is not confined to a specific antimicrobial agent - pathogen combination. It could be extrapolated to other antimicrobial agents (e.g., antibacterials, antifungals and antiretrovirals) with different mechanisms of action, as well as to other pathogens (e.g., Neisseria gonorrhoeae, Candida auris, and HIV) with different microbiological characteristics.

NIH Research Projects · FY 2026 · 2016-04

Abstract High visual acuity, binocular alignment and binocular coordination of eye movements are important in foveate species and are susceptible to visual development disruptions leading to enormous negative impact on public health and the economy. Thus, developmental loss of sensory or motor fusion leads to ocular misalignment (strabismus) and associated binocular oculomotor disturbances in as much as 5% of all children and amblyopia is the leading cause of monocular visual impairment in the U.S., disabling over two million children. In Aim 1, we investigate how strabismic subjects orient their eyes to visual targets within their environment. We will build upon our recent work, recording from the superior colliculus in non-human primate models for strabismus, that has focused on a curious gaze orienting behavior, wherein under binocular viewing, many strabismic subjects choose their eye of fixation depending upon location of the eccentric visual target. In the proposed experiments, we will investigate the contribution of a critical area for visual target selection, the Frontal Eye Fields and use a unique stimulus (the double-step paradigm) to test the validity of a competition framework as the basis for gaze orienting behavior in alternating strabismus. In Aim 2, we will test, in the monkey, an innovative new therapeutic approach to treat MD amblyopia that has demonstrated remarkable recovery of vision in the MD eye, involving temporarily inactivating the fellow eye by intravitreal injection of a low volume of low concentration tetrodotoxin (TTX). If TTX therapy were shown to be an effective and safe substitute for patching therapy, it would foster a revolutionary advance in treatment of amblyopia. Following induction of amblyopia via MD in infant NHP, TTX will be injected into the vitreous cavity of the good eye. Rigorous vision testing will be performed after MD to establish the severity of amblyopia and repeated after TTX treatment to test treatment efficacy. Within this specific aim, we will also determine whether TTX microinjection is safe and has no permanent effects on eye function or structure. Our approach to investigating parameter space will include experiments in animals at two ages (within and outside the critical period), at two dosage levels and with two frequencies of application. Control experiments will include sham injections and a reverse occlusion cohort. Before and after each round of TTX injection, visual function testing will be conducted, including visual acuity evaluation via VEP or CSF testing, testing of stereo function, evaluation of the pupil, refraction, ERG, bio-microscopy, biometry, and OCT retinal nerve fiber layer/optic nerve imaging. Finally histologic evaluation of the eyes will evaluate any evidence of TTX-induced damage and histological evaluation of brain will evaluate support for amblyopia recovery. Thus, each of the two aims leverage our unique expertise in working with monkey models for visual development disorders and is likely to significantly advance understanding of mechanisms underlying neural circuitry. Moreover, this project has the potential to help guide the development of rationally based therapies for amblyopia.

NIH Research Projects · FY 2025 · 2016-01

PROJECT SUMMARY The etiology of congenital brain growth anomalies is complex, but prenatal alcohol/ethanol and nicotine exposure (PEE/PNE) are common causal factors in the US and worldwide. Research has mainly focused on the growth deficits in neural stem cells (NSCs) and their progeny following PEE/PNE. However, we recently used high- resolution imaging to document that PEE results in complementary deficits in blood flow in major cranially- directed arteries. During the previous project period, we adapted Optical Coherence Tomography (OCT) to document that both PEE and PNE resulted in a similar loss of blood flow in the efferent peri-neural vascular plexus (PNVP). The PNVP and its companion, the sub-ventricular vascular plexus (SVP), give rise to capillaries that penetrate the parenchyma of the developing brain. In the NSC niche of the fetal ventricular zone (VZ) these give rise to an atypical class of fenestrated capillaries that contain 50-100 nm-sized trans-endothelial windows. The function of capillary fenestration in the fetal brain is unknown. Still, in the adult brain, the presence of fenestrated capillaries in selected circumventricular brain regions facilitates the transfer of systemic macromolecules into the brain, and persistent activation of brain microglia, and in residual neurogenic niches, facilitates neurogenesis. Based on preliminary and published data, we hypothesize that prenatal ethanol will increase brain angiogenesis, capillary fenestration, and microglial immune cell precursor trafficking to the fetal brain. We further hypothesize that prenatal nicotine will potentiate the alcohol-mediated increase in new blood vessel formation in the fetal brain and additively increase capillary permeability and immune cell migration into the NSC niche of the fetal VZ. To test these hypotheses, our team will develop a new sensitive, high-resolution imaging platform (Aim 1) that combines the complementary benefits of OCT and two-photon light-sheet microscopy (2pLSM) for in utero time-resolved structural imaging of fetal brain capillary micro-vessels with molecular specificity. We will also adapt our innovative intravital imaging technology and mouse reporter models to assess the effects of PEE and/or PNE on the dynamic growth of fetal VZ capillaries and their capacity to transfer macromolecules from fetal systemic circulation to the brain (Aim 2) and the adhesion and diapedesis of immune microglial cell precursors into the fetal NSC niche (Aim 3). This proposal will result in innovative high-resolution imaging tools for in utero fetal imaging and enable for the first time, dynamic, time-resolved assessment of capillary permeability and monocyte precursor invasion, to fill a significant gap in our understanding of the genesis of brain growth deficits due to PEE and/or PNE. These studies will also position us to begin to assess the efficacy of novel pharmacological intervention strategies targeted to prevent or reverse the effects of PEE and PNE on fetuses

NIH Research Projects · FY 2026 · 2015-09

Project Summary. By integrating AI-driven structural predictions with specialized domain knowledge, this proposal targets multiple conformations of bacterial translational G-proteins to profile small molecule interactions and elucidate drug resistance mechanisms. Key ribosome bacterial factors, EF-G and EF-Tu are promising antibiotic targets to treat methicillin-resistant Staphylococcus aureus (MRSA) and other multidrug- resistant infections. AlphaFold now enables predictions of previously inaccessible structural states, eliminating structural bottlenecks that hindered research progress. Continually evolving bacterial resistance demands a faster and more reliable fundamental research pipeline. Current methods often fall short, unable to keep up with new multidrug-resistant strains. We propose an integrated AI and experimental approach for rapid screening and testing to understand how small molecules interact with resistant protein mutations. The central hypothesis is that AI-predicted multiple conformational drug-target interactions, validated experimentally, will achieve breakthrough advances in compound discovery through faster screening and access to conformational states that experimental methods cannot capture. Using the novel AFDock algorithm, we aim to profile molecules targeting EF-G and EF-Tu conformations, including laterally transferable resistant variants, to address the critical challenge of MRSA and other drug-resistant bacterial infections. Aim 1. Develop the AFDock algorithm and validate drug candidates, targeting multi-drug-resistant strains like MRSA (S. aureus) and P. aeruginosa. This fundamental research approach will provide molecular interaction profiles rather than direct drug development. Aim 2. Develop a dual force spectroscopic imaging (DFSI) platform, making the first instance in force spectroscopy of high throughput, high resolution, and low background. It will be well suited for simultaneous investigation of both the kinetics and concentration dependence of small molecule candidates. Aim 3. SURFS/DFSI on Power Stroke, GTP hydrolysis coupling, frameshifting and tetracycline resistance. This represents the first systematic investigation combining evolutionary analysis with high-precision force measurements to understand EF-G mechanism. Impact. This proposal will yield versatile tools and new insights that address critical gaps in fundamental understanding of small molecule-protein interactions and protein translation mechanisms. Rather than direct drug development, this fundamental research will provide the scientific foundation needed to understand how small molecules interact with constantly changing bacterial targets. Outcomes include the adaptable AFDock algorithm, novel EF-G mechanistic insights, and comprehensive molecular interaction profiles, all publicly available through open repositories. The DFSI technical platform will also be accessible to the broader research community.

NIH Research Projects · FY 2024 · 2014-11

Cardiovascular diseases are the leading causes of morbidity and mortality in developed countries. One such disease is left ventricular noncompaction (LVNC, OMIM604169). The prevalence of LVNC reportedly ranged from 0.01% to 0.3%, and is higher in patients with heart failure, reportedly 3% to 4%. Genetic inheritance occurs in at least 30–50% of patients and genes that cause LVNC include the genes that encode sarcomeric or cytoskeletal proteins and Notch signaling pathway genes. In LVNC, trabeculae fail to undergo compaction. Trabeculae are sheet-like structures extending from the myocardium to the heart lumen that function to increase surface area when the coronary circulation system is not developed yet. A lack of trabeculation causes embryonic lethality, and excess trabeculation causes LVNC and heart failure in humans. Our studies demonstrated that the orientated cell division and directional migration of cardiomyocytes in the single-cell- thick myocardium contribute to trabecular initiation by forming a multiple-layer myocardium. Then endocardial cells (EndCs) invade the multiple layered myocardium and allocate cardiomyocytes to form trabeculae before E9.5. Many mutations of contractile protein genes correlate with LVNC, and it has been speculated that the contractile function of the myocardium is required for ventricular compaction; however, no genetic models have been made to test this hypothesis. The subsequent questions in this field will be what are the mechanisms that regulate the trabecular formation, de novo trabeculation, and ventricular compaction. Our preliminary data show that early the Itgb1 gene causes defects in trabecular formation, growth, Notch1 activation and deposition of Fibronectin (Fn), and late deletion causes defects in compaction and Notch1 activation. Furthermore, global deletion of the Itga5 gene or Fn1 gene causes defects in cardiovascular morphogenesis, but early lethality prevented the study of their functions in trabecular morphogenesis. Our heart-specific deletion of preliminary data show that heart-specific Itga6 gene (encoding integrin α6 subunit or α6), which is expressed specifically in the trabecular zone during compaction, reduces cardiac contractile function. Therefore, our central hypothesis is that integrin α5β1 and α6β1 have distinct functions in cardiac morphogenesis with α5β1 regulating trabecular formation and growth, and integrin α6β1 regulating ventricular contraction and the subsequent compaction and Notch1 activation. There are two aims to test the hypothesis. Genetic tools such as trabecular specific and compact zone specific Cre lines will be used to test these hypotheses. We have developed some unique expertise, e.g., single cell lineage tracing assay to study the mechanisms of trabeculation; ECHO to measure the contractility of embryonic hearts treated with drug or vehicle; rAAV9 system to rescue the LVNC defect. Completion of the studies will determine whether α5β1 axis regulates the trabecular formation and α6β1 regulates compaction in vivo and determine whether enhancement of contraction and activation of Notch1 can rescue the LVNC cardiomyopathy. deletion of the

NIH Research Projects · FY 2025 · 2014-09

ABSTRACT Overweight and obesity directly contribute to cardiovascular risk factors for cardiometabolic multimorbidity (i.e., type 2 diabetes, hypertension, coronary heart disease, chronic kidney disease, and stroke) and can lead to the development of cardiovascular disease independent of other cardiovascular risk factors. Recent projections indicate that nearly half of all adults in the U.S. (48.9%) will be obese by 2030 and severe obesity will be the most common body mass index (BMI) category among women, African Americans, and low-income adults. Numerous reports have called for effective interventions for weight loss and weight management to slow and ultimately reverse current trends. Evidence from leading scientific organizations suggests that advancing this effort requires diversifying the biomedical research workforce with individuals from underrepresented groups also most affected by the obesity epidemic. Increasing the size, skill, and diversity of the scientific workforce calls for investment in training, and the National Heart, Lung, and Blood Institute (NHLBI) answers this call with its signature initiative – Programs to Increase Diversity among Individuals Engaged in Health-Related Research (PRIDE). Our site, Obesity Health Disparities (OHD PRIDE) joined the NHLBI PRIDE family in 2014 and has implemented and evaluated a comprehensive research training and mentoring program for early- career faculty and transitioning postdoctoral fellows underrepresented in biomedical sciences. OHD PRIDE is the only funded site focused on obesity research and the only program specifically designed for eligible faculty employed at or who were trained at Minority Serving Institutions (MSIs). In this renewal proposal, we describe our strategy for implementing and evaluating a refined evidence-based, culturally- and contextually driven research training and mentoring program specifically designed for research-oriented, early-career faculty who are employed and/or trained at MSIs. OHD PRIDE will consist of five phases: (1) an initial 10-day intensive summer institute delivered in a phased, hybrid format; (2) longitudinal mentoring and networking during the academic year, including Writing Accountability Groups (WAGs); (3) tailored mentor support to submit competitive small research grant proposals (SRP); (4) a 3-day face-to-face mid-year meeting; and (5) a face- to-face culminating summer institute that will emphasize completion of SRP manuscripts for journal submission, career coaching, grant writing, and mock study sections. Our proposed program will draw from lessons over the past nine years to continue training and mentoring in obesity health disparities research across the life course, training in the responsible conduct of research, and secondary data analysis. OHD PRIDE features a dedicated group of trained research mentors, career coaches, and researchers (many of whom are faculty of color) with a strong track record of conducting a range of faculty development, research training, and mentoring programs with diverse populations employed in MSIs and majority institutions.

NIH Research Projects · FY 2024 · 2014-04

Project Summary Arterial medial calcification (AMC) and arterial stiffening are a prevalent pathological process in different pathological conditions or diseases such as hypertension, aging, atherosclerosis, diabetes and chronic kidney disease. Enhanced exosome secretion by smooth muscle cells (SMCs) has been reported to be an essential mechanism for calcifying nidus formation and extracellular matrix mineralization in the arterial wall to result in AMC. Recent studies have also shown that lysosome function plays a critical role in controlling multivesicular body (MVB) fate and enhancing exosome secretion and thereby in the development of arterial calcification. However, it remains poorly understood how lysosome function is controlled to determine exosome secretion and thereby lead to AMC. This proposal seeks to explore a novel epigenetic mechanism that regulates lysosome trafficking and exosome secretion, which may contribute to the development of AMC. This epigenetic regulation of lysosome function may be associated with the lysine methyltransferase Kmt6- mediated repression of gene transcription of Smpd1, a lysosome enzyme that hydrolyzes sphingomyelin into ceramide. Kmt6 is considered as a crucial epigenetic regulator that represses the target gene expression by methylation of lysine residue in histone proteins. In preliminary studies, we demonstrated that SMC-specific Kmt6 gene deletion exacerbated AMC and arterial stiffening, which were associated with increased Smpd1 expression and ceramide production, reduced lysosome TRPML1 channel activity, and lysosome trafficking dysfunction. These observations led us to hypothesize that Kmt6 is an essential epigenetic regulatory enzyme that controls lysosomal Smpd1-mediated sphingolipid metabolism and thereby regulates lysosome trafficking or its fusion to MVBs and subsequent exosome secretion in SMCs. Kmt6 gene defect or functional deficiency may disturb lysosome-mediated degradation of MVBs leading to increased exosome secretion, calcifying nidus formation, osteogenic transition, and ultimately AMC in face of different pathological challenges. To test this hypothesis, the following Specific Aims are proposed. Aim 1 will determine loss of Kmt6 contributes to osteogenic transition and AMC in SMC-specific Kmt6 knockout mice with analysis of SMC phenotypes and calcification. Aim 2 attempts to test whether Kmt6-mediated epigenetic regulation of Smpd1 critically controls lysosome trafficking and exosome secretion by increasing TRPML1 channel activity and associated Ca2+ release using patch clamping of isolated lysosomes and lysosome-specific Ca2+ imaging. Aim 3 will explore the molecular mechanisms how Smpd1 gene is epigenetically regulated by Kmt6 with a focus on its action on histone and DNA methylation in cultured arterial SMCs. Our findings will for the first time define an epigenetic mechanism controlling Smpd1 expression and activity via Kmt6 in SMCs and reveal a novel role of epigenetic dysregulation of sphingolipid metabolism in the development of AMC and arterial stiffening. These findings may also identify novel therapeutic targets for the treatment of AMC under different pathological conditions.

NIH Research Projects · FY 2025 · 2012-06

PROJECT SUMMARY The fundamental physical properties of the outer tunic of the eye determine the structural characteristics of the ocular globe and may be altered in several devastating disease states, including axial elongation in myopia, pathological deformation in keratoconus, and iatrogenic keratoectasia following corneal refractive surgery. These biomechanical tissue characteristics not only influence our clinical interpretation of diagnostic tests, e.g., intraocular pressure measurement, but have been implicated as important factors in the development of glaucoma. In our previous studies, we have developed a new method to perform quantitative measurements of corneal elasticity in vivo in healthy and diseased eyes. Here, we will develop a next-generation method for the assessment of corneal viscoelasticity in 3D with high resolution, no contact, and in real-time that could potentially be used for routine clinical diagnosis and treatment. This method will take advantage of the interference of multiple mechanical waves and ultra-sensitive detection and analysis of the interfering waves in 3D throughout the cornea. Ultra-fast optical coherence tomography imaging and a new method for correcting for the loss in temporal and spatial coherence will enable 3D mechanical imaging within milliseconds, which is not possible with any existing methods. Our previous work has made fundamental advances in understanding corneal biomechanics through a novel approach with potentially impactful applications in other disciplines (e.g., cataract surgery, LASIK, corneal cross-linking (CXL), and tissue transplants with personalized treatments). The proposed studies will accelerate the transition of this technology into clinics, influence our selection and application of corneal surgical treatments, and help us understand the structural consequences of corneal disease and wound healing.

NIH Research Projects · FY 2026 · 2000-02

Neurons throughout the central nervous system employ two types of synapses, chemical and electrical, to communicate. Electrical synapses, made from gap junction channels, support fast, bidirectional and transmitterless signal transfer between cells that organizes neurons into networks and forms defined and sometimes specialized circuits. Both chemical and electrical synapses display plasticity, which is an essential substrate for local circuit optimization and plays a critical role in learning, behavior and sensory signal processing. The majority of electrical synapses in the mammalian central nervous system are formed by Connexin 36 (Cx36), the product of the GJD2 gene. This connexin is intrinsically capable of functional plasticity through variations in phosphorylation that open or close the channels, and so is dynamically regulated by cellular signaling at the location of the electrical synapse. This project seeks to understand the mechanisms that control this plasticity in neurons of the retina, in which Cx36 plays central roles in rod pathway signal flow and in adaptation of many circuits to different light levels. In chemical synapses, many proteins that regulate function and turnover of neurotransmitter receptors are assembled in the post-synaptic density. In an analogous manner, many proteins that regulate the function of electrical synapses are assembled near them, but our knowledge of these assemblies is minimal. In this project, we will identify proteins that regulate the function and turnover of Cx36 electrical synapses through proteomic strategies. We will harness evolutionary conservation of regulatory mechanisms to identify proteins found to be associated with Cx36 in both mouse and zebrafish retina, and investigate the roles of novel proteins discovered in regulation of Cx36 plasticity and turnover. Key elements of assemblies associated with the electrical synapse are scaffold proteins, which are required for electrical synapse formation and stability. However, our studies indicate that a critical scaffold that binds to Cx36 inhibits its channel function when bound, but that binding to Cx36 is weak. We will investigate the hypothesis that Cx36 is evolutionarily tuned to bind weakly to certain scaffolds and that binding can be further weakened by phosphorylation of sites on Cx36, allowing it to dissociate and enter functional states. Finally, we will investigate whether this modification of Cx36 binding to associated proteins can modulate the size of electrical synapses in a manner that correlates with the electrical synapse functional state. These studies will shed light on mechanisms that regulate the function of electrical synapses in the vertebrate retina, and will provide insight relevant to electrical synapses throughout the central nervous system.

NIH Research Projects · FY 2026 · 1997-03

The NEI P30 Center Core Grant for Vision Research at the University of Houston (UH) provides ongoing and stable funding for four high quality and productive vision research resource/service Modules: Instrument Design, Research Computer Programming, Biostatistics Support, and Biological Imaging. These Modules are directed by established vision scientists, and run by an exceptionally talented staff with considerable long-term experience in supporting and advancing innovative vision research at UH. The Modules provide needed research resources and services, with prioritized and equitable access, to the present group of 22 Core vision scientists who come from three departments at the University (Biomedical Engineering, Vision Sciences and Clinical Sciences in Optometry). These Core vision scientists have diverse training and research interests; they collaborate effectively with one another, as well as with other vision researchers at this University or other institutions. Together, 11 of the Core investigators hold 16 active NEI R01 grants, with three other core investigators as Co-Is. Core investigators also have other NEI, NIH and nonfederal vision research funding. The College of Optometry and University provide substantial additional commitments in support of vision research. During the past five years of P30 funding at this university, the Core Grant and the University have created a favorable vision research environment, including new instrumentation and collaborative arrangements that have contributed directly to 170 out of 300 published papers by UH Optometry. Core modules have facilitated competition for six entirely new NEI R01 grants by four investigators. The Core Grant also was instrumental for recruiting eight investigators, established and new, to the UH Core group of vision scientists, three of whom brought NEI R01 funding, and two, other NEI support. These accomplishments reflect the Core's previous and current aims reinforced by the oversight of the Administrative Core, that focus on advancing collaborative and innovative vision research to increase knowledge and prevent or cure diseases that impair vision. Through these aims the Core grant provides stable funding, quality research services, new independent vision researchers, and new projects attracting NEI and other NIH support. Especially emphasized in the coming five years will be innovative research and recruitment of vision researchers to fill existing and future open positions.

NIH Research Projects · FY 2026 · 1995-08

PROJECT SUMMARY The gene encoding peripherin 2 (PRPH2), is mutated in 3-5% of inherited retinal degeneration (IRD) cases. PRPH2 variants lead to a spectrum of retinal diseases, including retinitis pigmentosa (RP) and various forms of macular and pattern dystrophy (PD). These diseases often entail secondary impairments in adjacent tissues like the RPE and retinal/choroidal vasculature. Despite considerable scientific advancement, the lack of clinically viable therapeutic options for PRPH2 retinal diseases persists due to several factors including the diverse roles of PRPH2/ROM1 (retinal outer segment membrane protein 1, a core binding partner of PRPH2) in rods versus cones, limited genotype/phenotype correlations, extensive variability in disease phenotypes within and between families, the role of secondary sequalae in disease progression, and the necessity for precise PRPH2 dosage to offset the effects of its haploinsufficiency. PRPH2 plays a crucial role in the formation, maintenance, and renewal of the outer segment (OS). In its absence rod OSs are not formed. On the other hand, cones form extended membranous structures that lack evaginations of the lamella but retain function, highlighting the different roles for PRPH2 in rods and cones. We aim to elucidate the precise role of PRPH2 and ROM1 complexes in OS rim, incisure, and disc/lamella formation, and to expand our knowledge of the PRPH2 interactome with the goal of potentially influencing severity of disease phenotypes. Gaining a thorough grasp of the mechanisms associated with PRPH2 diseases is crucial for designing effective therapies. The mechanisms underlying photoreceptor disc morphogenesis are not well understood and are of longstanding interest. To bridge the gaps in our knowledge, we established mouse models and various therapeutic platforms, enabling us to evaluate disease mechanisms and test therapeutic strategies for PRPH2 diseases. Our multidisciplinary team is comprised of leaders in photoreceptor cell and molecular biology, advanced imaging technologies, structural biology, and non-viral therapeutic formulations and will employ cutting-edge experiments to achieve the following objectives: 1) Investigate the role of PRPH2 complexes in forming the highly curved, hairpin-shaped disc rim structures crucial for OS formation. 2) Explore ROM1’s influence on disc rim morphogenesis, particularly in timely closure of the newly synthesized discs and incisure formation. 3) Identify interacting partners contributing to the diverse disease phenotypes associated with PRPH2 variants. 4) Investigate mechanisms underlying variability among patients with identical PRPH2 variants. 5) Develop therapeutic platforms to mitigate severe PRPH2- associated phenotypes. Understanding these mechanisms is crucial for advancing our knowledge of OS morphogenesis and the diversity of PRPH2-associated disease phenotypes.

NIH Research Projects · FY 2025 · 1984-09

Short Term Training in Health Professional Schools The long-term objectives of the proposed short-term training program are: 1) to inspire commitment to research careers in vision science among optometry students, including women and underrepresented groups, and 2) to foster a better understanding of vision research and evidence based clinical practice. The specific aim is to increase the number of clinician scientists who can do basic, clinical, and translational investigative work on vision and vision disorders through early exposure to research. The program has operated successfully since 1985. Almost 390 optometry students have been trained, including students from underrepresented groups, and students from 11 optometry schools other than the University of Houston. The program provides opportunities for academically qualified and motivated students to spend three months learning to formulate testable vision- research questions and to develop research skills by doing a research project mentored by 1 of 19 experienced vision scientists. The mentors' research programs fall into the following broad areas: 1) visual development, plasticity, repair, and aging of structure and function, 2) visual optics and refractive error, 3) ocular surface and anterior segment, 4) oculomotor systems, 5) structure and function in normal and diseased eyes, and visual pathways, 6) visual cell and molecular biology and immunology, 7) spatio-temporal vision, and 8) binocular vision. Twelve students will be recruited each of the next five years for NEI fellowships, with another two or more supported by local funds for the program. Selection will be based on scholarship, particularly in sciences, as well as on research interest, potential, and experience. Trainees will be first year optometry students. In addition to research, trainees will participate in: 1) a 2-hr course on responsible conduct of research, research design, reproducibility, methodology and communication of findings, 2) a 1-hr weekly seminar given by local and visiting vision scientists, and 3) lab meetings and journal clubs. Trainees will have access to first-rate facilities and resources, including well-equipped basic and clinical/translational research space, a full scope of technical services (bio-imaging, research computer programming, instrumentation, biostatistics), animal viviarium, and a vision and health science library with full electronic access – all in modern buildings on a major university campus. Public Health: The proposed short term training program for optometry students will improve visual health by increasing the number of clinician scientists doing basic, clinical and translational research on vision disorders. The program encourages participation by underrepresented groups in vision care and science.

NIH Research Projects · FY 2025 · 1981-02

PROJECT SUMMARY/ABSTRACT Soon after birth, most infants develop the optimal refractive error (i.e., “clinical” emmetropia) in both eyes that is maintained throughout childhood and into adult life. However, for reasons not currently understood, a significant and rapidly increasing proportion of the population develop myopia, or nearsightedness. Because of structural changes that take place as the eye becomes myopic, even low degrees of myopia pose a significant risk for multiple blinding conditions. As a consequence, myopia is now one of the leading causes of permanent visual impairment in the world. Additionally, myopia represents a substantial economic burden. In addition to lost productivity, billions of dollars are spent annually on optical corrections and pathologies caused by myopia. The long-term goal of our research program is to provide a better understanding of the etiology of common forms of myopia, juvenile and early adult-onset myopia, and to develop effective treatment strategies that reduce the burden of myopia. The specific aims of our proposed research are to determine how visual experience affects refractive development, to characterize the operational properties of the vision-dependent mechanisms that regulate eye growth, and to explore new pharmaceutical approaches to eliminate myopia. Our purpose is to generate knowledge that can be applied to the human eye; however, many of the required experiments cannot be conducted in humans. Therefore, these experiments will be conducted using rhesus monkeys. Previous studies in our lab and others show that characteristics of light, such as intensity, wavelength, and duration of exposure, influence eye growth. Potential mechanisms include alterations in retinal and choroidal visual cascades and ocular remodeling, particularly of the sclera, the outermost coat of the eye. Preliminary data also show that prostaglandin analogs and alpha-adrenergic agonists influence eye growth. Here, controlled rearing strategies, rigorous optical and biometric techniques, and histopathological investigation will be used to determine: 1) the effects of duration and dosing of red light exposure on in vivo eye growth and myopia and on in vitro human scleral fibroblast culture and 2) whether prostaglandin analogs and alpha-2 adrenergic agonists can slow the development of myopia. The role of scleral fibroblast activity, scleral remodeling, and intraocular pressure in eye growth will be examined. The proposed experiments focus on fundamental issues concerning the manner in which visual experience influences refractive development. Findings will be important in determining how and to what extent visual experience contributes to the genesis of common human refractive errors. More importantly, the results of these studies will potentially provide the scientific foundation for novel treatment and management strategies for the most common forms of myopia in children to prevent and slow the progression of myopia, increase quality of life, reduce the risk of associated pathologies, and decrease the economic burden caused by myopia.