University Of Houston

NIH Research Projects · FY 2025 · 2022-09

Globally, there are over 16 million orphans and vulnerable children (OVC), with estimates of between 1.9-3.7 million for South Africa (SA). Despite high mental health needs of OVC, there is a crisis in scarcity of mental health workers in SA. Community-based organizations (CBOs) offer a strategic point of intervention. In a prior NIH-funded quasi-experimental feasibility trial we showed that the Mediational Intervention for Sensitizing Caregivers (MISC) for CBO careworkers, thereafter named MISC-CBO, significantly reduced mental health problems in Sesotho-speaking OVC. MISC-CBO is a year-long semi-structured, manualized video-feedback intervention designed to enhance the caregiving capacity of CBO careworkers to improve child outcomes, by targeting the RDoC systems for social processes (affiliation and attachment). Building on this work, we now propose a repeated measures cluster randomized trial to fully establish the effectiveness and trans-diagnostic mechanisms of action of MISC-CBO in 7-11 year olds – a developmental stage critical for building mental health resilience against the adolescent onset of psychiatric problems. In addition, we will use Consolidated Framework for Implementation Research (CFIR) constructs and input from a Community Advisory Board (CAB) to leverage the RCT to evaluate implementation costs and readiness that would better position the RCT results for future uptake, scale up, and sustainability. In Aim 1, we will evaluate the direct effects of MISC-CBO on video-coded CBO careworker caregiving quality (affiliation and attachment) and children’s mental health outcomes over a 24 month period. 24 CBOs (360 children and 72 careworkers) will be recruited using our existing NGO partner (Childline) in the Mangaung and Xhariep districts in the Free State, SA. CBOs will be randomly assigned to receive either one year of bi-weekly MISC-CBO or TAU. We hypothesize that MISC-CBO will be associated with comparative increases in careworker caregiving quality and reductions in mental health problems in OVC. In Aim 2a, we will test the hypothesis that caregiving quality at end-of-intervention (12 months) accounts for intervention effects on child mental health at 18 and 24 months. Aim 2b will evaluate the moderating effects of orphan status and the quality of the home environment, expecting that OVC who are maternal and double orphans, and from impoverished home environments will show reduced response to intervention compared to children without these risk factors. Aim 3a will use World Health Organization metrics to test the hypothesis that MISC-CBO is cost-effective in terms of disability-adjusted life years (DALYs) averted. Aim 3b will use qualitative methodology to test the hypothesis that community stakeholders deem the context favorable and ready for the implementation of MISC-CBO, and that additional barriers and facilitators for scale-up and implementation will be identified. Our proposed work extends our formative work to now fully test the real-world effectiveness, mechanisms of action, cost-effectiveness and implementation readiness of MISC-CBO during the critical developmental window of at-risk children aging into adolescence, consistent with NIMH’s strategic objectives.

NIH Research Projects · FY 2025 · 2022-09

Abstract Myopia (nearsightedness) is one of the foremost causes of visual impairment worldwide, with severe myopia being linked to several serious eye diseases that can result in permanent blindness. The prevalence of myopia has been increasing and is estimated to affect 50% of the world’s population by 2050. Despite the identification of many risk factors for myopia progression such as age of onset, genetics, visual environment, and peripheral defocus, causes of myopia are not fully understood. Current interventions have shown some success, but without a clear explanation for their mechanism of action. It is therefore critical to investigate the mechanisms underlying myopia development in order to design effective interventions to control the progression of myopia in children, and to delay or ultimately prevent onset altogether. Our long-term goal is to understand the influence of peripheral optical and neural factors on myopia development. The specific objective of this proposal is to test the central hypothesis that optical and neural anisotropy in the human peripheral visual system plays an important role in axial elongation. To achieve these goals we will develop and implement innovative optical tools including a compact scanning ocular wavefront sensor, an open-view scanning adaptive optics vision simulator, and individually-customized contact lenses. Aim 1 is directed at characterizing how different aberration profiles impact through-focus retinal image quality and neural functions. First, measuring lower and higher order ocular aberrations across retinal eccentricity will characterize individual retinal image quality and blur orientations. Neural anisotropy at the same eccentricities will then be evaluated by administering psychophysical tasks while bypassing the ocular optics using a scanning adaptive optics vision simulator. Aim 2 will focus on determining how intrinsic peripheral aberration profiles and eye shape change over time in school children. To do this, we will develop a compact portable scanning wavefront sensor that can be transported to and used in a clinic for measuring longitudinal changes of school children’s optics across retinal eccentricity. This will allow us to delineate relationships between changes in peripheral aberrations at the crucial stages of myopia development, in those children who develop myopia. Aim 3 is proposed to further investigate a role of blur orientations in detecting the sign of defocus and altering directional neural sensitivity in the peripheral retina. To achieve this goal, the retinal response in term of changes in choroidal layer thickness (short-term) and neural sensitivity (long-term) will be examined during and after the peripheral retina is exposed to specific blur orientations.

NIH Research Projects · FY 2025 · 2022-09

Project Summary Every 30s, someone in the world has a limb amputated, with approximately 2.1 million people living with amputations in the U.S.A. Upper limb amputees traditionally use passive, body-pow- ered, or electrically powered prostheses that use surface Electromyographic (EMG) signals from intact muscles in the residual limb for movement and rely on visual and/or surrogate sensory input. Advanced peripheral nervous (PN) system interfaces have been proposed as a viable mechanism to improve the control by amputees by delivering naturalistic sensory feedback from sensorized robotic prosthetics. Unfortunately, current neural interfaces suffer from common chal- lenges such as electrode failure, signal deterioration over time, and unstable or problematic sen- sory percepts (“stinging and tingling”) that remain a challenge. Our Hypothesis is that we can obtain superior control over the somatosensory thalamus and cortex (S1/VPL), which will lead to more controlled sensory percepts by using molecularly guided regenerative peripheral nerve con- duits that entice cutaneous and proprioceptive axons down their respective molecularly cued arms of a Y-shaped Regenerative Ultra-thin Multi-Electrode Interface (Y-MG-RUMEI) implanted at me- dian nerve transections. As the Ultra-thin MEIs have much smaller electrode surface areas it is hoped they will offer more local control and decrease excitation of large, possible unrelated, axons in the peripheral nerve. Additionally, we will utilize optimized microstimulation (opMiSt) through UMEIs embedded in the 2 branches of the Y with their molecular cues for touch and propriocep- tion, respectively. Neural recordings will be made from the S1/VPL towards the optimization of the peripheral MiSt. Three specific aims are included: SA1. Achieve selective MiSt from Y-MG-REMEIs with Proprioceptive and Cutaneous conduits in a rat model. SA2. Determine controllability of VPL/S1 via MiSt in Y-MG-RUMEI sensory conduits in a rat forepaw (hand) amputee model. SA3. Deter- mine if Y-MG-RUMEIs allow better bidirectional Brain-Nerve-Machine Interface (biBNMI) control, as compared to control-RUMIs, without molecular guidance, based biBNMI performance in a rat amputee model.

NIH Research Projects · FY 2025 · 2022-08

Recent retrospective studies show that radiology's diagnostic error rates did not decrease significantly over the years. For example, missed lung cancer rates remain at 20-60% on chest radiography dependent on study design. This error contributes to 40,000-80,000 deaths annually in U.S. hospitals. This project aims to develop a computational framework for Al to collaborate with human radiologists on medical diagnosis tasks. To achieve this goal, we divide the project into three Aims, where the first two focus on fundamental theories, and the last one evaluates the proposed approaches on targeted applications. Aim 1: Develop computational principles for optimal Al-radiologist interaction. This Aim will develop a computational framework for guiding the interaction between radiologists and Al to achieve the best possible diagnostic performance while minimizing the time burden. Our framework consists of the first method for reverse-engineering radiologists' intention from the joint gaze and visual information based on reinforcement learning. This Aim is the first to provide an integrated system with gaze sensing, deep networks, and human radiologists. The knowledge from this Aim will fundamentally transform how one would build collaborative medical diagnosis systems. Aim 2: Design a user-friendly and minimally-interfering interface for radiologist-Al interaction. This Aim addresses an essential question of designing a minimally interfering interface that allows human radiologists to interact with Al models efficiently. Our proposed system combines an innovative "multimodal thinking with audio and gaze" (MTAG) methodology with user-centered iterative design. The process will result in a novel radiologist-Al collaborative interface that maximizes time efficiency while minimizing the amount of distraction. The outcome of this Aim will shed light on design principles for systems involving radiologists. Aim 3: Evaluation Plan. This Aim evaluates the proposed approaches in Aim 1-2 on two clinically important applications: i) Lung nodule detection and ii) pulmonary embolism. Lung cancer is the second most common cancer, and pulmonary embolism is the third most common cause of cardiovascular death. Studying how radiologists collaborate with Al to reduce diagnostic errors will lead to significant clinical impacts. RELEVANCE (See instructions): Diagnostic errors contribute to 40,000-80,000 deaths annually in U.S. hospitals. This project combines novel artificial intelligence (Al) algorithms, gaze monitoring software, and design principles to help doctors minimize diagnostic errors due to cognitive and perceptual biases. The project's success will fundamentally change how we design Al medical systems to increase diagnostic accuracy, save lives, reduce missed cancer diagnoses, improve public health, and advance NCl's mission.

NIH Research Projects · FY 2025 · 2022-08

Project Summary/Abstract The goal of this project is to develop novel methods for predicting human decisions with diagnostic images. Expected project outcomes include new insights into sources of radiologist variability and advanced tools to accelerate imaging trials in clinical research. Such trials with expert readers and known-truth cases are an accepted but burdensome gold standard for evaluating imaging technology. The necessary trial resources are not available to many clinical researchers. Virtual trials with sur- rogate model observers have been proposed, but important limitations, including primarily correlative estimates and persistent model reliance on human data for training, prevent their widespread adop- tion. Quantitative models with minimal dependence on human input will substantially improve clinical access to advanced imaging technology. Our approach to develop such “low-resource” models will explore reader variability in target detection and estimation tasks. Ideal observers (IOs) derived from gist-processing and extreme-value theories will be the starting point. These IOs are optimal for de- cision processes that maximize over sets of extracted feature values, a common premise for tasks involving visual search. The result will be adaptive observer models that produce tighter bounds on human performance compared to existing models. These new models will test if reader variability can be attributed to candidate pooling and cognitive threshold mechanisms that define image struc- ture of interest. Analytic figures of merit for diagnostic visual-search tasks will be developed. We will test model generalizability across radiological modalities, tasks, imaging models (e.g., simula- tion/patient data), and reader classes (lay/clinician), all of relevance for researchers. The tasks will include location-known, localization, and joint detection-estimation formats. The joint task compels more precise information extraction than target detection alone; we hypothesize that detection perfor- mance correlates with estimation skill, with the latter helping to resolve structure. We shall leverage our findings to devise multireader virtual trial protocols for improved statistical rigor. Enhanced stochastic target modeling for studies with 2D and 3D images will be supporting aims. The IO will also allow examination of nonlinear behaviors for individual readers. The project studies relate to dose reduction and reconstruction methods for x-ray and nuclear medicine modalities, but the methods can apply more generally. By accelerating the clinical adoption of advanced imaging technology, our model observers will have a direct and widespread impact on clinical operations and patient care.

NIH Research Projects · FY 2025 · 2022-08

There is a dire need for training early career clinicians and researchers with innovative research methodologies and research tools to make new discoveries and technological advances for effective diagnosis, prevention, and treatment of human brain disorders. The overall goal of this summer research training program entitled “Neuromotor Skill Advancement for Post baccalaureates or NSAP” at the University of Houston IUCRC BRAIN Center is to provide didactic and hands-on activities focusing on the development of highly specialized and highly sought-after technical skills to study the brain with the intention to complement and enhance the training of therapists, clinical and research fellows, and orthotists and prosthetists from a community for neurorehabilitation and neuroengineering research with the goals of improving health and well-being of children and adults and meeting the nation’s biomedical, behavioral and clinical research needs using emergent technologies. Trainees will be recruited nationally through announcements and advertisements. A group of 10 trainees in the science, bioengineering, neuroscience, or medical fields at the post baccalaureate level will be recruited to participate over 10 weeks in the summer months in workshops and seminars, didactic work, and immersive collaborative and personalized research experiences. The proposed collaboration with experts at Texas Medical Center (TMC) institutions, including Texas Woman’s University, the University of Texas Medical Branch and TIRR Memorial Hermann, and the faculty from the NSF BRAIN Center at the University of Houston leverages unique facilities, extensive expertise and mentoring experience to provide state-of-the-art training in neuroimaging, neuromodulation, and neurorehabilitation engineering. In addition, our NSAP faculty mentors represent the workforce in the fields of neurorehabilitation and neuroengineering.

NIH Research Projects · FY 2025 · 2022-08

DESCRIPTION Glaucoma is a group of diseases that results in a pathological loss of retinal ganglion cells (RGC) and irreversible vision loss. Increased intraocular pressure (IOP) is a major risk factor for glaucoma, but some individuals with elevated pressures never develop disease, and others with low pressures progress to blindness. Similarly, in the non-human primate experimental glaucoma model, animals with similar IOP profiles are shown to have significant differences in the extent and rate of retinal nerve fiber layer (RNFL) thickness loss. Both clinical and experimental models suggest that in addition to IOP, other factors need to be considered for glaucoma progression. We hypothesize the variability in disease progression can be explained by vascular factors. The retina is one of the most metabolic tissues in the body, and it is unknown if eyes with relatively lower vascular volume, or eyes that show greater change in perfusion with changes in IOP are at greater risk of pathology. Furthermore, although eyes with optic neuropathy have reduced vascular density, it remains unknown if there are changes in retinal vasculature that precede RGC loss. Optical coherence tomography angiography (OCTA) is a non-invasive method for three-dimensional vascular perfusion imaging. However, analysis of OCTA imaged vasculature is based on slab projections, where the three-dimensional nature of tissue is lost. In addition, OCTA vascular perfusion is often considered a static measure, but vascular flow velocity has temporal properties. For this project, we have optimized OCTA scans to quantify vascular volume and vascular volume density, and using sequential and registered scans, OCTA temporal variability. In the non-human primate experimental glaucoma model, we will determine; 1. if the rate of disease progression is related to baseline global and regional measures of vascular volume / volume density and regional OCTA temporal variability, 2. if there is loss of vascular volume prior to inner retinal thickness, 3. if the rate of structural and functional changes are is related to the extent to which vascular perfusion changes with IOP challenge, and 4. using post-mortem tissue, define vascular anatomy (pericyte coverage, endothelial cell density, capillary basement membrane thickness/integrity) in healthy and disease eyes and association with in vivo OCTA measures. Successful completion of these aims will establish if vascular measures as quantified using OCTA can be used to determine risk of pathology, and rate of glaucoma progression.

NIH Research Projects · FY 2026 · 2022-07

Rod/cone coupling is the entry point to the secondary rod pathway. Our overall hypothesis is that the circadian and light-induced modulation of rod/cone coupling changes retinal function and has profound effects throughout the visual system according to the time of day. Electrical synapses, also known as gap junctions, are common building blocks that connect neurons into coupled networks. Although electrical synapses display a high degree of plasticity, there is a fundamental gap in understanding how this plasticity modifies circuit activity and output. We anticipate that learning how to control electrical coupling may have useful clinical potential. We have developed (1) the capability to record from pairs of adjacent mouse photoreceptors to directly measure the trans-junctional conductance; (2) rod-specific and cone-specific connexin36 (Cx36) knockout (XO) mouse lines. In these mice, there is no rod/cone coupling, mimicking daytime or bright light. (3) a phospho-mimetic mutant Cx36 conditional knock-in (Cx36-DEDD) line, which displays saturated rod/cone coupling, equivalent to night time; and (4) a congenic B6 mouse line in which we rescued melatonin synthesis—an important circadian clock signal that is missing in most mouse strains. Retinas from the congenic line show robust circadian variations in dopamine release. In aim 1, by recording from rod/cone pairs, we will measure the gap junction conductance between rods and cones to test the hypothesis that rod/cone coupling spans from ~ 0 to 1,000+ pS, reflecting the collective action of melatonin, dopamine, and ambient light. We have shown there is no rod/cone coupling in the Cx36 XOs (mimics daytime) and we expect maximal coupling in the Cx36-DEDD (mimics nighttime). We will determine how the rod/cone gap junction conductance changes by time of day (congenic B6 line). In aim 2, we will record from cones and from ganglion cells to test the hypothesis that rod signals in the secondary rod pathway change by time of day. We expect our mutant lines to set the limits, with minimal input in the Cx36 XOs (mimics daytime) and maximal input in the Cx36-DEDD line (mimics nighttime). In aim 3, we will examine visual behavior in the intact mouse to measure the effect of an inactive (Cx36 XO, mimics daytime) and of a saturated rod/cone pathway (Cx36-DEDD, mimics nighttime). We will test the hypothesis that rod/cone coupling plasticity contributes to the daily modulation of contrast sensitivity and visually- guided behavior. Our work will offer a prime example of how a single electrical synapse can change retinal function to influence visual perception. This research will help define general principles underlying the role of circadian clocks and electrical synaptic plasticity in the daily changes in neural circuits relevant to brain function and behavior.

NIH Research Projects · FY 2026 · 2022-06

PROJECT SUMMARY Significant progress in recent years on the development of oncolytic virotherapy has led to the FDA approval of a type I herpes simplex virus (HSV-1) based oncolytic virus (Talimogene Laherparepvec or T-VEC) for the treatment of advanced melanoma. However, it has become increasingly clear that there is a need to further improve the current version of OV for a better clinical benefit. Our lab has constructed a HSV-2 based oncolytic virus - FusOn-H2, the first of its kind, by a novel mechanism. Our recent studies showed that arming FusOn- H2 with a chimeric NK engager (C-NK-E) that can engage the infiltrated natural killer (NK) cells with tumor cells could significantly enhance the effectiveness of this virotherapy. Moreover, we observed that tumor destruction by the joint effect of the direct oncolysis and the engaged NK cells led to a measurable elicitation of neoantigen-specific antitumor immunity. Based on these exciting findings, we propose to develop a three- pronged strategy to enhance the antitumor efficacy of FusOn-H2 via combinatorial immuno-oncolytic virotherapy (IOV). The antitumor activities from this strategic three-pronged IOV come in waves in a sequential order. The first wave comes immediately and it derives primarily from the virus-mediated direct oncolysis. The second wave comes from the NK-mediated tumor cell killing enabled jointly by the virotherapy-trigged NK cell infiltration and the released C-NK-E from the armed virus. The third wave is the outcome of a series of chain events that ultimately result in induction and homing of neoantigen-specific T cells. Our major hypothesis is that this three-pronged strategy will act in a consequential and concerted way to significantly enhance the therapeutic efficacy of this IOV. We have designed three specific aims to test our major hypothesis. In Aim 1, we will dissect the mechanism of C-NK-E-armed virus in generating neoantigen-specific immunity and to design additional strategies to further potentiate this effect. Neoantigens are attractive targets for cancer immunotherapy, but there lacks a simple and effective way of delivering them. In principle, OV offers a simple means to release these neoantigens in individual patients, and our proposed strategy will ensure their efficient and timely presentation to the host’s immune system without the need for additional procedures. In Aim 2, we will investigate if combining C-NK-Es that engage two different activation receptors can further potentiate the NK cell killing and neoantigen-specific T cell immunity. In Aim 3, we will demonstrate that the three-pronged IOV can produce an efficient therapeutic effect against metastatic diseases by the systemic delivery route. We have recently developed novel strategies to overcome key obstacles for systemic delivery - the rapid clearance by the macrophage system and the neutralizing antibodies. We hypothesize that the combination of the high potency of the three-pronged IOV with the improved systemic delivery will lead to effective treatment of metastatic diseases. Our studies in this proposal thus overcome the two major hurdles hindering OV - the relatively weak therapeutic activity and lack of means for effective systemic delivery, and the developed strategy can be translated into the clinic in the near future.

NIH Research Projects · FY 2025 · 2022-05

Project summary The prevalence of dry eye disease (DED) ranges from ~5 to 50% of the general population with an estimated US$ 3.8 billion dollars in associated medical costs. Symptoms of DED include pain, fatigued and/or sore eyes, photophobia and blurred vision, which lead to a decrease in productivity and reduce the quality of life. Unfortunately, treatment options for DED are limited. Clinical studies suggest 85% of overall DED cases are caused by Meibomian gland dysfunction (MGD). As humans and mice age, their Meibomian glands (MGs) undergo age-related changes, including decreased acinar basal cell proliferation and atrophy, and these changes result in age related-MGD (ARMGD). The precise cause of ARMGD remains elusive, which makes the development of therapies extremely challenging. Hyaluronan (HA) is a major extracellular component that interacts and binds to a myriad of molecules forming complex macromolecules which regulate major physiological functions, such as development and stem cell specification. Our recently published work shows that compound HA synthase (Has)-1 and -3 null mice, namely Has1-/-;Has3-/- mice, have enlarged MGs when compared to age matched wild-type (wt) mice. Our preliminary data show that the MGs of Has1-/-;Has3-/- mice continue to increase in size throughout life, and, interestingly, these mice do not develop ARMGD. At 1 year of age, Has1-/-;Has3-/- mice have a striking 4-fold increase in MG volume and an overall 10-fold increase in lipid production, compared to age matched wt mice. We hypothesize that the increase in HA expression in and around the MGs of Has1-/-;Has3-/- mice is capable of maintaining viable progenitor cells as they age, which in turn prevents ARMGD. Specific aim 1 of this proposal will characterize the extracellular matrix in the MGs of wt and Has1-/-;Has3-/- mice with a focus on the composition of the HA matrix. Specific aim 2 of this proposal will analyze the distribution of MG progenitor and proliferating cells in order to identify how the MGs of Has1- /-;Has3-/- mice enlarge over time. This aim will also characterize the lipid composition of the meibum, and verify whether enlarged glands can prevent DED. Importantly, although Has1-/-;Has3-/- mice lack two isoforms of the enzyme responsible for HA biosynthesis, they up-regulate the third isoform (Has2), and, in turn, present a significant increase in HA expression in and around MGs when compared to wt mice. Therefore, we also hypothesize that increasing Has2 expression and HA bioavailability within MGs could prevent ARMGD in aged wt mice. Specific aim 3 will test whether Has2 overexpression and FDA approved HA-based treatment regimens to increase the bioavailability of HA within tarsal plates and MGs can prevent ARMGD in wt mice.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY Mutations in Peripherin 2 (PRPH2) account for a significant portion of inherited retinal diseases (IRD). Delineating the role of PRPH2 in photoreceptor morphogenesis and rim formation is vital to understand how mutations in a single protein could contribute to such diverse group of pathologies, ranging from retinitis pigmentosa (RP) to pattern dystrophy (PD) and macular degeneration (MD). Even patients with intrafamilial mutations can exhibit a notable degree of phenotypic variability, attesting to the complex nature in which PRPH2 functions. My objective in this application is to advance our current knowledge of the role of PRPH2 in outer segment (OS) formation in order to have a better understanding of disease pathogeneses and for future development of effective therapeutic strategies. Over the years, our lab has developed an extensive toolbox of in vitro and in vivo mutant models, and are currently exploring innovative imaging techniques to further our understanding of the role of Prph2 in OS landscape. Thus far, it has been determined that the association between Prph2 and its homologue, Rod OS Protein 1 (Rom1), contributes significantly to the phenotypic variability observed in patients and that lowering Rom1 levels could shift a sever Prph2-assocaited PD phenotype to milder RP. Furthermore, it is know that the proper function of Prph2 at the disc rim is contingent upon proper complex assembly of Prph2-oligomers and Prph2/Rom1-complexes. The central focus of this investigation is to understand how Prph2 and Rom1 function differently in rods and cones with particular interest in Prph2 homo- and Prph2/Rom1 hetero-complex formation/trafficking, and the effects of Prph2 mutations on these processes. We propose two aims to address these goals: Aim 1 will assess the role of Rom1 in cones and the mechanism by which it modulates Prph2-disease phenotypes. By eliminating or overexpressing Rom1 in Prph2-disease models, we will conduct careful biochemical, structural, and functional analyses to assess phenotypic differences, as they pertain to complex assembly and OS trafficking. Aim 2 will investigate the role of interacting partners in the differential behavior of Prph2 in rods vs cones. In order to properly traffic and function in the OS, Prph2 forms membrane microdomains to organize and house a network of proteins that are necessary/specific for the formation of the closed rims in rods and open lamellae/rims in cones. In this aim, we will identify critical Prph2 binding partners and determine how these interactions differ between rods and cones. The outcomes of these studies will elucidate the specific function of Prph2 and Rom1 in rods and cones, determine how modulating Rom1 affects disease phenotypes, and will further our understanding of the role of Prph2 in the closed rim structure in rods and the open rim structures in cones. Given the lack of effective treatments for Prph2-associated diseases, these studies are essential and bring attention to the role of Rom1 as a common disease modulator for future development of effective therapeutic strategies.

NIH Research Projects · FY 2024 · 2021-09

Our objective is develop and rigorously validate a transformative technology that integrates cellular functions/activities with their deep molecular signatures at single-cell resolution, in high-throughput. Immunotherapy has emerged as a highly effective approach for the treatment of human cancer, and works by harnessing the power of the immune system and its ability to recognize and eliminate cancer cells. Immunotherapy has distinct advantages, including: (i) sustained and durable responses; (ii) defined mechanisms of action; and (iii) higher specificity and fewer-off target effects than traditional approaches. Along with antibody immunotherapy, genetically engineering T cells for redirecting immune responses has recently received Food and Drug Administration (FDA) approval. Adoptive cell therapy (ACT), based on infusing in vitro expanded T cells bearing either T-cell receptors (TCR), or chimeric antigen receptors (CAR), have demonstrated dramatic and durable responses, even in heavily pretreated patients. Despite these initial clinical successes, patient responses vary widely. Recent correlative data indicate that variability in the manufactured T cell products may be the primary determinant of clinical success. Since cellular infusion products are a heterogeneous mixture of cells, mapping the complexity of the population requires the ability to identify the function and molecular profiles of cells at single-cell resolution. There is an essential need for technologies that are able to map this complexity in T-cell functionality and being able to link function to molecular profiles at single-cell resolution. We propose the development and validation of Multiscale Intelligent Convergence (MusIC). MusIC will provide multi-scale data from molecules to subcellular dynamics to cell-cell interaction biology on the same cells across thousands of cells. Given the heterogeneity in the composition of cells being used for ACT, it serves as the ideal system for the development and validation of MusIC. Our team of investigators has expertise in single-cell technology development and immunotherapy, machine learning, and image analysis and data modeling. We anticipate that the successful implementation of this proposal will enable the validation of MusIC as a platform for studying multi-scale cell biology. This in turn, will lead to the more reliable biomanufacturing of T-cell infusion products, and the engineering of more potent immune cells can have a broad impact on immunotherapy.

NIH Research Projects · FY 2025 · 2021-09

Despite being one of the largest and fastest-growing demographics in the United States (US), Hispanic persons experience striking health disparities, particularly in terms of hazardous drinking and co-occurring clinical anxiety. No interventions to date have targeted hazardous drinking in the context of clinical anxiety among Hispanic persons. The current R01 proposal builds upon our past work by developing a brief, single-session, computer-based, personalized feedback intervention (PFI) designed to enhance knowledge regarding adverse anxiety-alcohol interrelations, increase motivation and intention to reduce hazardous drinking, and reduce positive attitudes and intentions regarding the use of alcohol for anxiety. Specifically, we propose to develop a low-cost, highly disseminatable, integrated PFI for Hispanic hazardous drinkers with clinical anxiety (AA-PFI 1.0) that will be implemented and tested for effectiveness in community-based health clinics. Our approach will follow a staged model consistent with National Institutes of Health (NIH) guidelines for developing and standardizing behavioral interventions. Phase IA activities will involve collecting qualitative and quantitative feedback from three iterative focus groups (N = 21) to refine intervention content and evaluate treatment acceptability and feasibility. Phase IB activities will include a rigorous randomized clinical trial designed to compare the effectiveness of AA-PFI 2.0 to a control PFI (C-PFI) among a sample of 250 Hispanic hazardous drinkers with clinical anxiety who receive care within community-based health clinics. This study represents an important and pivotal step in the larger landscape of translating basic research to more efficacious strategies for reducing hazardous drinking in vulnerable populations with biobehavioral comorbidities. The proposed research project supports the 2017-2021 strategic plan of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) by advancing research in two of the key areas. First, the current proposal has the end goal of improving strategies to prevent alcohol misuse, alcohol use disorder, and alcohol-related consequences among an ‘at-risk’ population for these conditions (goal 3). Second, it enhances the public health impact of NIAAA-supported research by focusing on one of the fastest-growing and largest demographics in the US who demonstrate disparities in hazardous drinking (goal 5). The current application aligns with the goals of RFA-AA-21-001 by proposing to examine the effectiveness of a low cost, highly disseminatable, personalized, culturally adapted PFI for Hispanic hazardous drinkers with clinical anxiety within community-based health clinics. Given the collective public health impact of concurrent anxiety and alcohol use, we believe the proposed study will yield findings that enhance scientific knowledge, advance our understanding of mechanisms in anxiety-alcohol use relations, and inform the development of novel treatments for hazardous drinkers with clinical anxiety that are adaptable and easily implemented across a variety of healthcare settings.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY Forty percent of patients with the most prevalent luminal hormone receptor positive (HR+) breast cancer (BCa) subtype are unresponsive to conventional endocrine therapy (ET) and readily present with incurable metastatic disease. Patients with ET resistant (ET-R) BCa exhibit an “endocrine-switch” to androgen receptor (AR)- dependent tumor growth and metastasis. Anti-androgens are emerging as promising therapy for other advanced BCa subtypes but surprisingly, AR overexpressing ET-R BCa cells are unresponsive to AR antagonists. Our new findings show constitutively active AR accumulate and evade the inhibitory actions of anti-androgen Enzalutamide (Enz). Hence, the objective of the current project is to design a therapeutic strategy to effectively target AR and prevent metastatic progression of ET-R BCa. We demonstrate that unlike other cancer models, persistent SUMO post-translational modification (PTM) of AR (SUMO-AR) occurs natively in acquired and intrinsic ET-R BCa cells. SUMO-PTM is a critical dynamic cellular process and an imbalance in SUMO-specific enzymes drive select types of BCa including basal and Myc- dependent BCa as reported by us and others. Independent of the established SUMO enzymatic system, we identify a dual SUMO-ubiquitin ligase that is druggable and destabilizes SUMO-AR in ET-R BCa. This proposal will delineate the regulatory control of this novel ligase in ET-R BCa and its role in Enz-response. Our new data suggests that constitutive SUMO-AR genomic activity requires interaction with a lncRNA. Hence, we will delineate how SUMO-AR/lncRNA interaction facilitates ligand-independent genomic activity in ET-R BCa cells. Finally, the proposed studies will test unique approaches to either 1) inhibit AR activity or 2) potentiate AR degradation versus the current standard Enz. In the process, we will generate novel therapeutics and evaluate clinically relevant compounds specifically for advanced ET-R BCa. Consistently, completion of the project will validate the need and establish the tools for more comprehensive translational studies on SUMO-AR in ET-R HR+ BCa.

NIH Research Projects · FY 2024 · 2021-08

ABSTRACT One in four children (26%) in the U.S. are exposed to intimate partner violence (IPV), with higher rates among children of African American women. IPV exposure constitutes a traumatic stress environment with severe consequences for psychosocial outcomes in children. While maternal caregiving has been identified as a critical buffer against the effects of trauma on children, current IPV parenting interventions suffer from cultural insensitivity , and design and methodological limitations impeding scalability. Our scientific premise is that the adverse effects of IPV trauma on children can be interrupted through an intervention that enhances maternal caregiving capacity, and which is delivered by community-based paraprofessional caseworkers who are already delivering services to IPV-exposed African American women. The objective of this application is to adapt an established caregiver intervention program, Mediational Intervention for Sensitizing Caregivers (MISC), for the IPV and African American context (thereafter named MISC-IPV). MISC-IPV will be evaluated for acceptability, feasibility, and preliminary mechanisms and outcomes, guided by an evidence-based framework consisting of three aims (Adapt, Process Evaluation, Outcome/Mediator Evaluation). For Aim 1, (Adapt), we will adapt MISC through an iterative process involving qualitative interviews and focus groups with caseworkers and mothers in an IPV rehousing program until fit with context is achieved . Cultural adaptation and adaptation for the IPV context will be guided by a Community Advisory Board. For Aim 2 (Implementation and Process Evaluation), we will recruit N = 132 mothers/child pairs (children age 7 to 11) through the Harris County Domestic Violence Coordinating Council (HCDVCC) Collaborative of Houston, TX. Half will be randomly assigned to TAU+MISC-IPV vs. TAU. After initial training of caseworkers, one year of bi-weekly (every two weeks) intervention sessions of TAU+MISC-IPV vs. TAU will be delivered. Feasibility, adherence, and fidelity will be evaluated through percentage of sustained engagement, individual interviews, video-based observations, and questionnaire-based assessment. For Aim 3 (Outcomes and Mediators), we will evaluate the effects of TAU+MISC-IPV vs. TAU to interrupt the traumatizing effects of IPV exposure on children through assessing emotional, behavioral, and trauma symptoms at baseline, 6, 12, and 18 months in the children recruited in Aim 2. The mediational effects of enhanced caregiving capacity will be assessed through video observations and increase in knowledge. At the end of this formative study, we will have established the foundational assessments and intervention to apply for a multi-site RCT to fully test the efficacy, mediators, and moderators of MISC-IPV. This project will make possible a culturally sensitive, developmentally transportable, scalable, and sustainable evidence- and community-based intervention with proven in-vivo mechanisms of change that may serve as a model for future IPV programs also in different populations, that address the needs of IPV-exposed mothers and children simultaneously.

NIH Research Projects · FY 2024 · 2021-08

ABSTRACT Medication-related morbidity and mortality are a significant health concern in older adults, who are highly susceptible to medication-related problems. Safe medication use practices require coordinated efforts by providers and patients in the medication use process. Medication-related problems in older adults range from prescribing of high-risk medications to misuse of prescribed medications by older adults. Reducing medication errors and improving medication safety are major national priorities. Therefore, our objective is to host the Geriatric Medication Safety Symposium in the largest medical complex in the world, the Texas Medical Center (TMC), annually to disseminate and implement the evidence-based approaches for medication safety in older adults to improve the quality of geriatric care. The University of Houston College of Pharmacy in collaboration with the University of Texas McGovern Medical School organized the Houston Medication Safety Symposium for the past three years focusing on various aspects of medication safety issues such high-risk medications, prescribing cascades, and deprescribing with presentations from nationally recognized experts. An average of 151 diverse health professions participated in the symposium each year to enrich their practice and research on medication safety. In addition, the symposium included research podiums and posters that were published in a peer-reviewed journal. We are requesting five years of funding to host the Geriatric Medication Safety Symposium to continue our successful efforts to disseminate critical medication safety issues with respect to practice, research, and policy. This annual symposium will: (i) Provide an excellent interprofessional educational forum for practitioners and researchers to discuss evidence-based medication safety approaches in older adults; (ii) Increase collaborations for best practices in patient care and medication safety research; and (iii) Disseminate the knowledge and findings from the symposium nationally through webinars and publications. The proposal includes monthly planning committee meetings from representatives of selected TMC institutions to plan and organize the two-day symposium in the TMC, with a reach of over 20,000 healthcare professionals. The symposium includes four plenary sessions, podium and poster sessions, and practice/research workshops, with web-based content delivery and integration of virtual content over five years to allow for greater reach. The areas of focus for the upcoming symposiums include off-label drug use during the COVID-19 pandemic, drug burden, safer opioid use, adverse drug events, significant drug interactions, drug safety during transitions of care, and medication safety in inpatient care. The target audience includes physicians, nurses, pharmacists, students, residents, fellows, researchers, and others. Educational and media tools will be created in addition to publishing the proceedings in the Research in Social and Administrative Pharmacy journal. Overall, the Geriatric Medication Safety Symposium will provide a unique interprofessional educational and research forum for practitioners and researchers to make medication practices safer for older adults in the TMC and beyond.

NIH Research Projects · FY 2025 · 2021-06

PROJECT SUMMARY Detection of cancer biomarkers in the blood, known as “liquid biopsy”, can in principle improve the accuracy of measuring nearly invisible “minimal residual disease (MRD)”. Exosomes are cell- excreted extracellular vesicles that contain surface proteins and genetic materials (DNA and RNA) that reflect the characteristics and make-up of the parental cell. Analyzing exosomes would therefore provide direct insight into the state of the cancerous cell. For cancer diagnostics in particular, recent evidences have shown that several micro-RNAs are differentially expressed in CTE. Therefore, unlocking the wealth of information in CTE can potentially cause a paradigm shift. However, current barriers for profiling CTE are the following: (1) all existing technologies require blood withdrawal; (2) involve sophisticated protocols; (3) label-free sizing/counting lacks molecular specificity; (4) provide highly averaged results with high background from normal exosomes, thus leading to poor sensitivity. (5) provide “partial” information: either surface antigen or cargo DNA/RNA, but not both. All of the above has led to a simplistic binary outcome that lacks dynamic range and cannot be used frequently with high sensitivity. We propose a multi-pronged solution on a microfluidic arrayed nanoplasmonic sensor & actuator (MANSA) platform for: (1) streamlined isolation, concentration, and profiling. (2) improve sensitivity by monitoring individual unlabeled exosome binding events with dynamic imaging technology complemented by spectroscopic imaging. (3) improve specificity by profiling both surface antigen and internal D/RNA biomarkers at single exosome level. (4) eliminate blood withdrawal using an integrated needle device. (5) benchmark performance with various sample complexity from cancer cell line extracts to cancer patient blood samples. Our goal is to obtain a high-resolution, digital exosome map with both multiplex surface protein and cargo D/RNA biomarker profiles to facilitate high dynamic range enumeration and boost sensitivity. The proposed technology will become a cost- effective, point-of-care-friendly, translational platform that will address a critical need in early cancer and MRD detection to improve cancer healthcare outcomes. The technology can also be broadly applied to exosome-based diagnostics of non-cancer diseases and basic biomedical research.

NIH Research Projects · FY 2024 · 2020-09

PROJECT ABSTRACT Presbyopia, the progressive age-related loss of near visual function, is associated with a stiffening of the crystalline lens. There are currently several investigational approaches for presbyopia treatment that rely on lens softening or lens replacement with softer materials. Lens softening approaches are expected to have a transformative impact on the field because they are non-invasive and they preserve the anatomical relationship between the lens and other tissues involved in accommodation. They have therefore the potential to restore the natural dynamic accommodative function. However, one of the fundamental roadblocks towards the development of lens softening procedures is that there is currently no method available to directly measure lens stiffness and thus assess the efficacy of lens softening procedures in vivo. The goal of the project is to develop new technology capable of precise spatially-resolved non-destructive, noninvasive and depth-resolved quantitative measurements of the lens mechanical properties in a clinical setting. The technology will combine Brillouin microscopy, Optical Coherence Tomography (OCT), and Optical Coherence Elastography (OCE) - BOE. The instrument will be used to generate the first age-dependent data on lens mechanical properties quantified in vivo as well as quantitatively assess therapeutic procedures aimed to restore accommodation. Our overall hypothesis is that the novel BOE technology can acquire absolute measurements of the lens stiffness gradient with the accuracy and precision required to detect both age-related changes and changes induced by lens softening treatments. The ability to quantify lens softening in vivo will have a major impact on pre-clinical and clinical testing, validation and optimization of lens softening procedures. The project has three specific aims: Aim 1: Develop a combined BOE imaging device for depth-resolved quantitative lens elastography. Aim 2: Validate BOE measurements in animal and human lens ex vivo and animal lens in vivo. Aim 3: Quantify the mechanical properties of the human lens in vivo To accomplish our objective, we have assembled a multidisciplinary team with expertise in optical coherence tomography and elastography (Larin), Brillouin technology (Scarcelli), biomechanical modeling (Aglyamov), clinical ophthalmic instrumentation and crystalline lens physiology (Manns, Parel, Ruggeri, Yoo).

NIH Research Projects · FY 2024 · 2020-09

Abstract Irinotecan, a prodrug of SN-38, is used to treat many types of metastatic and drug-resistant cancers, and often represents the therapy of the last resort. Unfortunately, a large percentage (up to 40%) of these patients will experience serious (Grade 2) and severe (Grade 3-4) delayed-onset diarrhea (SDOD), which really downgrade patient’s quality of life. SDOD may lead to prolonged hospitalization and even death in some instances. The long-term goal of our research is to develop experimental therapeutics and/or nutritional supplemental approach to reduce SDOD, so patients can sustain their chemotherapy. Our recent studies have shown that inactivation of intestinal UDP-glucuronosyltransferases (UGTs) by SN-38 is a new mechanism by which SN-38 causes SDOD, and that a Traditional Chinese Medicine, Xiao-Chai-Hu-Tang (XCHT), could attenuate the inactivation of intestinal UGTs in mice. Therefore, the central hypothesis of this current proposal is Therefore, we hypothesize that XCHT will prevent or reduce irinotecan-induced SDOD by attenuating the decline in UGT activities, reducing gut SN-38 exposure, and promoting the recovery of gut UGT activities. We plan to test this hypothesis using four Specific Aims: (1) perform phytochemical, biopharmaceutical and pharmacokinetic characterization of XCHT to enable quality control, systemic and intestinal drug exposure determinations, and to provide bioanalytical methods and pharmacokinetic parameters needed for a clinical study and PK/PD modeling; (2) validate plasma raloxifene-4′-glucuronide levels as a probe to changes in intestinal Ugt/UGT activity; (3) Perform mouse “co- trial” studies to support human mechanistic trials and to determine the mechanisms of action of XCHT against irinotecan-induced SDOD using both in vitro and in vivo models; and (4) Conduct a mechanistic clinical trial using a randomized double-blind design with a safety “Run-In” to determine if XCHT can attenuate human intestinal UGT decrease and reduce incidence of Grade 3 or higher diarrhea caused by irinotecan chemotherapy. Aside from these primary outcomes, we will also determine if levels of Ral-4’-G, a probe of intestinal UGT activities is (negatively) correlated with systemic levels of inflammatory cytokines. Success gained through this research will provide a new mechanism by which we can target to treat SDOD caused by irinotecan chemotherapy.

NIH Research Projects · FY 2024 · 2020-09

ABSTRACT The proposed RCMI HEALTH Center for Addictions Research and Cancer Prevention is designed to establish a national exemplar for how community-engaged research can accelerate scientific breakthroughs that can be rapidly disseminated and implemented directly into the targeted community by trained laypersons or paraprofessionals. This will be achieved by the successful completion of five specific aims: Aim 1. Execute a centralized Research Infrastructure Core that will enhance scientific rigor, productivity, and impact of health-equity science through five primary services: (1) Research Methodology; (2) Laboratory Techniques and Facilities; (3) Data Management and Biostatistics; (4) Health Informatics; and (5) Responsible Conduct of Research, Ethics, and Compliance in health-disparities research; Aim 2. Execute a group mentoring program in the Administrative Core that provides data-driven career enhancement activities for underrepresented minority (URM) postdoctoral fellows and assistant professors pursuing careers in health-equity science; Aim 3. Strategically increase the application and success of investigators – underrepresented in the health sciences – securing competitive NIH research grants through the Pilot Grant Program and Innovation Research Talks administered by the Investigator Development Core; Aim 4. Leverage the Community Engagement Core to facilitate equitable, collaborative, and sustainable partnerships with community members, organizations, and stakeholders to enable a bidirectional “exchange of information” that advances the potential impact of research findings for achieving health equity; and Aim 5. Promote research on minority health and health disparities by disseminating RCMI outcomes through publicly available peer-reviewed publications, presentations, white papers, policy briefs, and other materials, activities, or services disseminated into the community. This transformative infrastructure – in partnership with UH administrators, community members, stakeholders, organizations, and elected officials – provides a sustainable data-driven approach for saving lives and preventing addictions and cancer from disproportionally afflicting marginalized and underserved communities in metropolitan Houston and beyond.

NIH Research Projects · FY 2024 · 2020-08

PROJECT SUMMARY Dietary changes in metal nutrients, including zinc and iron, influence the composition of the microbiota and correlate with increased infection susceptibility and gastrointestinal diseases, but the molecular mechanisms underlying these effects remain largely unknown. This lack of knowledge severely limits our ability to predict how diet or host metal status will impact treatment of gastrointestinal diseases or infection. Our long-term goal is to elucidate the molecular mechanisms governing how essential metals affect the human gut microbiota. The overall objective of the proposed work is to determine how essential metals affect growth and communication within probiotic bacterial communities of Lactobacillus species. Our research strategy is 1) to develop and apply protein-based fluorescent sensors that do not rely on oxygen and 2) to uncover molecular mechanisms through which metal ions affect gut microbiota homeostasis. Oxygen-insensitive protein-based fluorescent sensors will be used in live anaerobic cultures containing Lactobacillus to study metal uptake and how metal ion levels vary over time. Pure, multispecies, and in vitro gut model cultures will be used to evaluate how metal ion homeostasis varies with additional bacterial species and increasing complexity. Beyond direct detection and tracking of essential metals in culture with fluorescent sensors, we are carrying out systematic studies to measure how changes in essential metals affect Lactobacillus physiology and cell-cell communication (quorum sensing). Here, we are investigating the capacity of Lactobacillus species to store excess metal ions and aiming to identify the genes affected by varied metal levels in growth cultures. We are also measuring how varied metal levels affect the abundance of Lactobacillus quorum sensing signaling molecules. This research program is enhanced by collaborations with experts in microbiology, microbiome, and advanced fluorescence microscopy. The research is significant because it will provide mechanistic insight to how dietary metals affect gut microbiota composition and function. This insight is important because it will be useful for predicting the effects of metal-based dietary interventions and could potentially identify new targets to mitigate these effects. Furthermore, it will provide a knowledge basis for probiotic dietary interventions to combat gastrointestinal diseases and potentially identify new drug targets. The research is innovative because it represents a substantive departure from current work by shifting focus to uncover molecular-level mechanisms and roles for metal ions in gut bacteria that affect microbiota composition and function. By studying the Lactobacillus genus, we take advantage of well-established genetic approaches while focusing on an abundant organism in the small intestine, where most metal nutrient uptake occurs. Furthermore, Lactobacillus are well accepted as probiotics, but much remains to be learned about their beneficial mechanisms of action. Developing new protein-based metal sensors to overcome the oxygen- dependency of current protein-based sensors will allow detection of bacterial metal uptake and exposure in culture and in in vitro gut models under physiological (anaerobic) conditions.

NIH Research Projects · FY 2026 · 2020-07

Development of Spectral X-Ray Phase-Contrast Micro-CT Project Summary A challenging aspect of in vivo micro-CT relates to the required deleterious radiation dose levels - particularly for studies required to follow the same subject longitudinally. The main constraint is the poor attenuation contrast for x-rays in soft tissue and the need for long imaging times. Researchers have studied the use of multi-energy (or spectral) x-ray acquisitions to perform material decomposition with micro-CT systems, but the versatility of these methods is again constrained by the same contrast-dose trade-off. Phase-contrast imaging (PCI) can provide significant phase-enhanced contrast at higher energies, thus potentially reducing micro-CT dose. However, existing PCI methods still require high dose and long imaging times for accurate phase retrieval. We have recently developed an algorithmic approach to spectral PCI that enables dose and imaging times commensurate with attenuation imaging. Our hypothesis is that PCI performed under normal clinical constraints can yield better tissue quantitation and small feature delineation at lower dose than attenuation imaging. We shall develop a unique spectral micro-CT system with both PCI and non-PCI capabilities to test this hypothesis. A key system component will be an innovative high-performance, high-resolution photon- counting detector (PCD) to be developed jointly under this grant by the University of Houston and Advacam s.r.o. Two non-interferometric PCI geometries will be evaluated. The first specific aim is to design the micro- CT system based on considerations such as source kVp and the PCD sensor thickness, pixel size, and energy bin configuration. PCI-specific criteria include magnification and the x-ray mask properties. Optimization studies will be carried out for both the PCI and the non-PCI modes. For Aim 2, we will work with Advacam to develop the wide-area, high frame rate and high Z sensor PCD for the system. The high-performance PCD will be constructed based on Medipix3RX ASIC technology and will feature high resolution and built-in spectral correction schemes and fast readouts. Under Aim 3, the micro-CT unit will be constructed and energy calibration and correction schemes will be developed to allow efficient system performance. Our fourth specific aim is to compare the performance of the PCI and non-PCI modes of spectral micro-CT with physical phantoms and animal studies to evaluate the enhancement of low contrast sensitivity. In vivo studies using liposomal iodine nanoparticles will examine the ability of PCI to distinguish differences in blood vascularity for treatment- responsive and treatment-resistive prostate cancer models in mice.

NIH Research Projects · FY 2024 · 2020-07

Project Summary Endothelial dysfunction is an early defect in obesity, which is a major contributor to increased cardiovascular morbidity and mortality such as arterial stiffness, atherosclerosis, and hypertension. Recent studies have demonstrated a critical role of acid sphingomyelinase (ASM)-ceramide signaling in instigation of Nlrp3 inflammasomes and endothelial dysfunction during obesity and diabetes. The present proposal seeks to explore a novel mechanism mediating transcriptional control of ASM gene expression in ECs and determine how dysregulated ASM expression and activity promote vascular injury in obesity. Enhancer of zeste homolog 2 (Ezh2) is a histone methyltransferase that normally suppresses methylated genes, serving as a crucial epigenetic regulatory mechanism in gene expression. In preliminary studies, we found that loss of Ezh2 function increased ASM expression and ceramide levels in the intima leading to neointimal lesions in the carotid arteries of mice fed high fat diet (HFD). Such Ezh2-mediated suppression of ASM gene expression and ceramide signaling were also confirmed in cultured ECs. Based on these observations, we propose a hypothesis that loss of endothelial Ezh2 function upregulates ASM gene expression and augments ceramide production under hyperlipidemic conditions, which trigger Nlrp3 inflammasome activation and produce endothelial injury resulting in subsequent neointimal lesions on the carotid arterial wall. To test this hypothesis, the following Specific Aims are proposed. Specific Aim 1 will determine whether endothelial ASM activation due to loss of Ezh2 function contributes to endothelial dysfunction or injury at the early stage of obesity using endothelium-specific Ezh2 knockout mice (Ezh2ecKO) and their wild type littermates. Specific Aim 2 attempts to test how Ezh2-regulated ASM activation leads to endothelial dysfunction or injury by studying the role of ceramide and ceramide-enriched membrane rafts, Nlrp3 inflammasome activation, pyroptosis, endothelium- dependent vasodilation, inter-endothelial junction disruption, and adaptive endothelial progenitor cell landing or differentiation. In Specific Aim 3, we will explore the molecular mechanisms by which loss of Ezh2 function activates ASM with a main focus on the roles of histone and DNA methylation in cultured ECs from Ezh2ecKO mice and their wild type littermates. The findings will provide new insights into the pathogenesis of endothelial dysfunction and identify Ezh2-ASM pathway as therapeutic target for prevention or treatment of vaculopathy associated with obesity.

NIH Research Projects · FY 2024 · 2020-02

Project Summary/Abstract: Corneal pain is an important mechanism to detect injury or damage, leading to protective responses to limit injury if possible (tearing to remove a foreign object), initiate healing and protect the ocular surface required for clear vision. When maladaptive, corneal pain can be so debilitating as to limit daily function, dramatically reduce quality of life, and cause significant economic burden. There is considerable understanding of the molecular and cellular underpinnings of pain perception in response to mechanical, chemical and thermal stimuli, but the ability of light to influence pain (photoallodynia) after corneal injury is not well understood. Accumulating evidence suggests photoallodynia uses melanopsin-expressing trigeminal ganglia sensory neurons in addition to the classic retinal pathways, and that these same trigeminal ganglia neurons contribute to corneal mechanical sensitivity. In this proposal, the knowledge gap concerning how this class of trigeminal neurons contribute to corneal pain in normal and sensitized pathophysiological states in disease models of corneal surface injury/dry eye disease, allergic eye disease and migraine will be addressed. Preliminary data shows that melanopsin is expressed in both C-fiber (thermal and chemical) and Ad (pressure) sensing mouse and human trigeminal neurons, some of which co-express CGRP. These melanopsin- expressing neurons contribute to corneal mechanical and light sensitivity in normal and pathophysiological conditions, and can respond to light ex vivo. Finally, the optic nerve is not required for behavioral measures of light sensitivity in a model of trigeminal sensitization. Thus the hypothesis that melanopsin-containing corneal trigeminal neurons function to modulate corneal mechanical sensitivity and light sensitivity by directly contributing to corneal innervation, and use neuropeptides to modulate the corneal milieu to effect pain perception and sensitization will be tested. Aim 1 will evaluate corneal innervation in adult and developmental stages in mice lacking melanopsin-expressing trigeminal neurons to identify the mechanism by which these mice have decreased corneal mechanical sensitivity. Aim 2 will evaluate the ability of melanopsin-expressing corneal nerves to alter mechanical and light sensitivity by altering secretion of a representative neuropeptide in normal and sensitized corneas in response to light. Aim 3 will evaluate which trigeminal ganglia neurons (C- fiber of Ad) contribute to mechanical and light sensitivity in models of corneal disease, injury or sensitization. The expected outcomes will elucidate molecular, cellular, anatomical and neurobiological mechanisms of corneal innervation, pain and photoallodynia in normal and pathophysiological states.

NIH Research Projects · FY 2025 · 2019-09

Project Summary A current research interest of my group is to develop conceptual models to explain, to understand, and to predict structure and reactivity in organic photochemistry. The premise is that Baird’s rule, i.e., the reversal of electron-counting rules for aromaticity and antiaromaticity in the ground and lowest excited-states of organic compounds, underlies many photochemical reactions essential to biology and biological applications. Some examples include light-induced bond twisting, photoheterolysis, electron transfer reactions, and proton-coupled electron transfer reactions. The innovation is that linking reactivity to the structural features of aromaticity and antiaromaticity may provide important chemical insights for designing new and useful reactions. Our research involves the use of a variety of computational quantum chemical tools, including time-dependent density functional theory (TD-DFT) and complete active space self-consistent field (CASSCF) methods. A five-year goal is to significantly demonstrate the usefulness of Baird’s rule in many areas of organic photochemistry. An overall vision of my research program is to prepare and foster a next generation of computational organic chemists and to translate theoretical insights into experimental opportunities for biological and biomedical research.