University Of Illinois At Chicago

NIH Research Projects · FY 2025 · 2020-09

Abstract Demonstrating the feasibility, effectiveness, and cost-effectiveness of electronically delivered smoking cessation interventions via patient portals in Federally Qualified Health Care (FQHC) settings has the potential for wide-spread dissemination and significant public health impact. on patient populations with demonstrated high rates of smoking. The specific aims of are to: UG3: Aim 1. Examine the burden of tobacco use and its influence on pulmonary health disparities (lung cancer, COPD, and asthma) in the patient population and the economically disadvantaged and racially segregated catchment areas of Mile Square Health Centers. Aim 2: Evaluate knowledge, attitudes, barriers and facilitators to: smoking cessation, engagement with the tobacco quit line, linkage to the tobacco quit line via a patient health portal and receipt of patient navigation to facilitate access to the tobacco quit line among MSHC patients and health care providers.. Aim 3: Evaluate the use of community engagement strategies to increase uptake of the UI Health Patient Portal among low-income patients receiving care at Mile Square Health Center. Aim 4: Test the acceptability, feasibility, and capacity of Mile Square Health to deliver Mi Quit CARE, an evidence-based and multi-level intervention to increase engagement with the quit line via the UI Health Portal. UH3: Aim 1: Determine the effectiveness Mi Quit CARE compared to standard of care in increasing patient engagement with the Illinois tobacco quitline and subsequent smoking cessation outcomes. Aim 2: Evaluate the scalability of Mi Quit CARE to multiple sites within the UI Health FQHC Mile Square clinic network and by translating the intervention to Spanish. Aim 3: Examine the cost effectiveness of Mi Quit CARE on smoking cessation outcomes compared to standard of care among a high risk FQHC population.

NIH Research Projects · FY 2024 · 2020-09

Project Summary/Abstract: Chronic exposure to background noise during childhood negatively impacts language, literacy, and cognitive development, with repercussions for children’s academic achievement and future employment potential. A putative mechanism linking noise to decrements in language and cognitive development is that noise disrupts young children’s ability to build a vocabulary. A robust literature demonstrates that noise disrupts the perception of spoken words primarily through energetic masking, in which noise limits high fidelity encoding of target speech, and informational masking, in which noise taxes cognitive processes such as attentional control and working memory. Background noise likely disrupts word learning through similar mechanisms. Although there have been studies testing the effects of noise on word learning, these studies are few in number and variable in methodology. The noises in children’s naturalistic environments vary in type (e.g., environmental noise [air conditioners] and background speech), intensity level (i.e., how loud it is), semantic content (i.e., whether the child understands the background speech), and spatial location: factors that exert different amounts of energetic and informational masking. Additionally, differences in cognitive and language abilities among preschool-age children likely affect their susceptibility to the negative effects of noise. Thus, we lack knowledge about how cognitive factors interact with variations in noise to affect word learning in young children. This is a critical gap because spoken input is the sole source of word learning in prereaders and an important source of word learning over the lifespan. The present study will test the time course of novel word learning in the presence of background noise that varies in type, spatial location, semantic content, and intensity level, which are factors that influence young children’s perception of target speech. Specifically, the noise will vary by whether it contains speech content or not (Aim 1), whether it is co-located or spatially separated from the target speech (Aim 2), whether it contains familiar semantic and phonetic content versus only familiar phonetic content (Aim 3), and its intensity level (Aims 1, 3). To accomplish these aims, a large cohort of children between 4 and 6 years of age will be trained on novel word- referent pairs across three subsequent days. This age range is targeted because children’s speech perception is highly susceptible to the effects of noise during this time in development, and it is an important age to build foundational vocabulary skills. Each child will be tested in one noise condition, and the noise will be systematically changed across conditions. Through this approach, we will determine how various noise conditions affect both the number of words learned and the phonological precision of children’s representation of the words throughout the learning process. This work aligns with the research priorities of the Child Development and Behavior Branch of the NICHD as we will identify how aspects of children’s environments affect word learning, a critical process for long-term language, cognitive, and academic outcomes.

NIH Research Projects · FY 2024 · 2020-09

PROJECT SUMMARY Diabetes affects more than 30 million people in the United States, with 90-95% having type 2 diabetes. Diabetic retinopathy, one of the most serious complications of diabetes, is the leading cause of blindness. While diet, exercise and medications have been cornerstones of diabetes treatment to control glucose levels, the influence of sleep and circadian regulation on metabolic control are increasingly recognized as potential targets of future preventive treatment strategies. Recent work discovered that there is a dysfunction of the melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) in patients with diabetic retinopathy. These ipRGCs are a crucial part of entraining (synchronizing) the circadian system, which influences melatonin secretion and regulates sleep/wake timing and metabolic physiology. Recent data indicate that individuals with diabetic retinopathy show abnormalities in ipRGC function and abnormal melatonin physiology. The novel hypothesis we propose to test is that ipRGC dysfunction associated with type 2 diabetes and diabetic retinopathy leads to disturbances in sleep and circadian regulation, which further adversely affects their metabolic control and could accelerate disease progression. Further, we hypothesize that melatonin supplementation will disrupt this vicious cycle. The proposed study will comprehensively examine ipRGC function via pupillometry in patients with type 2 diabetes with and without diabetic retinopathy. These groups will provide a range of ipRGC function. Sleep duration and quality (via wrist actigraphy), at-home electroencephalography (EEG), polysomnography, nocturnal melatonin secretion (measured from urinary 6-sulfatoxymelatonin), circadian regulation (24-hour blood sampling for melatonin and cortisol) and standard metabolic outcomes (hemoglobinA1c, fasting glucose, 24-hour mean glucose levels from continuous glucose monitoring) will be the outcomes and examined as a function of ipRGC function. Then, patients with diabetic retinopathy will be randomized to receive nightly melatonin supplementation or placebo for 8 weeks. The primary outcomes will be assessed at the end of the study which include sleep as measured by actigraphy and circadian regulation as assessed by 24-hour hormone sampling. Glucose parameters will also be assessed (hemoglobinA1c, fasting glucose, 24-hour mean glucose levels from continuous glucose monitoring). The proposed study will advance our understanding of the relationship between ipRGC function and the nonvisual health of people with diabetes, and provide evidence of potential benefits of melatonin in patients with diabetic retinopathy. These data will be highly relevant given the current epidemic of diabetes and diabetic retinopathy, and will inform potential therapeutic interventions, leading to improve disease outcomes in these patients.

NIH Research Projects · FY 2024 · 2020-08

The University of Illinois at Chicago (UIC) is an urban, research intensive university committed to serving and educating students from diverse and underserved backgrounds. UIC is a national leader in providing education to under-represented minorities as demonstrated by its status as a Minority Serving, Hispanic Serving, and Asian American and Native American Pacific Islander-Serving institution. We propose the Chicago ARea Excellence in Education & Research (CAREER) program, designed to provide rigorous and balanced team-based training in both teaching and research to a diverse group of postdoctoral fellows, with the goal of producing scholars who are well-equipped to be leaders in academia at research- and teaching-intensive institutions alike. CAREER is a partnership between UIC and Governors State University (GSU), the only public university in Chicago's south suburban area and a school that boasts not only a diverse student body, but also a highly diverse faculty. With the UIC CAREER program we will 1) recruit and retain a diverse cohort of IRACDA scholars and tailor training for individual career goals/trajectories; 2) structure a research-intensive training experience that supports a successful transition of scholars to faculty positions; and 3) design a collaborative curriculum with GSU to train scholars in the core competencies required for excellence in teaching. By drawing upon strong institutional support from the UI Cancer Center, CCTS, Teaching and Learning Center, and the Office of Diversity, our program fills a natural void. Not only are there no IRACDA programs in Chicago or any other urban Midwestern city, but UIC currently has no training programs that support and prepare postdoctoral fellows to be educators and researchers within our diverse community. The CAREER program will bring together faculty from the UIC Colleges of Pharmacy and Medicine into a collaborative partnership to support the research and career development of fellows, while Governors State University will provide the support for developing teaching skills at an undergraduate institution. The structure of the program will not only train postdoctoral fellows, but also help to solidify a pipeline for GSU students to join graduate or professional programs at UIC. The relationship will also foster collaboration between GSU and UIC faculty to encourage new research programs and to develop a culture of educating a diverse community of scientists. The program will encourage postdoctoral fellows to participate in state-of-the-art research programs in well-funded mentor labs from Pharmacy and Medicine focused on a wide variety of research related to NIGMS goals. Fellows will engage in teaching and career development workshops at both UIC and GSU. They will also develop professionally under the guidance of a mentoring team with continued use of the IDP to ensure adequate progress in obtaining funding, publications, and networking. Scholars will have the opportunity to teach in lab based courses, introductory lecture courses, and introduce new pre-health course content missing from the GSU curriculum. Overall, the proposed CAREER program helps to fulfill the mission of UIC by training educators for diverse populations as researchers, mentors, and teachers.

NIH Research Projects · FY 2024 · 2020-08

Abstract This national study addresses the most salient psychosocial causes of the reversal in the decline in midlife mortality for U.S. white non-Hispanics of lower educational attainment since 1998, largely due to death rates from drug and alcohol poisoning and suicide. The specific aims are to 1. Empirically demonstrate the associations between individual chronic stressors and community-level stressors, alcohol and drug abuse, and health outcomes over time among middle-aged whites compared to non-Hispanic blacks linked with educational attainment and 2. Model the salient mediators and moderators of the relationships between chronic stressors, alcohol and drug abuse, and health outcomes in middle-aged individuals, including social- psychological factors (perceived achievement limitations compared to salient reference group), social engagement (social support, political engagement, religious involvement, marital/partner status) and access to and utilization of health, mental health and substance abuse services. Our theoretical model embodies factors derived from reference group theory, social engagement versus anomie and lack of access to health, mental health and substance abuse services to treat stressor-derived symptomatology which may be alternatively self-medicated with alcohol and drugs and negatively impact health. Our hypotheses will be tested by conducting a longitudinal four wave mail survey (N=2500 at wave 1). We will utilize a nationwide address- based sample of middle-aged adults (40-60), oversampling by race, educational attainment and rural versus urban/suburban location. Data analytical techniques will include structural equation modelling and longitudinal growth curve analyses. Qualitative interviews with a small sub- sample of respondents (N=40) will explore how and why the main hypothesized factors predict alcohol and drug abuse and diminished health over time differentially for whites compared to non-Hispanic blacks. The findings from this study will contribute to the formulation of evidence- based social policies and treatment interventions with the most promise for halting increased midlife mortality in an understudied group at high risk for alcohol and drug abuse.

NIH Research Projects · FY 2024 · 2020-08

Project Summary/Abstract: Speech is multimodal in nature: communication partners have access to both auditory and visual speech cues during face-to-face communication. In adults, access to visual speech cues are particularly critical for maintaining accurate speech recognition when the auditory components of speech are compromised by hearing loss, background noise, or sound distortion. In the absence of visual speech cues, poor auditory-only speech recognition has negative cascading effects on the ability to comprehend and learn from the speech input. Despite this evidence, there is an unresolved debate about whether visual speech cues facilitate speech recognition or disrupt the development of auditory skills in children with hearing loss. This debate is reflected in the variety of language intervention approaches that vary in their reliance on visual speech cues. The extent to which visual speech cues are critical to spoken language processing and development in children with hearing loss, however, has not been directly tested. As a first step at addressing this gap in knowledge, the objective of the proposed study is to examine the extent to which the addition of visual speech cues facilitates lexical processing in school-age children with or without hearing loss. Children who are expected to benefit the most from audiovisual speech are children with cochlear implants (CIs), who have permanent bilateral severe-to-profound sensorineural hearing loss. Children with CIs often have poor recognition of auditory-only speech due to limitations of the CIs to fully compensate for the loss of high fidelity auditory representations of speech. The proposed study will test the hypothesis that audiovisual speech facilitates lexical processing relative to auditory-only speech in children with CIs and that this improved processing has positive downstream benefits for language comprehension. Children who are ages 4 to 10 years who use CIs or who have normal hearing (NH) will be recruited. The age range was chosen because audiovisual speech perception matures over the first decade of life. The study will utilize existing validated measures of incremental lexical processing and language comprehension to test the hypothesis. Real-time lexical processing of auditory-only speech (Aim 1) and of audiovisual speech (Aim 2) will be characterized in children with CIs and children with NH. The effects of audiovisual speech on language comprehension skills will also be characterized in the same children (Aim 3). We will relate performance on lexical processing and language comprehension tasks. Theoretically, the results will support the creation of a comprehensive model of lexical processing with and without visual speech cues in school-age children with CIs and children with NH. This work has practical implications for spoken language interventions for children with CIs as well as children with less severe hearing loss, who may differentially utilize visual speech cues. In addition, the results will inform future studies of spoken language interventions that vary in their inclusion of visual speech cues.

NIH Research Projects · FY 2024 · 2020-08

Project Summary Cellular membranes not only compartmentalize intracellular processes but also serve as the dynamic hubs for the assembly of many multi-protein signaling complexes, oncoproteins, and tumor suppressors. Accordingly, a majority of current therapeutics (>60%) target membrane proteins that make up approximately 23% of human proteome. In response to environmental cues and pharmacological drugs, the protein complement of cellular membranes is altered to mount a calibrated response, which, if perturbed, impacts the disease state, e.g., cancer, cardiac and neurological disorders. The ubiquitin-proteasome system (UPS) aptly fits the task to swiftly turnover the regulatory proteins with unmatched precision. To date, our understanding of the molecular details of how membrane protein turnover is regulated by UPS-mediated proteolysis remain sketchy. We are conducting the mechanistic studies in the investigations of novel UPS-regulated protein degradation pathways at membranes modeled on our previous work with FBXL2, a highly conserved F-box protein containing a typical C-terminal CaaX prenylation motif for localization to cellular membranes. The integrity of the CaaX motif is necessary for FBXL2 to assemble into an active SCF ubiquitin ligase complex and interact with two substrates, p85β and IP3R3, at cellular membranes. Interestingly, we recently discovered GGtase3, a new mammalian prenyltransferase and identified FBXL2-ubiquitin ligase as the physiological target for prenylation by GGTase3. This proposal uses an interdisciplinary approach to investigate the regulation and biological relevance of membrane anchored protein turnover by UPS in mammalian cell survival and proliferation, and full characterization of GGtase3 biology.

NIH Research Projects · FY 2024 · 2020-07

Atrial fibrillation (AF) is a growing epidemic with ~16 million Americans affected by 2050. Despite recent advances in catheter-based therapy, antiarrhythmic drugs (AADs) are still commonly used to treat patients with symptomatic AF. However, response in an individual patient is highly variable and can be associated with significant toxicities. The limited success of AADs in treating AF is due in part to heterogeneity of the underlying substrate and our inability to predict individual responses to therapy. Thus, a major knowledge gap is predicting which patients with AF are likely to respond to antiarrhythmic therapy. Emerging evidence supports the overarching hypothesis to be tested here that variability in response to AADs is modulated by a single nucleotide polymorphism (SNP) associated with AF. Although genetic approaches to AF have revealed that susceptibility to and response to therapy is modulated by the underlying substrate, the translation of these discoveries to the bedside care of patients has been limited in part because of poor understanding of the underlying mechanisms by which risk alleles cause AF, challenges associated with determining the therapeutic efficacy and lack of prospective genotype-guided studies. Aim 1 will test the hypothesis that a common chromosome (chr) 4q25 AF SNP modulates response to AADs in patients with symptomatic AF using burden as a measure of therapeutic efficacy. The scientific premise for this proposal is based on our published study which showed that a chr4q25 SNP not only predicted successful symptom control of AF but that patients who carried the risk allele responded better to Na+-channel than K+-channel blocker AADs; a recent study that confirmed our clinical observation; and preliminary data generated in our pilot and feasibility study. We propose a randomized cross-over study whereby patients will be given flecainide/sotalol and therapeutic efficacy will be assessed by implanting insertable cardiac monitors. While we showed that AF patients who carry the chr4q25 AF risk allele are more likely to respond to flecainide than those who carry the wild-type (WT) allele, the underlying mechanism for this differential response to AADs is poorly understood. Aim 2 will elucidate the underlying cellular mechanisms by which a chr4q25 risk SNP differentially modulates response to AADs in patients with AF using human atrial induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs). First, we will generate atrial iPSC-CMs from chr4q25 risk and WT allele carriers. Second, we will test the hypothesis that the electrophysiologic (EP) and structural maturity of atrial iPSC-CMs can be enhanced by precise microenvironmental engineering of in-vivo relevant cell-cell, cell-extracellular matrix, and cell-soluble factor interactions. Third, we will determine the EP phenotypes of mature atrial iPSC-CMs from chr4q25 AF risk and WT allele carriers and examine the effects of flecainide and sotalol ex-vivo. The proposed studies will not only improve the prediction of response to AADs for AF patients and pave the way for a genotype-guided approach but also facilitate the practice of personalized medicine.

NIH Research Projects · FY 2024 · 2020-07

The overarching goal of the study is to obtain the necessary training to better understand the neural mechanisms underlying the rewarding, reinforcing properties of cannabis. The proposed study aims to characterize individual differences in subjective reward response and neural reward processing to delta-9- tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, among healthy young adults who may be at-risk for problematic cannabis use. Individuals differ in their subjective response to THC on self- report measures of drug reward. Few studies have examined how THC impacts brain reward circuitry in humans. As cannabis becomes increasingly available in the U.S. there is serious concern about negative outcomes related to problematic use. To minimize the adverse impact of increased use, it is critical to identify risk factors that make certain individuals more vulnerable to problematic cannabis use. One factor implicated in risk for drug use and abuse is the sensitivity and function of brain reward circuitry, especially in response to early drug use. Preliminary evidence indicates that THC activates brain reward circuitry, especially the ventral striatum (VS) and medial prefrontal cortex (mPFC), which might be linked to individual differences in rewarding effects of cannabis. To date, little is known about the neural mechanisms underlying the rewarding, reinforcing properties of cannabis and how these may contribute to individual differences in subjective reward response to THC, a marker of drug abuse liability. In the current K23 application, I propose to examine the affective reward mechanisms that identify individuals who may be at risk for cannabis use and abuse. In the proposed study, 80 healthy young adults (aged 18-25), who report occasional cannabis use (≥10x in life, but use ≤1x a week), will undergo two double-blind, within-subject, drug-challenge visits (placebo, 7.5mg THC). During these visits, participants will complete neural measures of reward during electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI), as well as subjective measures of drug reward. By combining neural and behavioral measures with an acute drug administration design, I will (a) determine if THC enhances brain reward reactivity; (b) examine if THC-induced alterations in neural reward reactivity are related to subjective reward response; and (c) determine if “baseline” neural reward reactivity (i.e., during the placebo session) predicts subjective reward response to THC. This study concurrently provides an excellent opportunity to receive mentor-directed, hands-on training in several key areas necessary to refine my knowledge and skill- sets. Specifically, the proposed training plan will focus on four new domains: 1) EEG, 2) Addiction and drug administration studies, 3) Biostatistics, and 4) Professional development. This study, coupled with completion of the training goals will launch my independent career in the translational affective neuroscience of drug abuse and will lay the foundation for future, high impact R01 studies focused on behavioral-brain risk phenotypes and intervention targets for Substance Use Disorders, including Cannabis Use Disorder.

NIH Research Projects · FY 2024 · 2020-07

PROJECT SUMMARY BACKGROUND: Depression and anxiety are the leading causes of disability and lost productivity, and are often underdiagnosed and undertreated owing to access, cost, and stigma barriers. Novel and scalable psychotherapies are urgently needed. Advances in artificial intelligence (AI) offer a transformative opportunity to develop intelligent voice assistants as virtual health agents accessible on personal devices. Meanwhile, major advances in human neuroscience have fueled a paradigm shift to study brain mechanisms underlying behavioral health interventions. OBJECTIVES: Leveraging our collaborative team’s transdisciplinary expertise in these emerging areas, we will develop and rigorously test a novel voice-enabled, AI virtual agent named Lumen, trained on Problem Solving Therapy (PST), for patients with moderate, untreated depressive and/or anxiety symptoms. We will investigate the effect of Lumen on engagement of a priori neural targets—amygdala for emotional reactivity and dorsal lateral prefrontal cortex (DLPFC) for cognitive control—as putative mechanisms. DESIGN/ METHODS: The project has 2 phases. In the R61 phase (years 1-2), we will further develop Lumen building on the current prototype and conduct iterative user-centered design evaluations that include focus groups, scenario-based clinician evaluations, and a formative user study with 20 participants. We will pilot test Lumen in a 2-arm randomized clinical trial (RCT, Study 1), with 60 participants with depression and/or anxiety randomized in a 2:1 ratio to receive PST with Lumen (n=40) on a secure study iPad or be on a waitlist (n=20). At weeks 0 and 14, participants will complete functional magnetic resonance imaging (fMRI) to assess neural target engagement as well as validated surveys of patient-reported outcomes (e.g., depressive and anxiety symptoms, functioning, quality of life). In addition, they will complete naturalistic end-of-day assessments of mood, stress, appraisal and coping for 7 days every 2 weeks. If the Go milestone criteria are met, the R33 phase (years 3-5) will include a 3-arm RCT (Study 2) with 200 new participants randomized in a 2:1:1 ratio to 1 of 3 arms: Lumen (n=100), waitlist control (n=50), and in-person PST as active control (n=50). Participants will complete baseline and follow-up assessments using a refined measurement protocol based on Study 1. SPECIFIC AIMS: R61 aims are to (1) establish the functionality, usability, and treatment fidelity of Lumen; and (2) demonstrate feasibility, acceptability, and neural target engagement according to pre-specified Go milestone criteria. R33 aims are to (1) confirm neural target engagement by a superiority test (primary) comparing the Lumen and waitlist control arms and a noninferiority test (secondary) comparing the Lumen and in-person PST arms; and (2) examine the relationships of target engagement to outcomes. The results will provide the basis for future confirmatory efficacy testing of Lumen. IMPACT: This project’s public health impact lies in that a mechanistically tested, PST-trained AI agent could bring proven psychotherapy to people with depression/anxiety who do not seek professional help or who desire more personalized, connected care.

NIH Research Projects · FY 2024 · 2020-07

Chronic kidney disease is present in a large proportion of adults with sickle cell disease (SCD) and is associated with increased morbidity and early mortality. The mechanisms for how chronic kidney disease develops are, unfortunately, poorly understood and therapies to prevent and treat sickle cell nephropathy are urgently needed. This proposal will leverage robust preliminary data from the applicant's K23 and R03 awards to innovatively address the mechanistic pathways and susceptibilities for kidney disease and investigate targeted interventions to mitigate kidney damage in SCD. The underlying hypothesis is that cell-free hemoglobin mediates damage to the kidney cortex and microvasculature if not efficiently scavenged and processed. The applicant will apply exciting preliminary data to test this hypothesis via three specific aims. Specific aim #1 will determine whether functional variants in HP, the main scavenger of cell-free hemoglobin in circulation, and HMOX1, the rate limiting enzyme for degrading heme, are associated with acute kidney injury risk during a vaso-occlusive crisis, when concentrations of cell-free hemoglobin increase approximately 2-fold. Specific aim #2 will determine whether cell-free hemoglobin leads to kidney microvascular dysfunction through aberrant function of thrombomodulin, an endothelial bound protein critical for maintaining vascular health. Specific aim #3 will investigate whether voxelotor, an oral small molecular inhibitor of sickle hemoglobin polymerization and hemolysis, reduces cell-free hemoglobin exposure and damage to the kidney in transgenic sickle mice. Integrating genetic analyses of cell-free hemoglobin processing with therapies to improve vascular function or reduce cell-free hemoglobin exposure to the kidney will lead to a deeper understanding for the mechanisms of kidney damage and guide individualized and preventive therapeutic strategies for sickle cell nephropathy. This research team is exceptionally positioned to achieve the goals outlined in this proposal through a strong history of productivity and the institutional environment. The University of Illinois at Chicago Comprehensive Sickle Cell Center cares for over 800 SCD patients and has a long-standing tradition of successful implementation of research studies. At the present time, there are only limited therapeutic options available to treat SCD. Developing a better understanding of the susceptibilities and pathways for kidney disease may potentially have a significant impact on this underserved high risk population.

NIH Research Projects · FY 2025 · 2020-06

Thrombotic cardiovascular diseases remain the leading cause of death in US and world. Blood platelets play key roles in both hemostasis and thrombosis. Not only do platelets adhere and aggregate to form thrombi at the site of vascular injury, platelets also facilitate coagulation (formation of a fibrin clot). Both platelet thrombus formation and coagulation are important contributors to the morbidity and mortality of thrombotic diseases such as heart attack and stroke. Thus, anti-platelet drugs and anti-coagulants were developed and are clinically used to prevent and treat thrombosis. However, current anti-platelet drugs and anti-coagulants have deficiencies. First, anti-platelet drugs and anti-coagulants all have the major adverse effect of bleeding, which can be life-threatening. Furthermore, anti-platelet drugs are not as effective in treating coagulation, and vice versa, but combined use of anti-platelets and anti-coagulants greatly exacerbates bleeding risk. Thus, it would be highly significant to develop dual anti-platelet and anti-coagulant drugs, which do not cause bleeding. Furthermore, thrombosis can be induced by chronic and acute inflammatory conditions such as atherosclerosis and sepsis. Conversely, thrombosis induces and exacerbates inflammation. Thus, it is also highly desirable to develop a drug that is more potent than aspirin in anti-thrombotic and anti-inflammatory efficacy. The Integrin family of adhesion receptors plays key roles in both in platelets and leukocytes. Platelet integrin aIIbb3 (GPIIb- IIIa), upon activation by inside-out signaling stimulated by agonists, not only mediates platelet adhesion and thrombus formation, but also transmits outside-in signals leading to thrombus expansion and occlusive thrombosis, but is dispensable for primary hemostasis. Leukocyte b2 integrins, aLb2 and amb2, mediate leukocyte adhesion and outside-in signaling, leading to cell migration, cytokine release, phagocytosis, etc., and thus play critical roles in inflammation. We recently showed that outside-in signaling of integrins requires the binding of G protein subunit Ga13 to an ExE motif conserved in the cytoplasmic domains of both b2 and b3. Project 1 of this proposal is to investigate the mechanisms of Ga13-dependent integrin outside-in signaling. Project 2 is to investigate the important role of b3 outside-in signaling in shear- and agonist-induced platelet procoagulant activity, and the conceptual basis for targeting Ga13-b3 interaction to develop a dual anti- platelet/anti-coagulant drug with minimal bleeding risk. Project 3 is to investigate the role of Ga13-dependent b2 integrin outside-in signaling in proinflammatory functions of leukocytes and in severe sepsis, and the conceptual basis for developing dual anti-thrombotic and anti-inflammatory drugs for treating severe sepsis and other thrombo-inflammatory conditions.

NIH Research Projects · FY 2024 · 2020-05

Herpes simplex virus (HSV) is the most common cause of infectious blindness and viral encephalitis in the Western countries. Primary or recurrent infection can lead to severe disease, yet no licensed vaccine is available. HSV typically initiates infection in the epithelial cells of mucosa and spreads to sensory neurons where the virus establishes latency. Reactivation from latency occurs intermittently, which is a lifelong source for recurrent lesions. Although viral replication in the mucosa or penetration into the nervous system inflicts damages or inflammation, the disease mechanism is less clear. As a large DNA virus, HSV evokes antiviral responses through the innate immune pathways that regulate TANK-binding kinase 1, a key factor required to activate cytokine expression and autophagy in mammalian cells. Remarkably, while the interferon- stimulated gene (STING) drives the cytokine response the tripartite motif protein 23 (TRIM23) serves to mediate autophagy. Despite such regulatory control, HSV is able to compromise host restrictions, which depends on an HSV virulence factor γ134.5. A central hypothesis of this proposal is that HSV differentially reprograms host immunity, where a dynamic interplay between viral and cellular factors may determine HSV spread, virulence and inflammation. Current effort is directed to decipher mechanisms of HSV pathogenesis. Several aspects of HSV infection will be investigated in a multi- faceted approach. Accordingly, recombinant HSV will be generated to determine the nature of HSV interactions with the innate immune factors in epithelial and neuronal cells. This will dissect elements pertinent to viral interference of the nucleic acid sensing complexes and autophagy machineries. Furthermore, genetic studies will explore viral features relevant to ocular replication, spread and neurovirulence. In parallel, gene expression analysis will assesses ocular and neuoinflammation. Collectively, these studies will provide an insight into genetic determinants of HSV virulence, which may inform design of novel antiviral therapeutics or vaccines.

NIH Research Projects · FY 2025 · 2020-05

The overall goal of the University of Illinois at Chicago (UIC) Building Interdisciplinary Research Careers in Women’s Health (BIRCWH) program is to foster research career development of junior faculty members engaged in research relevant to the health of women and to the understanding of how sex as a biological variable influences health and disease. We are based in the University of Illinois College of Medicine, but draw on the interdisciplinary strengths of UIC’s seven health colleges, including the only School of Public Health in the Chicagoland area. Over the next 5 years, we aim to train 8 junior faculty, including 4 MDs and 4 PhDs, in research relevant to women’s health and/or the use of both sexes to understand the influence of biological sex of health and disease. Scholars will have 75% protected time for BIRCWH activities (50% for surgeons) and $35,000 in career development funds matched by $25,000 in institutional support. The Multiple Program Director/Multiple Principal Investigator (mPD/mPI) plan involves a PhD clinical scientist and an MD basic/translational scientist, each with strong records of success in research relevant to the health of women and mentoring. Thirty-five senior mentors with records of NIH funding in interdisciplinary research will be available to participate in Scholar mentor teams. We will build upon our demonstrated success across three BIRCWH funding cycles in mentoring 26 BIRCWH Scholars and 1 BIRCWH Postdoctoral Trainee to date. Leveraging the highly interdisciplinary environment and strong institutional support, we will use evidence-based mentoring practices to advance our short-term objectives, including: a) supplementing team, peer, and individual mentoring programs with didactic and interactive Mentor training and new Scholar career development tools; b) implementing the UIC BIRCWH Bridging the Scientific Workforce Initiative by incorporating new models of collaboration and institutional support that bridge basic, translational and clinical science approaches to create innovation at the interface between disciplines thereby improving the competitive edge of all scholars; c) fostering partnerships with UIC’s NIH-funded Center for Clinical and Translational Science (CCTS, UIC’s CTSA) and KL2 program, the UIC Alcohol Research Center, and AI.Health4All (a center for artificial intelligence and health technological innovation); and d) augmenting our strong didactic curriculum in research relevant to the health of women across the lifespan with new training initiatives in data science and management, precision medicine, comorbidity/multimorbidity, and prevention research and care, all priority areas identified by the Office of Research on Women's Health (ORWH). These UIC BIRCWH activities will accelerate the translation of knowledge into improved health care for women*

NIH Research Projects · FY 2026 · 2020-05

Project Summary The overall goals of my laboratory over the next 5 years are to better understand the heterogeneity of inflammatory cell function over the course wound healing, focusing on monocytes, macrophages and Natural Killer cells. We plan to address three focus areas using models of normal (non-diabetic), impaired (diabetic) and improved (LIV-treated diabetic) skin wound healing: First, we will elucidate mechanisms that enable inflammatory cell proliferation after entry into the wound. We will identify mechanisms underlying transitions of monocytes from a proliferative state in bone marrow, to a non-proliferative state in blood, and then back to a proliferative state in damaged tissue. We will also investigate mechanisms that regulate Natural Killer cell proliferation in wounds. Second, we will elucidate the role of infiltrating versus resident inflammatory cells in wound healing. We will use lineage tracing techniques to determine roles of infiltrating versus resident macrophages and Natural Killer cells in wound healing. Third, we will elucidate inflammatory cell communication pathways with other wound cells. We will use spatial transcriptomics to refine our current models of monocyte, macrophage and Natural Killer cell communication with other wound cells over space and time and will perform mechanistic testing of these models. To address each of these focus areas, we will use scRNAseq, scATACseq, spatial transcriptomics and downstream analysis to identify pathways involved in the regulation of inflammatory cell heterogeneity These studies will guide mechanistic experiments using available blocking antibodies, transgenic mice and bone marrow transfer. For the most promising candidates, cell-specific transgenic mice will be generated. To determine the degree to which our mouse data relates to human wound healing, we will map our results to published human wound scRNAseq and spatial transcriptomics datasets. The overall vision of our approach is that by identifying novel regulators of monocyte, macrophage and Natural Killer cell function during wound healing, we can develop novel approaches to manipulate inflammation and improve healing of difficult wounds, and in the process, generate a pipeline of candidate therapies to translate into clinical studies.

NIH Research Projects · FY 2024 · 2020-02

Project Summary African Americans have disproportionate rates of cardiovascular disease (CVD) in the US. African Americans with type 2 diabetes (T2DM) have twice the risk than non-Hispanic whites for developing CVD. Poorer sleep and greater chronic psychological stress may contribute to this additional risk. Consequently, African Americans have worse glycemic control among those with diabetes and higher CVD risk. One promising approach to improving CVD risk in African Americans is mindfulness meditation (MM). MM can potentially reduce cardiovascular risk through attention control, emotional regulation, and self-awareness. The overall purpose of this K01 training grant is for Dr. Alana Biggers to obtain research training and develop skills needed to become an independent investigator and use those skills to adapt and evaluate an established MM curriculum (Mindfulness Based Therapy for Insomnia, or MBT-I). The specific aims are to: (1) adapt and refine the MBT-I curriculum for African-Americans with T2DM and incorporate text messaging; (2) conduct an 8- week, pilot randomized, controlled trial of the adapted curriculum with 68 African-Americans with T2DM; and (3) explore the impact of the intervention on cardiometabolic risk factors (blood pressure, glycosylated hemoglobin, and lipid profile) and inflammatory biomarkers (C-reactive protein, interleukin-6, and tumor necrosis factor α). Primary outcomes will include sleep quality and perceived stress evaluated at baseline, 8, and 16 weeks. The proposed research design consists of a pilot study, utilizes mixed-methods research, and involves both primary data collection and analysis. This K01 training grant provides Dr. Biggers career-building activities to further develop skills and a knowledge base in quantitative and qualitative methodology, health disparities research, and mobile health (mHealth)/behavioral health strategies in minority populations. With the guidance of an interdisciplinary mentorship team and institutional support, Dr. Biggers receives the necessary assistance and training to work toward her long-term career goal of being an independent researcher with expertise in health disparities, mixed-methods, and mHealth behavioral research.

NIH Research Projects · FY 2024 · 2019-09

Poor dietary and physical activity (PA) behaviors escalate risk for obesity, cancer, and other chronic diseases, and contribute to disparities. Mid-life is a vulnerable life stage when obesity rates peak and chronic diseases emerge. Neighborhood environments provide opportunities, barriers, and cues/triggers to engage in healthy or unhealthy behaviors. Overall, however, research findings on environment-behavior associations are inconsistent and effect sizes are small. This research is limited by sole focus on residential neighborhoods, failure to consider the environment’s role in within-person daily and momentary differences in behaviors, and scarce attention to identifying for whom the environment matters and under what conditions. A new approach is needed that considers the broader environment where people spend time (activity space). Our objective in the proposed study is to address misspecification of environmental exposures ubiquitous in prior research and provide a definitive test of activity-space environment explanations for between-and within-person diet and PA variations during mid-life. The central hypotheses are that activity-space environmental exposures contribute to both between- and within-person variations in dietary and PA behaviors and more strongly influence these behaviors than residential-neighborhood environments alone. Drawing on Temporal Self-Regulation Theory, we also hypothesize activity-space environmental exposures are more consequential for diet and PA when self-regulatory capacity—trait or state factors that affect a person’s ability to make efforts to regulate behavior—is diminished. An in-depth, rigorous study of 510 Latinx, African American, and White adults ages 40-64 is proposed. We will use a rich combination of cutting-edge geographically-explicit ecological momentary assessment (GEMA) methodologies: global positioning system (GPS) location tracking; smartphone-based mini-surveys of diet, PA, and state factors; and accelerometry, as well as three 24-hour dietary recalls, anthropometric measurements, and questionnaires of trait and other factors. Sophisticated routine, daily, and momentary activity-space measures will be derived based on the spatial extent of their movement, but also duration of exposure. Multiple features of the residential and activity-space environments will be measured using GIS including absolute and relative availability of healthful and unhealthful foods, walkability, recreational resource availability (e.g., parks, fitness facilities, greenness), and crime. For the first time, this innovative research will employ a dynamic environmental exposure approach using GEMA to supply evidence on the environment’s role in between- and within-person variations in diet and PA during mid-life, a pivotal time, in a racially/ethnically diverse sample. As such it will contribute to a much-needed shift in how environmental determinants of behaviors are studied, making a lasting impact on the field. Our research is significant because the results can inform new targets for lifestyle and place-based interventions to improve health during mid-life and set the stage for better later-life health.

NIH Research Projects · FY 2026 · 2019-09

Abstract. Single-cell proteomics (SCP) enables direct protein quantification at the single-cell level, offering unprecedented insight into cellular function. However, current SCP approaches face key limitations: high cost, low throughput, and suboptimal quantitative accuracy. These barriers restrict SCP’s broader adoption in biomedical research. The overarching goal of this proposal is to overcome key challenges of current single-cell proteomics (SCP) methods and transform SCP from a “technological marvel” to an accessible, robust tool for biomedical discovery. We will build upon the Levcell system, a container-less cell processing platform developed by the Gao lab at UIC, which has shown significant improvements in protein recovery and throughput. We will focus mainly on three aspects: 1. High-throughput, container-less single-cell multiomics. We will develop a multi- Levcell single-arm system for parallel processing of 700–1,000 cells/day. Innovations include ultrafast digestion protocols and direct infusion MS to shorten processing time and reduce costs. 2. MS1-based "cell fingerprinting" for classification and quantitation. Inspired by metabolomics, we will implement MS1 spectral profiling for sensitive, label-free single-cell classification and improved quantitation. This will enhance detection limits and streamline data acquisition. 3. Detecting cell heterogeneity in real-world biological application. We will apply the platform to map the human cell cycle at single-cell resolution, evaluate fallopian tube organoids for cancer modeling, and profile tumor cell heterogeneity and hypoxia in breast cancer. Upon completion, we aim to reduce SCP costs to <$1 per cell, enable >500 cells/day throughput, and deliver unbiased, high-accuracy data. Achieving these advancements will allow most of the core facilities of major research universities within the US to offer highly sensitive SCP analysis, transforming SCP from a niche, costly technique into a widely utilized tool capable of driving groundbreaking biomedical discoveries

NIH Research Projects · FY 2025 · 2019-07

Ovarian cancer is the most lethal cancer of the female reproductive system, with over 21,000 new ovarian cancer diagnoses and 14,000 deaths annually in the US. The total lifetime number of ovulations is a key risk factor for developing ovarian cancer. Factors that repress ovulation reduce the risk of ovarian cancer, such as oral contraceptives, pregnancy, lactation, and late menarche. The most common and deadly histotype of ovarian cancer, termed high grade serous cancer (HGSC), likely originates from the fallopian tube epithelial cells, and not the ovary. The frequent detection of tumors in the ovary, which resulted in the name “ovarian cancer”, suggests that the ovary provides a unique anatomical location for tumor migration and expansion. Since most research supports that the fallopian tube epithelium (FTE) is the source of ovarian cancer, it becomes critical to understand how ovulation contributes to tumor initiation in this site. Our team developed three-dimensional organotypic cultures supported in a state-of-the-art microfluidic platform that supports the ovary to produce dynamic hormone profiles that closely mimic the 28-day human reproductive menstrual cycle and ovulation on platform. This R01 renewal builds on this successful collaboration to expand our technology and models to elucidate the mechanisms whereby blocking ovulation prevents FTE carcinogenesis and ovarian colonization. We hypothesize that ovulation and the ovarian microenvironment contributes to the development FTE-derived high grade serous tumors and that ovarian secreted factors drive primary metastasis. Aim 1 leverages our ability to ovulate multiple ovaries in our MPS system called PREDICT-MOS to investigate mechanisms of transformation. Using a unique panel of isogenic cell lines that include non-tumorigenic cells, preneoplastic lesion models, and tumor models all derived from fallopian tube origin we will investigate how secreted factors from the ovary produced during ovulation impact proliferation, soft agar colony formation, and spheroids. We will determine if ovarian secretions increase DNA damage, replication stress, and copy number variation. Lastly, we test if exposure to ovulation drives tumor formation. Aim 2 will focus on the notion that ovulation generates a preneoplastic lesion and increased stemness through a secretory cell outgrowth using innovative iPSC-derived fallopian tube organoids. Organoids will be engineered to model early tumor lesions and monitored in terms of transformation in response to ovulation on platform. In Aim 3, we will investigate the mechanisms responsible for fallopian tube tumor cell colonization of the ovary. Proteomics of ovulatory secretions found both versican and IGF2 are higher after ovulation. We will investigate prevention of ovarian colonization by blocking versican and IGF2 signaling in cell lines, 3D bioprinted models, primary tissue, and in vivo. Overall, this grant will employ unique devices, primary human tissues, and three dimensional preneoplastic and tumor models to unveil new biological targets to reduce tumor initiation and spread of fallopian derived high grade serous cancer in the ovarian microenvironment.

NIH Research Projects · FY 2025 · 2019-07

Alcohol use disorder (AUD) is characterized by a pattern of compulsive alcohol drinking or a loss of control over alcohol drinking. The development of addiction involves neurobiological and functional changes in several key brain regions that play a role in the behavioral manifestations of AUD. Epigenetic regulation (Histone, DNA, and RNA chemical modifications) of gene expression is an important area in the field of neuroscience that emphasizes the importance of gene interactions with environmental factors in the regulation of structural and functional changes in the brain. This renewal T32 training grant entitled "Alcohol Research Training in Epigenetics and Pathophysiology" (ARTEP) is designed to provide training directly to pre-doctoral (PhD in neuroscience, psychology or biology related field) and post-doctoral fellows (PhD, MD/PhD graduates) on epigenetic and biological processes that play a role in the neuroadaptive and behavioral responses to ethanol as well as the pathophysiology of AUD. Besides outstanding training in addiction research, trainees will also receive several supplemental targeted training opportunities that will include didactic courses, seminars, presentations at national and international scientific meetings, as well as training in responsible research conduct, research data handling and management and manuscript and grant writing. ARTEP-supported trainees will receive the guidance and mentorship necessary to become independent alcohol researchers. The overarching goal of this alcohol research training program is to continue to provide training to pre- and post-doctoral fellows in epigenetics and the underlying mechanisms of molecular and behavioral phenotypes of AUD. The objectives are: 1) To provide unified training and apply a multidisciplinary approach by involving established investigators as faculty sponsors with expertise in areas of animal models, human research, tissue culture, human post-mortem brain studies, neuroimaging, electrophysiology, psychiatry, anatomy, epigenetics, molecular biology, and bioinformatics to cover a wide range of topics relevant to addiction. 2) To provide resources and a scientifically enriched environment for pre- and post-doctoral fellows for suitable training in neurobiological and behavioral studies in AUD that will enable them to become successful independent alcohol researchers. 3) To provide administrative and scientific leadership to trainees to help them develop into leading alcohol researchers. 4) To provide training in the preparation of competitive research grant applications (F or K grant mechanisms), to perform independent research and to prepare competitive applications for faculty positions at leading universities. The fact that this training program focuses on epigenetic mechanisms underlying behavioral phenotypes associated with AUD is very unique and will provide crucial training to the next generation of bright junior scientists and clinicians in the field of alcohol research.

NIH Research Projects · FY 2026 · 2019-06

In alignment with RFA-DA-25-027, this application seeks to renew the Great Lakes Node of the National Drug Abuse Treatment Clinical Trials Network (CTN) and expand its mission to serve a broader geographic reach. This expanded node will draw on an experienced set of investigators in the Greater Chicago region and augment this with expertise from Howard University, RTI International, and allied scholars from across the country to address the needs of individuals with substance use disorders using precision medicine approaches. The node will continue to serve as a vital Midwestern CTN hub (covering Chicago, Milwaukee, and rural areas of the Midwest) and adds the Mid-Atlantic region with Washington, DC, as a hub led by Howard University. Within this context, the GLMN will support engagement with CTN protocols and also add the following: Aim 1: GLMN will develop substance misuse intervention studies and clinical trials focused on various populations using precision medicine approaches. Aim 2: The node will develop and maintain a national network of experts in treatment interventions. Aim 3: Leveraging this network, the GLMN will serve as a national resource for CTN nodes and trials to improve inclusion, recruitment, and retention of all populations in clinical trials. Aim 4: The GLMN will develop and maintain a training infrastructure using its experienced faculty to facilitate the recruitment and development of substance use researchers. Aim 5: The GLMN will implement a coherent succession and development plan to advance junior researchers into leadership roles within the node and the CTN, more generally. Ideally, this will result in multiple scholars advancing to PI roles on research trials and within nodes across the CTN. This project is part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative bolsters research across NIH to improve treatment for opioid misuse and addiction.

NIH Research Projects · FY 2026 · 2019-05

Cardiac arrest (CA) is a leading cause of death around the globe. In the USA, it affects about 650,000 people annually with an overall survival rate for out-of-hospital cardiac arrest less than 10%. Despite this enormous public health burden, no pharmacological drugs exist to improve CA survival. This proposal is a renewal application of R01HL147031-01 that investigated a novel cell-permeable biological peptide TAT-PHLPP9c to improve CA outcome. This peptide inhibits the phosphatase PHLPP and activates Akt in the heart and brain within minutes after intravenous administration during cardiopulmonary resuscitation (CPR). Remarkable improvement in neurologically intact survival in both mouse and swine CA models was demonstrated, with new biomarkers of metabolic resuscitation identified. However, in addition to metabolic dysfunction, marked intravascular coagulation in the microcirculation of organs after CA also contributes to poor outcomes. This renewal application builds upon new preliminary data showing that in addition to Akt-related metabolic recovery, platelet activation and related thrombo-inflammation via the G Protein α13-Integrin β3 interaction affects CA outcome. Proposed work will examine a novel treatment strategy for CA that combines the use of TAT-PHLPP9c and M3mP6, a lipid-stabilized, high-loading peptide nanoparticle designed to inhibit integrin signaling and platelet activation. Our pilot studies suggest substantial platelet activation and related inflammation within hours after both mouse and swine CA, with only partial attenuation of this thrombo-inflammation by TAT-PHLPP9c. Furthermore, M3mP6, when given during CPR, provides substantial synergistic benefit from TAT-PHLPP9c to 5-day CA survival in a mouse CA model. New aims will use these two complementary novel peptides to examine the synergistic roles of metabolic derangement and thrombo-inflammation in CA survival, and develop a transformative approach to CA with the potential to protect against even prolonged >10-15 min of untreated cardiac arrest. New proposed work will: Aim 1. Examine whether combined treatment of TAT-PHLPP9c and M3mP6 during CPR improves 5-day neurologically intact survival after mouse CA. Aim 2. Study the mechanisms of the synergistic effects of these two peptides in the heart and platelets. Aim 3. Validate the efficacy of TAT-PHLPP9c and M3mP6 in a swine CA model. The concept of administration of novel cell-permeable peptides during CPR to protect against two critical aspects of post-CA syndrome is practical, innovative and highly translational. New mechanistic insights into metabolic injury and thrombo-inflammation and how they interact to affect CA survival would have great potential to develop novel approaches for CA care. Given the magnitude of protection the combined peptides demonstrate in preliminary work, this proposal has potential to transform cardiac arrest care.

NIH Research Projects · FY 2026 · 2019-05

PROJECT SUMMARY/ABSTRACT The overall goal of our research program is to delineate molecular mechanisms that regulate cell proliferation and differentiation in the context of animal development. This knowledge will help to advance the understanding of normal processes in the developing multicellular organisms, explain why dysregulation of these mechanisms leads to disease, and provide strategies to ameliorate these unwanted effects. We focus on the highly conserved Retinoblastoma (RB) pathway, which is involved in plethora of biological processes but is best known for its role in cell cycle control. One of the key targets of the RB pathway is the E2F family of transcription factors that is negatively regulated by the Retinoblastoma protein (pRB). Mammalian RB research has traditionally centered around its prominent role in cancer and therefore, its function in development remains poorly understood. A major hurdle to studying the RB pathway in mammalian development is redundancy and compensation, as the large multigene Rb and E2F families make genetic analysis daunting. The Drosophila model system provides an attractive alternative because the Drosophila RB pathway is highly conserved yet it is simpler. In previous years, we have focused on identifying tissues and functions of E2F and Rbf, the fly pRB ortholog, that are essential for animal viability. During these studies, we have found that the RB pathway is particularly important in adult skeletal muscle. Surprisingly, in the muscle, both E2F and Rbf are needed in late muscle development to directly activate the expression of metabolic genes. We will use genomics approaches coupled with genetic analysis to investigate the molecular details of E2F/Rbf dependent activation. We will focus on the role of E2F/Rbf at enhancers and how the loss of E2F/Rbf binding at these regulatory regions changes chromatin state and gene expression. Previosuly, we have found that the phenotype of E2F deficient animals is a combination of both tissue intrinsic and systemic effects. Our future research will build on this discovery to determine why E2F inactivation in skeletal muscle leads to lethality. Another area of interest is focused on interaction between the RB pathway and Hippo signaling pathway. Combined inactivation of both pathways leads to photoreceptor dedifferentiation because the cells inappropriately turn on the eye progenitor transcriptional program, which is dependent on Homothorax (Hth) and Yorkie, a transcriptional effector of the Hippo pathway. Our future experiments will leverage the power of single cell genomics and single cell epigenomics to determine the upstream regulatory events and identify the role of Hth-Yorkie in transcriptional regulation in dedifferentiating photoreceptors and in normal eye progenitor cells. Collectively, the proposed research will advance our understanding of normal development and animal physiology, and how perturbations in growth pathways may lead to disease.

NIH Research Projects · FY 2026 · 2019-02

Abstract The neurovasculature plays a key role in homeostasis of the central nervous system. Blood vessels prevent unwanted molecules from entering the brain while supplying essential nutrients and signaling molecules to meet the demand of neurons. Specialized brain endothelial cells are the central component of the neurovasculature. Brain endothelial cells must maintain their own functions while exposed to acute and chronic fluctuations in circulating molecules from both the brain interstitial fluid and plasma in physiological and pathological states. Evidence supports that brain endothelial cell dysfunction is a significant pathology in neurodegenerative disorders and is exacerbated by genetic risk factors. One such factor is APOE genotype, which has long been linked to neurodegenerative disorders. Compared to APOE3, APOE4 is associated with greater cognitive decline in aging, poorer outcomes following stroke and traumatic brain injury, and is a major genetic risk factor for Alzheimer's disease. Several studies, including our own, have identified that one-way APOE4 disrupts neurons via neurovasculature dysfunction. Therefore, fundamental research identifying cellular mechanisms of how APOE regulates brain endothelial cell function is important. We have recently identified a new concept that brain endothelial cell APOE plays a key role in regulating neurovascular function. Supported by our published and preliminary data, our central hypothesis is brain endothelial cell APOE3 protects the neurovasculature to a greater extent than APOE4 to maintain behavioral function. Successful data will be significant by identifying a novel cellular mechanism of how APOE impacts brain function.

NIH Research Projects · FY 2025 · 2019-01

PROJECT SUMMARY Clinically there are examples of small molecules including finasteride and dutasteride that can reduce the risk of prostate cancer and potentially may be effect in minimal low risk disease. AR targeting drugs can prove extremely beneficial for a patient, however, the benefit is short as many of these agents are only effective for approximately 1 year. In our data collected during the initial 5-year R37 MERIT award we are characterizing the AR degradation properties of α-mangostin against known AR polymorphisms associated with resistance. Briefly, PC3 cells were transfected with AR constructs expressing the following Polymorphisms including E256K, T818D, and T878A. A second biological target for prostate cancer we have evaluated during the initial 5-year R37 MERIT award was the role of binding immunoglobulin protein (BiP), also known as GRP78 or HSP70. Our central hypothesis is that xanthones including α-Mangostin from the mangosteen are SARDs that promote proteolytic degradation of the AR and this mechanism is critically regulated by the multi-functional chaperone protein BiP. Furthermore, the multi-functional BiP protein in addition to promoting AR degradation is able to serve as a receptor on the cell surface for the apoptotic ligand Isthmin-1. Importantly, we have observed that benign prostate epithelial cells when treated with alpha-mangostin do not increase the UPR pathway or the expression of BiP [2, 4]. Our objective in this proposal is identify opportunities to exploit the multi-functional properties of BiP that are involved in AR degradation and receptor properties of BiP when localized to the cell surface involved in apoptosis using xanthones and recombinant Ishthmin-1. Our objective herein will be to identify key domains of BiP that bind to AR in prostate cancer cells involved in AR degradation. A second objective will be to functionally characterize the interaction BiP and Isthmin-1 in prostate cancer in combination with xanthones from the mangosteen fruit. Our third objective will be to optimize the pro-apoptotic properties of the BiP ligand Isthmin-1 in combination with isoprenylated xanthones.