University Of Illinois At Chicago

NIH Research Projects · FY 2024 · 2018-09

ABSTRACT Reducing new HIV and STI infections among South African (SA) adolescent girls and young women (AGYW) is global public health priority.1 SA has world's largest HIV epidemic,2, 3 and SA AGYW acquire HIV at twice the rate of and seroconvert on average 5 – 7 years earlier than male peers.3 As new infections continue to outpace access to and availability of PrEP and ART, primary prevention remains the most viable strategy to stem new transmissions.1, 4, 5 SA efforts to prevent HIV transmission in youth focus mostly on individual-level behavior change,6-8 but AGYW’s persistent HIV disparities are explained by broad social and structural inequities that shape and constrain HIV-risk behaviors.9-14 Comprehensive HIV prevention packages that are integrated, synergistic, and tailored to the local epidemiology and cultural context are likely to achieve and sustain maximum reductions in HIV-risk.15-22 Female caregivers (FC) are an untapped resource in the HIV prevention toolbox23, 24 and offer a novel opportunity to strengthen AGYW prevention efforts. AGYW may also be change agents for their FC who want to be positive role models for AGYW, and thus, adopt HIV prevention behaviors, including HTC and PrEP. Guided by an ecological framework, our highly experienced multidisciplinary team will evaluate the effectiveness and cost-effectiveness of IMARA- SA, a multilevel, innovative, family-based HIV prevention program that targets individual, social, and structural drivers of risk to decrease HIV and STI incident infections, reduce risky sexual behavior, and increase HTC and PrEP uptake (where appropriate) in AGYW and FC. IMARA previously demonstrated a 43% reduction in incident STI at 12-month follow-up among Black 14-18 year-old girls in the US,25 and the curriculum was carefully and systematically adapted to the South African context (IMARA-SA).26, 27 This study will be integrated into the adolescent-friendly services at DTHF in the Western Cape metropolitan area facilitating sustainability if effective. We will conduct a 2-arm RCT with 645 15-19 year-old AGYW and FC comparing IMARA-SA to a time-matched family-based health promotion program (HP). FC and AGYW will complete baseline, 6-, and 12-month assessments, including testing for three STIs. We will offer HTC and PrEP at each assessment and track uptake and linkage to care. AGYW and FC who test positive for a STI and/or HIV will receive free treatment at DTHF. We will collect data to determine the costs of IMARA- SA. Analyses will compare AGYW and FC across the intervention and control programs on sexual risk taking, STI and HIV incidence, PrEP and HTC uptake, and theoretical mediators. The study answers an urgent need to evaluate the effectiveness and cost-effectiveness of combination HIV prevention packages for AGYW to achieve an AIDS-free generation.

NIH Research Projects · FY 2025 · 2018-09

From the previous R01 funding period we have generated compelling new evidence that human Heparanase-1 (HPSE), a heparan sulfate (HS) endoglycosidase, is a virulence factor responsible for triggering angiogenesis and inflammation in the eye during herpes simplex virus type-1 (HSV-1) infection. Our in vivo studies have shown that HPSE presence can significantly increase HSV-1 replication and severity of ocular disease with poor prognosis. Investigation of transcriptional and proteomic landscapes revealed a multitude of non-enzymatic roles for HPSE during HSV-1 infection and identified new druggable targets. Upon further investigation, we found that the significance of HPSE in corneal infection may not be limited to promoting viral pathogenesis only, but also in the induction of inflammatory cell death in a protein kinase B (Akt) dependent manner. Making things even more interesting and potentially more significant, our new preliminary data suggests that HPSE and Akt2 isoform phenocopy each other both in inflammatory cell death and deficiency in virus production. Therefore, based on our published observations of HPSE’s non-enzymatic roles and preliminary results, we hypothesize an important, yet interconnected regulatory role for HPSE and Akt2 in HSV-1 mediated ocular inflammation, nerve damage, and the resultant vision loss. We propose that their inhibition through small molecules can reduce disease severity and viral replication in the eye and reduce the incidences of viral encephalitis. This proposal will focus on understanding HPSE driven inflammatory cell death mechanisms and the role for Akt2 during HSV-1 replication, spread and disease pathology in the cornea. Successful completion of our studies will identify new and more effective HPSE and Akt2 inhibitors that can reduce inflammation as well as virus load without causing any adverse effects. Results generated through the proposed experiments will be broadly relevant, as aberrant HPSE activity has been implicated in a wide array of ocular pathologies and other neurodegenerative diseases and disorders such as multiple sclerosis and Alzheimer’s Disease.

NIH Research Projects · FY 2026 · 2018-06

Project Title: Targeting Troponin T Regulation to Sustain Cardiac Function in Heart Failure Project Summary Sufficient blood pumping of the heart depends on ventricular filling and the contractility of cardiac muscle against arterial resistance. Cardiac insufficiency and failure remains a major challenge in the management of cardiovascular diseases. Cardiac muscle contraction and relaxation is regulated by the troponin complex in the sarcomeric thin filament. Troponin consists of three protein subunits: troponin C (TnC), troponin I (TnI), and troponin T (TnT). A restrictive proteolytic cleavage to selectively remove the N-terminal hypervariable region of cardiac TnT (cTnT) occurs as a physiological adaptation to ventricular inotropy-afterload mismatch such as that in acute myocardial ischemia or pressure overload. The N-terminal truncated cTnT (cTnT-ND) remains in the cardiac myofilaments with modified functionality to moderately tune down ventricular peak-systolic velocity, which elongates the time of rapid ejection to sustain stroke volume. Without increasing the peak systolic pressure, this myocardial kinetics-based mechanism also improves the efficiency of cardiac pumping. Based on strong scientific premise, substantial progresses made in the previous funding period of this research project and promising preliminary studies, the proposed new studies focus on investigating the molecular mechanism by which cTnT-ND modulates the kinetics of cardiac myofilament activation and deactivation via the newly identified C-terminal tropomyosin-binding site 3 of TnT for translational applications in treating inotropy-afterload mismatch and diastolic dysfunction of failing hearts. Three new Specific Aims will be pursued: Aim 1 is to characterize how the newly identified tropomyosin-binding site 3 in the C-terminal end segment of TnT functions in tuning the kinetics of cardiac myofilament activation and deactivation. Aim 2 is to assess the effects of cTnT-ND on ventricular systolic and diastolic kinetics in improving cardiac function in heart failures with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). Aim 3 is to develop applications of TnT C-terminal peptides in correcting the function of failing hearts. Significance: b-adrenergic blockade has a proven clinical benefit in treating chronic congestive heart failure and prolonging patient life. Without the side effects from systemic decrease in b-adrenergic tone, the cTnT-ND adaptation via the C-terminal tropomyosin-binding site 3 selectively tunes down myocardial peak- systolic velocity to elongate ventricular rapid ejection time and sustain stroke volume against afterload. This myofilament mechanism simulates a therapeutic effect of b-adrenergic blockade and targets a specific kinetic step of the cardiac cycle to improve pumping efficiency in failing hearts. This mechanism can also facilitate relaxation to alleviate myocardial hypertrophy- and over activation-caused diastolic dysfunction in diastolic heart failure. Our studies using integrative multi-level approaches and experimental systems will lay groundwork for ultimately translating this novel molecular mechanism into a new treatment for heart failure.

NIH Research Projects · FY 2025 · 2018-05

Program Director/Principal Investigator (Liang, Jie): PROJECT SUMMARY/ABSTRACT We will continue our study of biopolymers and their interactions at two levels. At the molecular network level, we will study the A) probability landscape of stochastic networks of molecular reactions. We will develop efficient computational tools to construct exact probability landscapes in high-dimension, quantify probability discrete fluxes, and characterize their exact topology. These powerful tools will be applied to gain mechanistic understanding of stochastic control of network phenotypes in a number of important biological problems. At the (sub)cellular level, we will study B) biophysics of 3D chromatin folding. We will develop algorithms to identify driver interactiomes that can generate large ensembles of accurate models of single-cell 3D chromatin conformations consistent with Hi-C and single-cell experimental data. Our methods will be applied to study foundational problems of 3D genome to gain understanding of principles of genome organization. In A), we will study stochastic reaction networks of molecules to gain mechanistic understanding of their behavior. Many important cellular processes involve a small copy number of molecules of transcription factors, enzymes, and signaling molecules. Stochasticity and rare events arising from such low copy number reactions are important for processes such as embryonic development, stem cell differentiation, and nongenetic heterogeneity. Our approach will be based on the fundamental framework of the stochastic kinetic processes and the discrete chemical master equation (dCME). The central tasks are: 1) constructing the probability landscape of the network, and from which to 2) gain analytical insight into mechanism of network behavior. For 1), we have developed the ACME method that can construct the exact probability landscapes of a large class of complex stochastic reaction networks and will make further improvement. For 2), we will develop landscape analysis tools using persistent homology that can compute the exact topology of the high-dimensional probability landscape. We have also developed the concept of discrete fluxes and methods for its computation. We will further formulate and generalize the concept of discrete rotational flux to higher dimension. These developments will enable global and mechanistic understanding of the behavior of stochastic networks through accurately constructed probability landscape and exactly computed topological structures. Our work will open up new frontiers for investigations, many of which are currently not computationally feasible. Specifically, we will construct probability landscapes of networks, study how global flux maps evolve and how phenotype switching occur. We will generalize the discovery of stochastic oscillation and investigate higher-order oscillatory behavior of networks, where probability mass may be transferred through higher-dimensional k-channels. In addition, we will carry-out in-depth analysis on a selected set of important biological problems, including stochastic control of mRNA splicing/transcription at single-cell level, initiation of protein fibril aggregation, network architectures for multi-stability and maintenance of epigenetic states, and switching of cellular phenotypes. In B), we will study the biophysical principles of 3D genome organization. We will develop computational tools to generate thoroughly sampled large ensembles of coarse-grained polymer models of 3D chromatin structures based on experimental Hi-C and other data. We will develop strategies to study a number of fundamental problems: We will determine and uncover the minimal sets of critical driver interactions sufficient to determine folding of chromatin at specific loci and at whole chromosome level. We will further investigate how chromatin-nuclear envelope interactions, along with chromatin driver interactome, nuclear bodies, and speckles, orchestrate the overall 3D genome organization. We will decipher the persistent driver interactomes at different genomic loci, which are preserved across different tissues and are responsible for the formation of common genomic structural scaffolds and folding landscapes. We will also identify adaptive interactomes that differ among tissues and inferring how they evolve and rewire during development. We will further infer how these temporally evolving structural interactomes spatially arrange genomic elements and how they may influence structural gene accessibility at genome scale. 0925-0001 (Rev. 03/16) Page Continuation Format Page

NIH Research Projects · FY 2026 · 2018-04

Salmonella enterica serotypes are invasive enteric pathogens spread through fecal contamination of food and water sources. It represents a constant public health threat in the U.S. and around the world. Impaired intestinal barriers are associated with bacterial infection. Vitamin D and its receptor (VDR) levels are inversely related to chronic inflammation in infectious diseases. The objective of this application is to study VDR regulation of intestinal tight junctions (TJs) in response to Salmonella infection. Our publications and preliminary data have shown that: (1) lack of VDR makes the host susceptible to Salmonella invasion; (2) Salmonella targets TJ proteins (e.g., ZO-1, Claudin) and facilitates pathogenic enteric bacterial invasion. (3) We have identified the sequence of functional vitamin D response element in Claudin- 5 and 15, two novel target genes of VDR; (4) impaired VDR leads to reduced expression of TJ proteins Claudin- 5 and 15, increased “leaky” protein Claudin 2, and increased permeability in infection; and (5) probiotics and their products enhance VDR function and inhibit Salmonella infection. Thus, we hypothesize that: “intestinal epithelial VDR regulation of barrier function is aberrant or lost in infectious states and restoring VDR function will attenuate severe infection and chronic inflammation.” We have now developed state-of-the-art transgenic models and cutting-edge methods, e.g., integrated three-dimensional microscopy for a spatial junction protein atlas and single-cell spatial proteomics for geographic profiling of the TJ protein expressions. Our research team includes experts in the following areas: epithelial biology, animal models, bioengineering, and microbiology. Two Specific Aims have been designed: Aim 1. Determine the cellular and molecular mechanisms by which intestinal VDR regulates barrier function that is essential for mucosal homeostasis. We will: A. Elucidate the mechanism for abnormal epithelial TJs coregulated by Claudins and their interactions in the VDR-/- organoids in vitro. B. Study regional and spatial Claudins, their interactions, and integrations with other barrier layers: microbiome and mucin. And C. Determine the mechanism for abnormal epithelial TJs, including spatial and omics studies of TJs, in the intestine of the VDRΔIEC and VDR overexpressed mice with or without infection. Aim 2. Investigate microbial metabolites and TJs vs. VDR for therapeutic strategies in inflammation and infection. We will A. Evaluate the roles and mechanisms of enhanced intestinal TJs vs. VDR expression by probiotic lactic acid bacterial proteins and metabolites in infected mice. B. Engineer probiotic bacteria strains for better outcomes in treatment of inflammation and infection. Our studies are innovative because they are focused on 1) understanding novel regulatory roles of VDR in Claudins and their interactions in infection; 2) developing cutting edge technologies and tools (organoids, transgenic mice, and spatial imaging) for studying intestinal biology; and 3) enhancing intestinal VDR expression by probiotics and microbial metabolites. This knowledge can then be exploited for strategies to prevent and treat digestive diseases by restoring VDR and enhancing barrier functions.

NIH Research Projects · FY 2026 · 2018-04

The research in the laboratory focuses on understanding the fundamental mechanisms of translation and action of ribosome-targeting antibiotics. One of the underappreciated aspects of translation that has transpired from our studies is its context specific nature. We learned that the ability of the ribosome to decode genetic information rapidly and efficiently is significantly influenced by the nature of its tRNA and mRNA substrates and/or properties of the polypeptide being made. Specific sequences have been identified as difficult to polymerize but, more than likely, there are many other that also present an obstacle for the translating ribosome. Why some sequences are challenging for translation and what mechanisms exist in the cell to help the ribosome overcome such problems are questions that have remained unanswered. Several conserved auxiliary translation factors (auxTFs) encoded in the bacterial genomes are thought to assist the ribosome in synthesizing proteins during fast growth or under stress, likely facilitating translation of the problematic sequence motifs. However, our knowledge of the nature of the sequences whose translation is facilitated by the auxTFs, about the molecular mechanisms of their action and of their physiological significance is limited at best. Answering these vexing questions is the goal of the proposal. We will use crosslinking-based ribosome profiling (XLRibo-seq) to map the genomic sites where auxTFs are recruited to the ribosome. Guided by these genome-wide data, we will select the most revealing gene models to dissect in vitro the precise nature of the problematic sequence motifs and elucidate the molecular mechanisms of the auxTF action. The inferred mechanisms will be validated in vivo and the physiological role of the auxTFs will be deduced by following the expression of specifically designed reporters under suitable growth conditions or using the appropriate mutants. The overall experimental approach will be first optimized using, as a model system, translation termination factors RF1 and RF2, and then applied to four most intriguing auxTFs (LepA, EttA, BirA and HflX) whose specificity, activity and physiological role remain enigmatic despite being investigated previously by other techniques. The approach could be extended to several other known or suspected auxTFs and even to the main translation factors whose activity could be conceivably modulated by the context of the translated sequence. The innovation of the proposal stems from the development of new methodologies (XLRibo-seq) with a broad application to studies of basic mechanisms of translation, and from revealing the functions and molecular mechanisms of action of conserved proteins playing important roles in expression of genetic information. The experiments build upon the long-term interests, previous findings, and expertise of our research group. The project will provide new training and teaching opportunities and facilitate the outreach activities of the lab.

NIH Research Projects · FY 2026 · 2018-04

This T32 renewal application seeks continued support for the Precision Lifestyle Medicine and Translation Research (PREMIER) training program at the University of Illinois Chicago (UIC). The program impact goal is to build a transdisciplinary, translational research training infrastructure for postdoctoral fellows who aspire to be both independent investigators and team scientists in precision lifestyle medicine. Specifically, the program will train highly talented and motivated postdoctoral scholars to be future leaders in research addressing the prevention and control of cardiovascular and respiratory chronic conditions and comorbidities. The specific aims are to: (1) Recruit and train a superb cadre of fellows; (2) Provide an academic “incubator” for an inspiring mentored research experience and individualized professional development; and (3) Sustain a pipeline of dedicated, skilled mentors at all academic ranks. PREMIER has 3 integrative scientific foci: Behavioral Sciences for Multimorbidity Prevention and Control as the central, patient-oriented research focused core; and the Mechanisms of Behavior Change and Disease and the Population Health and Policy cores traversing the central core. Supported by the Internal and External Advisory Committees, the Executive Committee, consisting of the 2 MPIs and the 2 co-leaders of each scientific core, will provide intellectual leadership and programmatic oversight. These 8 faculty along with 27 others from 6 science colleges at UIC (Medicine, Public Health, Applied Health Sciences, Nursing, Computer Science, Liberal Arts and Sciences) are PREMIER mentors. Collectively, they bring deep research and mentorship expertise, extensive professional experiences, and essential resources. Building on successes to date, the renewed program will support 12 full-time postdoctoral trainees in years 6-10, with expanded faculty mentors across all 3 scientific cores and enhanced faculty expertise and training resources in data sciences and methods. Every fellow will receive group mentorship from 1 primary mentor associated with the core of central interest to the fellow and 1-2 secondary mentors from either or both of the other cores. One of the mentors must have established expertise in the central core of this training program. Fellows will devote at least 75% effort to mentored research, supplemented by conferences, seminars, and coursework based on individual needs. Fellows will be selected from a national pool of MD and PhD (or equivalent) applicants based on past accomplishments and especially on their potential as future researchers and educators. Each trainee will develop an individual development plan (IDP), and progress is to be continuously monitored and formally evaluated. A multi-level evaluation plan is designed to ensure high quality training.

NIH Research Projects · FY 2025 · 2018-02

ABSTRACT / PROJECT SUMMARY Non-alcoholic steatohepatitis (NASH) represents a rapidly growing epidemic of liver disease that can predispose affected individuals to advanced fibrosis and hepatocellular carcinoma. Strategies for targeting cellular mediators of liver fibrosis, such as activated hepatic stellate cells (HSCs), remain limited due to an incomplete understanding of the mechanisms governing myofibroblastic differentiation and the signaling between liver parenchymal and non-parenchymal cell (NPC) types. The importance of microenvironmental signal crosstalk, including interactions between extracellular matrix (ECM) protein composition and mechanical stiffness in cell phenotypic alterations, is increasingly appreciated. Although animal models have provided insights into NASH, significant differences across species in drug metabolism and disease pathways exist. Thus, there is a need for human-relevant in vitro approaches that enable the investigation of hepatocellular phenotypes within physiological and NASH-like microenvironments and could facilitate the high-throughput discovery of novel therapeutics. The goal of this project is to implement engineered culture platforms for selectively modulating microenvironmental signals and utilize these systems to reveal key phenotypic programming pathways and interaction mechanisms within the context of a NASH-like microenvironment. Our approach will enable hypothesis-driven studies incorporating controlled perturbations of extracellular signals. In Aim 1, we will investigate the microenvironmental regulation of myofibroblastic phenotype. Utilizing defined ECM compositions and mechanical stiffness regimes in engineered cultures, we will examine the role of epigenetic gene regulatory mechanisms and test the hypothesis that combinatorial microenvironmental cues regulate epigenetic changes that are critical for the myofibroblastic programming of human hepatic stellate cells within the context of normal and NASH-like soluble triggers. In Aim 2, we will examine the influence of ECM composition and stiffness on Kupffer cell (KC) and primary human hepatocyte (PHH) functions including reciprocal intercellular interactions and cooperative effects of NASH-like soluble stimuli. Our approach will facilitate modular control and deconvolution of the effects of ECM composition, substrate stiffness, and soluble signals. In Aim 3, we will develop and implement multicellular 3D liver microtissues for the systematic analysis of multicellular phenotype regulation in the context of disease-like ECM alterations. We will investigate heterotypic cellular crosstalk mechanisms between non-parenchymal cell types (HSC, KC, and liver sinusoidal endothelial cells), and their collective influence on primary human hepatocyte functions. We will further establish capabilities for assessing NASH-relevant therapeutics within the multicellular liver platform. The proposed studies will provide a) fundamental insights into the microenvironmental cues and signaling mechanisms underlying cellular phenotypic alterations in NASH, which could aid the development of novel drug therapies, and b) novel engineered liver culture platforms that can serve as enabling tools for a broad range of physiological and disease outcomes.

NIH Research Projects · FY 2025 · 2017-09

Project Summary This T32 renewal application seeks support for the multidisciplinary education of trainees in Alzheimer’s disease and Related Dementia (ADRD). The goal of this program is to train the next generation of creative and meritorious ADRD researchers at the predoctoral level. We acknowledge that the development of future therapy for dementia will require strong training in multiple disciplines, such as, the molecular biology of dementia, drug discovery and development, clinical studies and the analysis of large data sets. We will answer the imperative need for scientists who can synthesize across disciplines. Our Training Program comprises of four discplines/themes: (1) biological mechanisms (2) drug discovery and development (3) clinical ADRD (4) computational science. Each student gets trained in at least two of the four disciplines, utilizing a multidisciplinary approach for tackling scientific questions in ADRD. Attentive to the latest recommendation of the NIA and Alzheimer’s Association guidelines, there will be special emphasize on the analysis of lifestyle, environmental factors and preventative approaches for ADRD. The mentor/preceptor team has outstanding expertise to establish this innovative, interdisciplinary training program, to integrate otherwise disparate centers of excellence at UIC and Rush, leveraged by industry collaborations. Preceptor expertise is diverse; from molecular mechanisms of dementia, vascular biology, diabetes and inflammation, neuronal and neural imaging to clinical diagnosis of human ADRD patients and large scale data analysis. Expertise is from 12 departments and 6 clinical and translational entities. We will train ADRD researchers with diverse backgrounds and cross- disciplinary skills, including neuroscientists, but also computational biologists, chemists, and engineers interested in translational ADRD research. To facilitate interdisciplinary training, trainees will have two preceptors from different disciplines. We will build individual development plans (IDPs) for each trainee and offer multidisciplinary coursework from ADRD-TP faculty and pharma scientists. Importantly, trainees can perform translational research at any of the affiliated clinical and translational entities. Trainees will be encouraged to collaborate with large community-based NIH-supported studies (ROS/MAP) or NIA’s large-scale collaborative consortia (AMP-AD, M2OVE-AD, ADNI, ACTC), and with our pharma partners, Eli Lilly, Abbott and Baxter. Trainees are encouraged to participate in workshops geared towards -omics and drug discovery and the CIM/MATTER entrepreneurial program that aids commercialization of scientific innovation. We seek to support 6 predoctoral trainees. The success of this program in the last five years is reflected by our alumni who have moved on to successful careers in academia and pharma. The ADRD-TP’s vitality is reflected by the numbers of highly qualified applicants and state-of-the-art scientific endevours and publications. We expect the next five year to surpass this success. In summary, the ADRD-TP will provide a rigorous, inspiring and nurturing environment to ensure training of the highest level of scientists needed to unravel dementia.

NIH Research Projects · FY 2026 · 2017-04

WONHWA CHO, PH.D. PROJECT SUMMARY/ABSTRACT Lipid regulation of cellular signaling and protein-protein interactions Cellular proteins accomplish their functions through interactions with other proteins, forming complex protein-protein interaction networks. Cellular protein-protein interaction typically involves small modular protein interaction domains, such as Src-homology 2 and PSD95, Dlg1, ZO-1 domains. Physiological significance of protein interaction domain-mediated protein-protein interaction networks has been well supported by a large number of protein interaction domains encoded by human genome and many human diseases, including cancer, caused by dysfunctional protein interaction domain-mediated cellular processes. Interestingly, most protein interaction domains have moderate binding affinity and a significant degree of promiscuity. This may be necessary for reversibility and redundancy of cell signaling pathways but raises a fundamental question as to how high-fidelity cellular function and regulation can be achieved through the protein interaction domain-mediated protein-protein interaction. We have recently shown that membrane lipids, including cholesterol and phosphoinositides, coordinate and regulate protein-protein interaction by directly and specifically interacting with protein interaction domains. This important new discovery and our innovative in situ quantitative lipid imaging technology provide us with a unique and unparalleled opportunity to elucidate the mechanisms by which lipids orchestrate spatiotemporal specificity of protein-protein interaction and cell signaling and develop new strategies to modulate these processes. Given the importance of protein interaction domain-mediated protein-protein interaction and cell signaling in health and disease, our proposed research should have a major impact on broad areas of biology and medicine and lay the foundation for a pioneering and innovative drug discovery strategy for human diseases, most notably cancer.

NIH Research Projects · FY 2025 · 2016-09

The proposed study employs a randomized, controlled design to assess the immediate and long-term effects of task-specific balance training for reducing environmental falls in at-risk community-dwelling older adults. >33% of older adults fall at least once each year, leading to serious injuries (e.g., hip fractures, head injuries) and comorbidities (e.g., Alzheimer’s disease and related Dementias). Most falls occur due to environmental disturbances which cause a loss of balance while walking (i.e., slips, trips). Overground perturbation training (repeated exposure to unpredicted perturbations) improves both volitional/anticipatory and reactive balance control and reduces real-life falls among older adults. However, overground perturbation training is not suitable for routine clinical application due to its complex design, space, and technology requirements. An alternative method for delivering perturbation training is commercial treadmill systems, which not only can enhance fall- resisting skills but are more feasible for community-translation. However, the equipment is costly and the translational effectiveness of treadmill perturbation training for reducing falls in community ambulatory older adults is lesser than overground training, probably as it mainly only entrains reactive balance control. Falls may also occur due to deficits in volitional balance control which affect gait stability during daily living. Training paradigms focused on improving volitional balance control have primarily comprised of conventional balance exercises delivered as a part of physical rehabilitation; however, conventional balance exercises generally do not translate to improvements in reactive balance control when exposed to an unpredicted external perturbation and have limited effects on reducing real-life falls. A fall prevention intervention that targets both volitional and reactive balance domains could more effectively reduce falls than existing paradigms which only train a single domain (e.g., treadmill perturbation training: reactive-dominant, or conventional balance: volitional- dominant). We have developed a novel task-specific balance program that includes both functional tasks and predictable perturbations specific to slips and trips and requires little set-up and equipment, making it a cost- effective, feasible and accessible fall prevention intervention. We will compare the effects of 8 weeks (16 sessions) of task-specific balance training with established fall prevention paradigms including treadmill perturbation training and conventional balance training. We will examine the immediate effects of task-specific balance training on reactive balance (Aim 1) and volitional balance (Aim 2). Additionally, we will evaluate the longer-term retention (18 months) of task-specific balance training and effects on real-life falls and falls efficacy (Aim 3). In an exploratory aim, will also examine the neuromuscular adaptations induced through training using simulation techniques (Aim 4). If successful, our novel intervention can be implemented as a feasible, safe, and effective fall-prevention intervention and has large potential for direct dissemination to clinical settings.

NIH Research Projects · FY 2024 · 2016-08

The University of Illinois at Chicago (UIC) Center for Clinical and Translational Science (CCTS) seeks to catalyze translational research, locally and nationally, as part of a national network to improve individual and population health. Since our initial funding by the NIH in 2009, the CCTS has been a catalyst for mobilizing institutional support and resources to enhance clinical translational research and expand multidisciplinary training programs to increase workforce diversity and promote team science. The overarching goal—and driving focus—of the CCTS is to improve population health, particularly among minorities and underserved populations. Our high- quality multidisciplinary clinical and translational research, spanning T1-T4 and paired with strengths in community engagement and implementation science and appreciation for the social determinants of health, help to accelerate discoveries into practice and policy. Building on our organizational foundation and record of success, the UIC CCTS is well-positioned to make substantial contributions by collaborating with other hubs, supporting national CTSA activities, and making unique contributions to community-engaged research with vulnerable and underserved populations. As we move forward, we will continue to develop streamlined processes and resources to facilitate research processes and aid collaboration; to develop and prepare a translational science workforce that is multidisciplinary and comfortable in team science; to use innovative informatics solutions to advance translational research; and to have ready-to-deploy systems to respond rapidly to innovative, collaborative projects. We will achieve our objectives through the following global specific aims: 1) Develop a skillful and diverse translational workforce to conduct multidisciplinary team science and advance translation of discoveries; 2) Engage a broad range of stakeholders in clinical translational research, including patients, community leaders, health care providers and clinicians, industry and policy makers; and further support collaboration among the CTSA hubs; 3) Integrate, support, and accelerate clinical translational research across the full translational spectrum with multiple disciplines and with diverse populations across the lifespan; 4) Promote advances in study and development of methods and processes of conducting translational science that will enable advances in translation; and 5) Support the use and advance of innovative informatics solutions to advance translational research and to help train the CTSA workforce. These aims will direct our course over the next five years, as we further evolve the clinical and translational enterprise, contribute to the CTSA network, and advance the health of the people of Illinois and the nation.

NIH Research Projects · FY 2024 · 2016-08

The UIC Clinical and Translational Sciences (CATS) Scholars Program was initiated in 2009 with the initial NIH funding for the UIC Center for Clinical and Translational Science (CCTS). Our Program has filled a significant gap in career development for biomedical research faculty at UIC, championing and creating a new culture of career mentorship and establishing a vibrant cadre of well-trained and highly successful faculty in clinical and translational science. Over the past 10 years, the CATS Scholars Program has provided mentorship and career development for 34 Scholars through both CTSA and institutional support. Our program supports a diverse group of Scholars who are >60% women, >35% from groups underrepresented in biomedical research, and from five different health sciences colleges. The overall goal of the CATS Scholars Program is to support the development of clinical and translational scientists who will engage the community and who will make substantive research advances that impact patient care. The specific goals of the program are 1) to provide a mentored career development experience that allows Scholars to develop the NIH/CTSA identified core competencies in clinical and translational research, 2) to provide Scholars with unique training opportunities that will drive innovation in research and 3) to systematically evaluate the Program and provide for continuous improvement and alignment with NIH/CTSA goals of advancing therapeutics, clinical interventions, and behavioral modifications to improve health. The program is supported by a cadre of more than 40 outstanding mentors who maintain vibrant and relevant research programs along with a commitment to mentoring. Innovative components of the program include an institutional commitment to a 3rd year of support for every Scholar, institutional support for external experiences to enrich Scholar training, extension of program activities to support additional “Affiliate” Scholars, engagement of former Scholars as mentors and advisors to the program, and a strong interactive career development program that spans all three Chicago CTSA hubs. Our Scholars benefit greatly from the core services, educational programs, and capacity of the UIC CCTS, and the utilization of these services has been instrumental to their growth. The activities of CATS Scholars align with the national CTSA goals of advancing therapeutics, clinical interventions, and behavioral modifications to improve health, as the Program Plan includes activities within these themes. The success of our scholars is evidenced by their rapid acquisition of independent extramural funding and by the continued advancement of Scholars as leaders in clinical and translational science. The CATS Scholar program, with its inclusive reach, provides a needed and highly valuable career development resource for clinical and translational science faculty at UIC.

NIH Research Projects · FY 2026 · 2016-05

Botanical dietary supplement use has skyrocketed over the last ten years. One significant portion of this market is herbal supplements targeted toward women, who commonly use them to treat their gynecological ailments, not only for their cost-effective advantage or affordability, but also for their health benefits. Progesterone is an endogenous hormone and synthetic progestins are used therapeutically for a variety of conditions including prevention of uterine hyperplasia, which increases the risk of uterine cancer, uterine bleeding, endometriosis, and prevention of preterm birth. Selective progesterone receptor (PR) modulators are also used in the treatment of prevention of fibroids, which occur in 80% of women. At a national level, treating benign gynecological conditions is expensive, with an annual cost of between $13–$22 billion. Thus, studying alternative therapies that women are already widely consuming is significant. However, a major technological and scientific gap exists: while botanicals are being widely consumed and contain compounds that are relatively safe, these compounds have not been identified or rigorously biologically evaluated, which is an area of emphasis for NCCIH (NOT-AT-21-006) that is specifically addressed in this application. Phytoprogestins need to be identified and studied in order to apply them for safe and effective use in uterine disorders. To address this, our team laid the groundwork for this new subfield of chemodietary prevention through the identification and biological characterization of molecules from dogwood, vitex, red clover, and yucca, as these contained compounds that modified PR signaling. In the current proposal our goal is to identify the structures of compounds in several other commonly consumed botanicals that modify PR signaling so that they can be examined for safety and efficacy in preclinical chemodietary prevention models, including prevention of fibroids, preterm birth and uterine hyperplasia. We aim to test our hypothesis that commonly consumed botanicals used to improve women’s health contain compounds that regulate PR signaling via three integrated aims. We will 1) Isolate and characterize the structures of phytoprogestin natural products from validated plant material through use of a cell-based PRE- luciferase assays and measure active compound abundance in commercial products; 2) Confirm that isolated compounds bind to a receptor, determine if they function as agonists, antagonists, or potentiators, determine if they modify off-target receptors, and refine their genome-wide transcriptional action using RNA seq; and 3) Confirm that chemodietary prevention using phytoprogestin-containing botanicals reduces preterm birth, uterine hyperplasia or blunts fibroid growth. Since little is known about phytoprogestin content and their associated biological activities from botanicals widely consumed by women, this study presents a profound opportunity to inform the treatment of gynecologic disorders and increase awareness in those consuming these botanicals already. Further, because women are already consuming these botanicals, studies should be conducted to understand their progesterone-modifying properties even if synthetic compounds exist.

NIH Research Projects · FY 2026 · 2016-05

Project Title: C-terminal Peptide of Cardiac Troponin I for the Treatment of Diastolic Heart Failure Project Summary Myocardial contractility is essential for cardiac function. Troponin-mediated thin myofilament regulation controls cardiac muscle contraction and relaxation. The troponin complex consists of three protein subunits: the calcium receptor troponin C (TnC), the inhibitory subunit troponin I (TnI), and the tropomyosin-binding subunit troponin T (TnT). Cardiac TnI plays a pivotal role in myofilament activation and deactivation, determining the kinetics of cardiac muscle contraction and relaxation, and pumping efficiency of the heart. Our research project focuses on a novel therapeutic peptide derived from the conserved C-terminal end mobile domain of cardiac TnI (cTnI-C27) for its effect on enhancing myocardial relaxation and the underlying mechanisms. Biochemical, genetic and physiological approaches and mouse models of diastolic cardiac dysfunction are employed to study cTnI-C27 peptide to understand its selective enhancement of diastolic function of the heart. The ultimate goal is to develop a targeted treatment for diastolic heart failure (HFpEF) that presently lacks an effective treatment. Three Specific Aims are proposed in the research plan: Aim 1 is to characterize the mechanism for exogenous cTnI-C27 peptide to modulate myofilament function as an activated state-specific myofilament Ca2+- desensitizer. We shall determine the binding site of cTnI-C27 peptide on tropomyosin in thin filament and characterize its effect on contractile kinetics and endogenous troponin regulation of myofibril actomyosin ATPase in reconstituted myofilaments and skinned cardiac muscle. The results will determine how exogenous cTnI-C27 peptide modulates cardiac muscle contractility, especially the enhanceing of Frank-Starling response without increasing sarcomere length. Aim 2 is to study the delivery of cTnI-C27 peptide into cardiomyocytes for functional effect. Heart-homing fusion peptide, AAV9 and inducible transgenic expression of cTnI-C27 peptide will be studied in vivo and in ex vivo working hearts. Effects on cardiac muscle contractility and heart function will be examined for therapeutic efficacy in normal and diastolic dysfunctional and fibrotic mouse hearts to evaluate the therapeutic potential of cTnI-C27 peptide. Aim 3 is to determine the chronic effects of exogenous cTnI-C27 peptide on cardiac function and remodeling. To develop the cTnI-C27 peptide for the treatment of chronic heart failure, we need to understand the effects of chronic presence of cTnI-C27 peptide on cardiac muscle. We shall examine the therapeutic and side-effects of chronic transgenic expression of cTnI-C27 peptide in normal and failing mouse heart. In vivo and ex vivo cardiac function, tolerance to hemodynamic stresses, and myocardial remodeling will be examined in young and aging mice to collect informative longitudinal data. With combined expertise in myofilament protein structure-function relationships and cardiac physiology and pathophysiology using multi-level experimental approaches, the study of a promising therapeutic peptide of endogenous origin will lay mechanistic and methodologic groundwork for translating a novel myofilament mechanism into a new treatment for diastolic heart failure.

NIH Research Projects · FY 2026 · 2016-04

PROJECT SUMMARY Molecular recognition is at the core of essentially all biochemical processes. Its studies, on scales from intramolecular and bimolecular to subcellular, are entering an exciting age, where close integration between experiment and computation is powering the quantitative prediction of biophysical properties. Indeed, in the previous funding period, our work has demonstrated that both the backbone dynamics and the membrane association propensities of intrinsically disordered proteins (IDPs) can be accurately predicted from their sequences. Moreover, we have begun to map out how individual acid acids code for phase equilibrium and material properties of biomolecular condensates. Building on these strong foundations, our efforts in the next funding period will focus on three interrelated directions. (1) By combining computation and experiment, we will determine the rules governing the sequence dependences and modes of action for IDPs binding with small molecules, inserting into lipid membranes, and interacting with DNA bases. To validate such deep mechanistic understanding, we will design IDP and DNA sequences to achieve specific binding properties. (2) We will characterize the determinants for the physical properties of biomolecular condensates at a fundamental level, by isolating the contributions of single amino acids and base pairs and by measuring the bridging forces stabilizing intermolecular interaction networks inside condensates. (3) We will conduct in-cell studies to elucidate the functions mediated by biomolecular condensates. For example, ATP is traditionally known as the energy source of cells, but we recently discovered that it drives basic IDPs into forming liquid condensates, leading us to hypothesize a new role for ATP, i.e., to keep IDP-nucleic acid condensates in a liquid state inside cells. Our in-cell studies will test this hypothesis. Protamine is a small IDP that replaces histones in the sperm nucleus and produces hyper-compaction of its chromatin, but the mechanism has been a puzzle. Our recent study using single-molecule force spectroscopy uncovered a piece of this puzzle, showing that protamine condenses DNA into “tangles” that can withstand forces that are strong enough to separate the two strands of DNA. Our in-cell studies will characterize the physical properties of protamine-driven tangles and other forms of condensates during the histone-to-protamine transition. Together, the planned research will advance fundamental biophysical understanding on multiple fronts, establish foundations for IDP- and condensate-based engineering, and uncover new opportunities for designing therapies.

NIH Research Projects · FY 2026 · 2016-01

Project Summary Staphylococcus aureus is a leading cause of nosocomial infection in the United States and is a predominant pathogen in communities. S. aureus survives during infection by subverting immune defenses and adapting to host-imposed nutrient restriction. Yet, we lack a unifying understanding of how these adaptations promote survival in the host. The work outlined in this proposal stems from our longstanding research on an essential cofactor required for metabolic enzyme function, lipoic acid (LA), which is a critical mediator of S. aureus growth and survival during infection. Our prior studies determined that differential scavenging and synthesis of LA promotes infection of host tissues and directly interferes with TLR2 signaling leading to reduced oxidative burst by innate immune cells. Furthermore, we recently defined a totally new pathway used by S. aureus to combat oxidative stress that converges on an accessory LA carrier protein and involves two post-translational modifications (lipoylation and ADP-ribosylation). These modifications are part of a molecular switch that responds to the redox state of the cell to protect LA from oxidative damage and promote rapid cellular recovery by using an ADP-ribose modification to regulate the delivery of reduced LA to metabolic enzymes. Thus, LA metabolism is critical for pathogenesis, oxidative stress responses, and metabolic homeostasis in the host, justifying further depth of study. This renewal application represents continued work to understand how S. aureus uses LA to promote infection. Our discovery of: (i) an entirely new mechanism to protect LA from oxidative damage; (ii) an unappreciated regulatory adaptation that favors LA salvage during infection; and (iii) a unique divergence in function for LA carrier proteins provides the foundation for our continued studies. This proposal will address major gaps in our understanding of the mechanics underlying (i) what regulates the switch between use of de novo synthesis of LA and salvage during infection (Aim 1); (ii) the precise mechanism by which Sa regulates LA redistribution and protects it from oxidative damage (Aim 2); and (iii) the convergence of lipoyl carrier proteins on LA synthesis, oxidative stress resistance, and glycine metabolism (Aim 3). Significant progress in the previous funding cycles leaves us poised to move forward in these new areas of research. The work has the potential to inform studies on other pathogenic Firmicutes, which all encode varied LA biosynthesis and salvage enzymes.

NIH Research Projects · FY 2025 · 2016-01

Bioengineering Experience for Science Teachers “BEST” Program ABSTRACT The Bioengineering Experience for Science Teachers at the University of Illinois at Chicago was first offered in 2016 to provide a collaborative summer research opportunity for Chicago Public School (CPS) pre-engineering and science teachers. Under the guidance of faculty from the College of Engineering and College of Education, teachers participate in a bioengineering research lab and use the experience to create a curriculum for their own classrooms. The goal of the BEST program is to enhance the skills of urban public high school science teachers and enable them to more effectively communicate the nature of bioengineering to their students. Teachers can choose among diverse research opportunities in rehabilitation engineering, bionanomaterials, biomedical imaging, microfluidics, biomaterials, and regenerative medicine. The BEST program places six teachers in bioengineering research laboratories and employs a Community of Practice model to support development of bioengineering curricula for use in the teachers’ classrooms. This proposal plan enhances the BEST program by expanding the analysis to evaluate curriculum improvement from a pre-program baseline, evaluating teachers in the classroom during curriculum implementation, and strengthened avenues for BEST teachers to disseminate their experience and curricula to a broader audience. The BEST program is scaffolded to support the development of appropriate teaching materials of bioengineering content which translates scientific knowledge into specific curriculum maps, instructional materials, and classroom assessments that are aligned with Common Core State Standards CCSS and Next Generation Science Standards NGSS. As it has been widely shown that teacher influence can be a significant factor in student career interests, the BEST program aims to provide effective professional development to increase teacher’s bioengineering content and pedagogical knowledge to ultimately increase the pipeline of bioengineers.

NIH Research Projects · FY 2026 · 2015-12

More than 230,000 women in the US will be diagnosed with breast cancer and nearly 40,000 will die from the disease annually. The majority of breast tumors express estrogen receptor α (ER), found in ~70-80% of all cases. Women with ER+ tumors typically receive endocrine therapy (ET), such as aromatase inhibitors or tamoxifen (TAM). While initial survival rates are generally good, it is estimated that ~40% of ER+ tumors will relapse, with almost half of these recurring after completing the standard 5 years of adjuvant ET. This risk for late relapse suggests that in many cases a population of tumor cells can persist or tolerate ET agents, only to contribute to relapse once ET is completed. This conclusion is supported by several studies showing that 10 yr of ET is superior to 5 yr. In studying how early responses to the selective pressure of ET might contribute to ET-tolerance, we found that activation of NFB was a common event in ER+ breast tumors of patients treated with neo-adjuvant ET, as well as in ER+ breast cancer cell lines, patient derived organoids, and xenografts. This activation appears to be the result of an expansion of NFB+ breast cancer cells that can proliferate and persist despite ET treatment. Importantly, inhibiting NFB prevents relapse, as determined by the lack of regrowth of cells and tumors once TAM treatment is terminated. Moreover, we found that a gene signature derived from ET-tolerant cells was associated with high tumor grade and increased risk of relapse in patients with ER+ disease. Based on these findings, we hypothesize that the selective pressure of ET allows for the expansion of NFB+, ET- tolerant cell populations and that targeting these populations therapeutically will prevent relapse and disease progression. To test this, we propose three aims: Aim 1. To define ET-tolerant cell populations in ER+ breast cancer models; Aim 2. To determine the mechanism of NFB regulation and action in ET-tolerance; and Aim 3. To investigate the consequences of targeting ET-tolerant cell populations. To address these aims, we will perform single cell RNA-seq on ET-treatment naïve preclinical models under the selective pressure of short-term ET and over time as adaptive resistance develops. We will then investigate the persistence of these populations in preclinical models of ET-resistance and validate our findings in human primary and metastatic tumors. We will also examine the hypothesis that NFB activity in ET-tolerant cells is a response to cellular stress caused by the selective pressure of ET, as well as a protective player in response to that cellular stress. In addition, we will use complementary genetic and small molecule inhibitors that inhibit the NFB pathway, as well as inhibitors of key NFB regulators and effectors, to test the role of ET-tolerant cells in relapse and disease progression, using both patient-derived tumors in immunocompromised mice and an immunocompetent mouse model. The successful completion of these aims will establish i) a novel role for NFB in promoting ET-tolerance and disease relapse of ER+ breast cancer, ii) mechanistic insight into the function of NFB in promoting ET tolerance, and iii) novel strategies to target ET-tolerant cells to prevent recurrence of ER+ breast cancer.

NIH Research Projects · FY 2026 · 2015-12

PROJECT SUMMARY Although there is growing consensus that diabetic retinal neurodegeneration (DRN) can precede clinically-apparent vascular abnormalities and may eventually be useful for staging diabetic retinopathy (DR), there is no agreement regarding how DRN is defined, staged, or which measures best reflect neural dysfunction in these individuals. Work completed during prior funding cycles, supported by other researchers, has shown that electrophysiological, psychophysical, and pupillometric approaches can provide sensitive, non-invasive, and quantifiable measures of DRN. However, prior studies that have measured functional consequences of DRN have generally been cross-sectional and performed under typical light- adapted clinical conditions. These studies provide little insight into important challenges reported by individuals with DR, including functioning under dim illumination and adjusting to changing illumination conditions. To address these limitations, we propose to develop and apply novel tools and approaches capable of characterizing the nature and extent of visual dysfunction and its relationship to DRN in individuals with mild or no DR (M/N DR). These approaches will evaluate visual function across a wide range of lighting conditions typical of daily life, assess the ability to adjust to changing illumination conditions, and will be performed longitudinally. Three complementary aims are proposed that use non-invasive tools to provide new views of retinal function under broad and varying levels of illumination: Aim 1 will define key pathophysiological changes in rod, cone, and post-receptor function in M/N DR; Aim 2 will develop and apply a battery of electrophysiological techniques to identify photoreceptor and downstream post-receptor dysfunction; Aim 3 will determine how M/N DR affects non-image- forming pathways. We will determine whether functional measures targeting the inner- or outer- retina show greater DRN progression and if either predicts ETDRS stage advancement. Completing these Aims will: 1) provide a novel framework using complementary approaches for assessing visual dysfunction and the underlying mechanisms in M/N DR, 2) introduce new tools and functional assays that can provide clinically-relevant indices of DRN that address common visual complaints of DR subjects, 3) permit comparisons among measures to define optimal tests of DRN with high diagnostic power. We expect these studies to drive significant advances in clinical DR staging and understanding of early neural deficits.

NIH Research Projects · FY 2024 · 2015-09

OVERALL – ABSTRACT The Chicago Cancer Health Equity Collaborative (ChicagoCHEC) is a comprehensive partnership to advance cancer health equity bringing together the synergistic strengths of two federally designated Hispanic Serving Institutions, the University of Illinois at Chicago (UIC) and Northeastern Illinois University (NEIU), with a world class NCI-designated comprehensive cancer center – the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (NU-LCC). ChicagoCHEC combines the attributes of these three exceptional institutions, each with robust capacity to interact with their urban-shared setting. Launched in 2015, ChicagoCHEC is dedicated to advancing cancer health equity through rigorous and innovative science, education, and outreach and engagement of Chicago’s underserved communities. This is reflected in the following goals: Aim 1. To strengthen a transformational alliance between UIC, NEIU, and the NU-LCC in pursuit of cancer health equity in Chicago; Aim 2. To initiate, conduct, and support innovative bench, translational, clinical, and prevention and control focused cancer research, with emphasis on cancer health disparities; Aim 3. To develop and implement cancer-related education and outreach activities generated with the engagement of underserved communities across Chicago; Aim 4. To coordinate research education and mentoring opportunities to recruit, retain, and advance a pipeline of underrepresented students in cancer research careers and to develop early career faculty who will forge independent cancer research careers; and Aim 5. To conduct ongoing rigorous evaluation of ChicagoCHEC activities. These goals are accomplished by a nurturing hub of four Cores (Administrative, Planning and Evaluation, Research Education, and Outreach) and a research project funding program. Since the launch of ChicagoCHEC in 2015, there has been rapid growth in collaborative infrastructure built across the three partnering institutions; enhanced cancer research engagement, capacity, and education; extensive community outreach and engagement; and encouraging advancement of ChicagoCHEC faculty and students. ChicagoCHEC projects and programs provided research experiences to 155 students, provided cancer research and leadership opportunities for 57 faculty (21 have been promoted/received tenure), and directly resulted in 94 peer-reviewed publications, 47 extramural grants submitted, and 24 grants awarded. ChicagoCHEC will leverage the momentum forged by the initial U54 award to drive innovative cancer research, research education, and community outreach and engagement that cuts across disciplinary and institutional boundaries. ChicagoCHEC will leverage its diverse team of faculty, students, and partners, connectivity to Chicago’s underserved communities, and guidance of internal and external advisory bodies. The next chapter will include two initial full cancer research projects and two initial pilot projects, continued support from four tri-institutional ChicagoCHEC Cores, and strong institutional commitment.

NIH Research Projects · FY 2024 · 2015-09

Gestational hyperglycemia and gestational diabetes (GDM) are associated with adverse pregnancy outcomes for mothers and newborns. Additionally, GDM, in particular, can also be detrimental to metabolic outcomes later in life. A large genetic study, ‘The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study’ previously identified a unique genetic association near hexokinase domain component-1 (HKDC1) to gestational hyperglycemia. This study has been confirmed by others and also shown to be associated with GDM. This grant renewal intends to continue our investigation of this important link to gestational glucose metabolism. The focus of this proposal is based on our data that HKDC1 interacts with the mitochondrial outer membrane protein, VDAC, in hepatocytes, where this interaction is disrupted when the amino terminus of HKDC1 is deleted. Further data shows that overexpression of HKDC1 in the liver improved glucose tolerance during pregnancy in mice and our data suggests that this results in a metabolic shift in the carbon flux toward anabolic pathways. Now, it is important to investigate the molecular basis of HKDC1 interaction with mitochondria and the impact of such interactions on mitochondrial morphology and function. Further, we expect that genetic variants contribute to GDM risk via HKDC1 expression, though the specific causal variants remain elusive. In sum, this proposal will mechanistically explore the role of HKDC1 in gestational glucose homeostasis and the genetic variants driving its expression in humans.

NIH Research Projects · FY 2024 · 2015-09

ABSTRACT Alcohol is one of the most widely used addictive drugs in adolescence, and continued use can lead to the development of psychiatric disorders, including alcoholism, in adulthood. Epigenetic processes, such as histone acetylation and DNA methylation mechanisms, have been shown to play a role in neuromaturation by contributing to the stability of gene expression during brain development. The Neurobiology of Adolescent Drinking in Adulthood (NADIA) consortium has revealed that adolescent intermittent ethanol (AIE) exposure produces epigenetic reprogramming in several brain circuits (prefrontal cortex, basal forebrain, hippocampus and amygdala) that persists until adulthood and might be responsible for adult psychopathology. These findings prompt determination of the global epigenome to determine AIE altered specific gene loci within key brain regions. The Epigenetic/Molecular Core is developed to evaluate epigenetic mechanisms in specific brain regions linked to key AIE phenotypes in adulthood. The Epigenetic/Molecular Core will also develop tools for CRISPR/dCas9 approaches for epigenetic editing of target genes to directly link AIE-induced behavioral phenotypes with molecular mechanisms. The objectives of the Core are to provide tools and scientific expertise to test NADIA’s hypotheses that perturbations of epigenetic targets due to AIE may lead to dynamic changes in epigenetic programming leading to transcriptomic changes in key brain areas (prefrontal cortex, amygdala, hippocampus, hypothalamus, and basal forebrain) which are responsible for persistent behavioral and molecular phenotypes in adulthood. These objectives will be achieved with the following proposed work: 1) To examine the status of the epigenome at the whole genome level. We will perform Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq) to determine the locations of open and closed chromatin domains in different brain regions studied across NADIA. The core will provide information on global chromatin states during AIE to each component and identify “hub” genes related to the component’s hypotheses for functional studies. 2) To determine gene specific AIE-induced epigenetic modifications (histone acetylation/methylation/DNA methylation) associated with changes in gene expression. 3) To provide gene specific CRISPR/dCas9 tools for NADIA components. The core will develop and test CRISPR/dCas9 technologies to make epigenetic editing (activating or silencing) at specific gene locations and evaluate both functional and behavioral consequences. These studies will provide a better understanding of AIE-mediated changes in gene expression via epigenetic reprogramming across NADIA components. In addition, we will be able to identify mechanisms that may lead to the development of novel treatment strategies for adult psychopathologies resulting from adolescent binge drinking.

NIH Research Projects · FY 2025 · 2015-08

Herpes simplex virus type-1 (HSV-1) is a herpesvirus known to cause long-term morbidities in the eye and serious vision problems. In our previously funded period, we discovered the high efficacy, unique mode of action, pharmacokinetics, safety, and superior antiviral properties of BX795 against HSV-1 in the eye. Our findings provided a new understanding of host protein targets involved in HSV-1 infection of the cornea. Through extensive transcriptomic and proteomic analyses of BX795, we uncovered a novel cell cycle regulatory mode of action with broader scientific implications beyond its antiviral properties. Due to our extensive studies, BX795 shows strong promise as a new topical antiviral for ocular herpes, and it can now be pursued for Phase 1 clinical studies. However, our studies also revealed an interesting challenge: BX795 failed to synergistically enhance other clinically relevant drugs, specifically nucleoside analogs like ACV and TFT, commonly used for ocular HSV- 1 infections. To address the scientific curiosity about whether a functional analog of BX795 can exhibit synergism with existing antivirals, we utilized our omics data, conducted in silico L1000 assay-based CMap predictions, and identified another small molecule, GW8150, as the closest functional analog of BX795. Our preliminary data demonstrated high efficacy, low toxicity, and, to our satisfaction, strong synergy with ACV and TFT. Thus, GW8150 presents a valuable new tool to study the pathways contributing to HSV-1 infection in the eye, understand why synergy was absent in BX795, and offer a potential candidate for topical or oral antiviral development. To achieve our goals, we have defined three specific aims for the competitive renewal period: first, to determine GW8510's antiviral action and its impact on corneal cells by analyzing Omics data and identifying interactions with corneal cell proteins and changes in cell proteomes; second, to assess the therapeutic benefits of topically delivered GW8510 in murine models of ocular HSV-1 infection, establishing it as a potent candidate for further development as an FDA approved antiviral for ocular indications; and third, to investigate GW8510's synergistic abilities in reducing ocular HSV-1 infection, potentially in combination with clinically approved drugs, with the aim of enhancing antiviral efficacy, improving treatment options, and exploiting transcriptomics and proteomics analyses to uncover the specific targets and pathways that underpin this synergistic antiviral action. Post-treatment corneal, as well as retinal health and associated vision functions, will be examined to determine the benefits (and/or any toxic effects) of drug administration. By completing these specific aims, we aim to gain valuable insights into ocular antiviral mechanisms, new proviral pathways targeted by GW8510, and develop more effective strategies to combat HSV-1 infections in the eye. This research holds promise for advancing our understanding and treatment of ocular herpes, improving patient outcomes, and contributing to the development of novel ocular antiviral therapies.

NIH Research Projects · FY 2024 · 2014-09

Erectile dysfunction (ED) affects ~ 50% of men aged 40 to 70 and has a high impact on men's health and quality of life. Current treatments are ineffective in the difficult to treat prostatectomy (16-82%) and diabetic (56-59%) patients due to injury to the cavernous nerve (CN), which provides innervation to the penis. With denervation the critical smooth muscle (SM) undergoes apoptosis and the penis becomes fibrotic, with increased collagen abundance and a change in subtypes, thus altering the architecture of the corpora cavernosa. This application is significant because we propose a novel integrative approach that targets the 3 main morphological changes that underlie ED, which are CN degeneration, SM apoptosis, and penile fibrosis. We've shown that sonic hedgehog (SHH) is a critical regulator of SM apoptosis in the penis and of CN regeneration. SHH pathway is of high interest as a candidate ED therapy because SHH regulates a critical nexus of pathways required to maintain erectile function. Our data in prostatectomy and diabetic patients shows altered morphology and decreased SHH protein in high fidelity to our rat ED model. In the rat SHH inhibition causes demyelination and axonal degeneration of CN fibers and CN crush decreases SHH protein 70% in the CN. SHH inhibition in the penis causes SM apoptosis and ED while CN crush decreases penile SHH. We show reversible penile remodeling with reestablishment of SHH signaling using two innovative peptide amphiphile (PA) delivery prototypes. In a crush model, SHH treatment of the CN (PA1) and of the penis (PA2) accelerates regeneration, improves erectile function >60%, suppresses apoptosis and preserves penile SM 56%. We will extend our observations to improve effectiveness of SHH delivery for maximal apoptosis suppression and CN regeneration in preparation for clinical translation (Aim 1), and design PAs that bind to SHH to fine tune release kinetics and duration in vivo in the penis (Aim 2). SHH PAs will be examined in an aged prostatectomy model that better simulates ED patient conditions (Aim 3). SHH PA is highly translatable for treatment of prostatectomy and diabetic patients by substituting human SHH protein for rat. SM apoptosis (2-7 days) occurs before increased collagen (7-14 days) in prostatectomy patients. We propose the innovative hypothesis that suppressing SM apoptosis can prevent the fibrotic response (Aim 4). Increased collagen is common in ED patients following prostatectomy. We show collagen abundance is responsive to SHH signaling (SHH inhibition increases collagen/SHH treatment decreases collagen), by an unknown mechanism. Microarray of corpora cavernosa from ED patients shows increased Gremlin 1, a BMP4 antagonist. SHH is a regulator of Gremlin in limb bud, Gremlin regulates fibrosis in lung, and BMP4 is inversely responsive to SHH during development. We hypothesize that reduced SHH that occurs in the penis with CN injury, up-regulates BMP4 leading to fibrosis (Aim 4). Understanding where intervention in the penile remodeling process will be effective to prevent ED is critical for development of novel therapies.