Virginia Commonwealth University

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY The goal of this project is to index individual resistance to psychoactive substance use (SU) during adolescence and use the indices to identify factors influencing resistance into early middle adulthood (30-40 years old), with a special focus on potentially modifiable factors. One possible cause for the limited success in reducing SU is a focus on factors that elevate risk for rather than resistance to SU. Although the risk and resistance aspects of liability to a disorder are symmetric, the respective factors are not. Factors enhancing resistance may more readily translate into prevention and treatment strategies. In addition, “environmental” variables, which are more likely to be modifiable than the genetic ones, may be confounded by the genetic influences. Failure to account for this confounding could hinder the detection of resistance factors. We address these limitations by measuring liability to SU/SUD in childhood/adolescence using previously collected and harmonizable data from the Virginia Twin Study of Adolescent and Behavioral Development (VTSABD; 1,214 twin pairs) and Minnesota Twin and Family Study (1,382 twin pairs), and assessing potential resistance factors. Long-term SU phenotype will be verified in a new wave of VTSABD data collection, where participants will be 30-50 years old. Aim 1. Develop continuous indices of resistance to SU and estimate genetic and environmental contributions to their variation. Two indices of SU resistance will be derived using a validated measure of childhood SU liability (Transmissible Liability Index) and SUD diagnosis in the same individuals as adults (verified in new Wave 7 SU data) to select psychological items measured in earlier waves. Two resistance indices will be generated via item response theory analysis: High Outset Resistance (based on items differentiating between low and average childhood SU liability) and High Realized Resistance (based on items distinguishing high and average childhood SU liability). Aim 2. Identify novel factors that have the highest probability of enhancing resistance to substance use. These factors will be sourced as most impactful on decisions related to substance use, using a Concept Mapping approach and existing data. Aim 3. Evaluate developmental trajectories of the resistance indices and SU outcomes while determining how these trajectories vary across levels of resistance factors. This will detail the influence of childhood/adolescent resistance on SU across the life course. This project will produce detail on potentially modifiable factors that can be targeted to reduce the likelihood of SU and addiction.

NIH Research Projects · FY 2025 · 2022-08

Despite decades of effort to reduce gaps in cancer care, some patients, particularly those in vulnerable populations, continue to die at higher rates from cancer. Because prevention is the key to the cost-effective and long-term control of cancer, the potential for cancer genetic counseling to play a central role in reducing cancer disparities is high. However, the benefits of genetic counseling are not equitable across all people. The overarching goal of this proposed research is to compare and contrast the nature of genetic counseling encounters and patient-centered outcomes across different patient populations in the naturalistic clinical setting. When patients and healthcare providers do not come from the same social backgrounds, the patients tend to have poorer quality patient-provider communication and receive suboptimal clinical recommendations. One major factor that contributes to these healthcare disparities is providers’ personal attitudes and beliefs. Drawing on findings from prior research, we hypothesize that genetic counselor providers’ attitudes that are activated spontaneously will be associated with the quality of patient-provider communication, while providers’ beliefs that are deliberately reported will be associated with the quality of clinical discussion of cancer risk and genetic testing depending on patients’ backgrounds. These disparities in encounters will be further associated with poorer patient-centered outcomes. We will test our hypotheses by addressing four specific aims: Aim 1) to compare/contrast the nature of patient-provider communication by patient characteristics; Aim 2) to compare/contrast the clinical discussion content by patient characteristics; Aim 3) to quantify the role of genetic counselors’ personal attitudes and beliefs in patient-provider communication (Aim 1) and clinical discussion content (Aim 2); and Aim 4) to quantify the role of patient-provider communication/clinical discussion content with patient-centered outcomes (trust, satisfaction, therapeutic alliance, empowerment, genetic testing uptake). These aims will be achieved through an observational study with a convergent mixed methods research design. We will analyze recorded cancer genetic counseling encounters both qualitatively and quantitatively, linking those data to data from pre- and post-encounter surveys and medical chart reviews. With COVID-19, many genetic counseling encounters have moved to telehealth, and telehealth is expected to continue to thrive beyond the pandemic. The proposed study will embrace this unique, transitional opportunity and addresses the overarching goal in the naturalistic clinical setting through multiple modalities (in-person, telehealth). Findings from this multi-center study will highlight specific aspects of cancer genetic counseling encounters (patient-provider communication and clinical recommendations) that are directly associated with patient-centered outcomes. Patient-provider communication and clinical recommendations are modifiable factors, and they are already being taught in genetic counseling training programs; thus, the findings can have immediate impact on genetic counseling training and practice.

NIH Research Projects · FY 2024 · 2022-08

PROJECT SUMMARY/ABSTRACT Anorexia nervosa (AN) is a serious illness with extremely high morbidity and mortality rates. Clearly efficacious treatments are lacking for adults with AN, especially during the post-acute stage following higher- level care (e.g., residential, partial-hospital program [PHP]). Most patients achieve symptom stability in intensive treatment, but up to 50% relapse and more experience residual or co-morbid (e.g., affective) symptoms after discharge. Appropriate outpatient treatment is often unavailable or inaccessible in this stage. Despite a rapid growth in the knowledge on the biobehavioral mechanisms promoting AN, this information has rarely been incorporated into treatment. One set of mechanistic targets increasingly acknowledged as relevant to AN are those of the reward system. The reward (a.k.a., positive affect or valence) system has been implicated in maintenance of myriad psychiatric disorders, including common AN co-morbidities (e.g., mood and anxiety disorders). A wealth of evidence, including our pilot data, suggests that individuals with AN show deficit reward sensitivity to experiences generally considered rewarding (e.g., social interactions, eating), similar to those with affective disorders. However, distinct from other psychiatric illnesses, individuals with AN also show elevated reward sensitivity to weight-loss experiences and cues (e.g., exercise, low-calorie foods). Starvation in acute AN appears to exacerbate these processes. However, these same problems affect weight- restored AN, suggesting they represent core illness mechanisms. Although reward anomalies have long been noted in the literature, currently no treatments for AN designate positive affect as a primary intervention target. To remedy this gap, we will test whether a remotely-deployed psychosocial treatment targeting positive affect, Positive Affect Treatment (PAT), can alter reward mechanisms and enhance treatment outcomes in post-acute AN. PAT is a cognitive-behavioral therapy originally designed to treat mood and anxiety disorders and adapted by our team to target reward anomalies in AN (PAT-AN). Our pilot data suggest that PAT-AN, delivered in person or via teletherapy, effectively targets positive affect and reward sensitivity to improve BMI and eating disorder, anxiety, depressive symptoms. We will extend this investigation to the post-acute period of AN, during which we expect to even more effectively engage the reward system, due to the removal of the biological constraints of starvation. Adults with broadly-defined AN (N = 70) leaving residential or PHP will be randomized to 24 weeks of PAT-AN or active control (psychoeducation and behavior therapy) as adjunctive to treatment as usual. Treatment will be delivered via the highly accessible and scalable format of teletherapy. Throughout treatment and follow-up, subjects will complete a novel multimodal battery (e.g., mobile-delivered and neurocognitive measures) assessing measuring reward sensitivity and clinical symptoms. This project will allow us to precisely test wither an innovative therapy informed by biobehavioral mechanistic science can, for the first time, directly target the reward disruptions long believed to contribute to post-acute AN.

NIH Research Projects · FY 2025 · 2022-08

Project summary: Lyme disease is the most common tick-borne disease in the northern hemisphere. The incidence of Lyme disease is steadily increasing as the Ixodes tick population expands. This proposal will identify the critical functional determinants of outer surface protein C (OspC), an essential virulence factor. In addition, we will determine how sequence variation in OspC influences infectivity and dissemination properties. Cutting edge genetic approaches will be employed to dissect the role that OspC plays in the pathobiology of the Lyme disease spirochetes. The outcome of these analyses will also advance ongoing efforts to develop vaccines and diagnostic antigens for use in humans.

NIH Research Projects · FY 2025 · 2022-07

PROJECT SUMMARY/ABSTRACT The public health success of FDA’s proposed ban on menthol cigarettes hinges upon whether menthol smokers who are unable to quit smoking switch to non-menthol cigarettes (no public health gain) or to potentially lower harm alternatives like heated tobacco products (HTP). In 2019, FDA authorized an HTP called “IQOS” and its tobacco- and menthol-flavored “HeatSticks” (HS) as a modified risk tobacco product (MRTP). One issue relevant to FDA’s future action regarding IQOS will be “whether and how certain flavors may help adult cigarette smokers reduce cigarette use and switch to potentially less harmful products” (FDA, 2018). Understanding the potential for HTPs like IQOS to reduce the health burden of cigarettes requires targeted research investigating the extent to which flavor availability is important for menthol smokers to switch to HTPs. For one tobacco product to substitute for another, their abuse liabilities should be congruent. Validated clinical lab methods exist for comparing tobacco product abuse liability by characterizing their nicotine delivery profiles (via plasma nicotine and puff topography) and reinforcing efficacy (via subjective and behavioral measures). Naturalistic assessment can validate clinical lab results regarding use patterns and product substitution. The current study involves a two-arm, two-week, parallel group trial. The first week is an own brand (OB) menthol cigarette baseline, during which tobacco use will be assessed daily using ecological momentary assessment (EMA). On Monday and Friday, participants will complete clinical lab sessions that involve using OB cigarettes and responding to subjective measures and an Experimental Tobacco Marketplace (ETM) task that assesses willingness to substitute menthol cigarettes with an array of tobacco products including IQOS. During the next week, participants will be randomized to receive IQOS-menthol (n=25) or IQOS-tobacco (n=25); EMA and clinical lab visits will be repeated. Aim 1 assesses IQOS’ abuse liability in a clinical lab setting. Outcomes include plasma nicotine levels, puffing behavior, responses about subjective effects, and product substitution from the ETM task. Aim 2 measures tobacco use patterns in naturalistic settings where participants will report daily OB and IQOS use outcomes via EMA. The overarching hypothesis is that, relative to OB, IQOS-menthol’s abuse liability profile will differ less than IQOS-tobacco’s, suggesting that menthol smokers will be more likely to substitute an HTP for combustible menthol cigarettes when a menthol-flavored HTP is available. Results will deepen our understanding of the public health impact of HTPs and policies that might restrict access to menthol-flavored MRTPs. Moreover, this application describes an excellent research environment for the proposed work, supported by a collaborative mentorship team with relevant expertise. Resultantly, the applicant will learn new skills in clinical lab assessments of tobacco products, behavioral pharmacology, clinical trials and translational research, addiction medicine, and professional development. This training will be invaluable towards the applicant’s goal of becoming an independent physician/scientist.

NIH Research Projects · FY 2026 · 2022-07

PROJECT SUMMARY / ABSTRACT For youth with type 1 diabetes (T1D), the transition into young adulthood is a high-risk period for deteriorations in glycemic control. T1D self-management, a key driver of glycemic control, is complicated by the transitional nature of this developmental period, which is associated with changes in multiple domains (i.e., biological, social, and environmental). Evidenced-based transition preparation interventions are needed prior to initiating adult healthcare to improve T1D self-management and glycemic control and increase transition readiness; however, evidence from rigorous trials is limited. To address this gap, we developed and conducted a single-arm pilot of SHIFT, a multisystem transition preparation intervention. Preliminary data from this pilot informed the current application, which proposes to conduct a randomized controlled trial (RCT) of a clinic-based transition preparation intervention (SHIFT2) for adolescents and young adults (AYAs) with T1D. Fifty AYAs (16-22 years) and a parent will be randomized to either: 1) a 6-month multisystem transition preparation program (SHIFT2), or 2) enhanced treatment as usual (TAU+). TAU+ includes usual T1D care, provider training, and standard patient education, matched to the intervention contact schedule. SHIFT2 will employ a hybrid delivery mode for intervention visits using clinic staff (Certified Diabetes Care and Education Specialists [CDCES]) and hospital- based technology platforms (e.g., virtual visits, patient portal). AYAs will receive evidence-based content across 3 domains: psychoeducation/skill building, behavioral self-management, and provider communication. Parents will receive psychoeducation and training in developmentally appropriate parenting strategies to support their AYA in increasing independent self-management and preparing for transition. Providers will receive a video module that highlights their role preparing AYAs for transition and provides evidence-based, practical tips to enhance communication with AYAs. In order to understand key stakeholders’ experiences regarding transitioning to adult care, qualitative interviews with a subset of AYAs who transitioned to adult care and their parents (n=20 AYA-parent dyads) and with providers (n=10 endocrinology providers and CDCES), will be conducted to inform further protocol refinement for future studies. This application has compelling scientific and clinical significance. It improves upon prior research via use of a rigorous RCT design, evidence-based intervention components within a multisystem framework, and objective assessment of the primary outcome (HbA1c). Findings will advance science and inform clinical recommendations regarding optimal strategies to promote independent T1D self-management in AYAs prior to transitioning to adult care. .

NIH Research Projects · FY 2025 · 2022-07

Abstract Background: Sleep disturbances, particularly insomnia, are prevalent in cancer patients undergoing chemotherapy. Our clinically based Brief Behavioral Therapy for Cancer-Related Insomnia (BBT-CI) is a new approach for treating insomnia symptoms during cancer care and can serve as a model for other behavioral interventions during medical treatment. Our design allows us to capture patients just as they are developing insomnia symptoms, but before their problems become chronic and require more intensive intervention. Our behavioral intervention is innovative because we can deliver it in tandem with patients’ biomedical treatments, at the bedside, which significantly reduces patient burden. BBT-CI is a brief (2 face-to-face meetings, four 15-minute phone calls), feasible and acceptable intervention that has shown promise in reducing insomnia and other cancer-related side effects and in improving circadian rhythms at four community oncology clinic sites. Methods: The proposed project will test the efficacy of a novel BBT-CI in multiple private practice clinical oncology settings (n=20) across the country through the University of Rochester Cancer Center NCI Community Oncology Research Program (NCORP). We propose to randomize 400 cancer patients receiving chemotherapy to either BBT-CI or Healthy EAting Education Learning for healthy sleep (HEAL). Our HEAL control condition has been tested in our preliminary trial and is matched to BBT-CI for time and attention while excluding active components of the BBT-CI intervention (i.e., stimulus control, physical activity, circadian entrainment). The proposed innovative study will: 1) test the efficacy of a novel BBT-CI intervention in a community setting (NCORP network), 2) train nurses and clinical assistants to deliver the intervention in the infusion clinic, making it easier to disseminate in the future, and 3) elucidate the psychophysiology of insomnia and treatment response by collecting physiological circadian and autonomic nervous system markers. The proposed study aims to change the paradigm of how behavioral treatments can be delivered by creating and delivering the intervention in tandem with acute cancer care.

NIH Research Projects · FY 2025 · 2022-07

Project Summary Doxorubicin (DOX) chemotherapy regimens play a prominent role in many cancer treatments. With long term cancer survivorship, a substantial population of cancer patients remain at risk of early cardiovascular morbidity and mortality due to DOX chemotherapy. Moreover, clinical studies have revealed that sequential treatment of DOX with the ErbB2 inhibitor, Trastuzumab has synergistic effects in improving the control of cancer progression and survival in breast cancer patients, and is better than either drug alone. However, the combination therapies with the ErbB2 inhibitor coupled with DOX cause severe and aggressive form of heart failure. To overcome this clinical problem, we propose a novel combination therapy with PDE5 inhibitor, sildenafil (Viagra) and mTOR inhibitor, rapamycin in preventing the severe cardiotoxicity caused by DOX and DOX with sequential use of Trastuzumab in breast cancer-bearing mice. We will evaluate the therapeutic effect of sildenafil and rapamycin on DOX-induced cardiomyocyte death in vitro and cardiac function in vivo. In addition, we will determine the role of inflammation in the development of cardiotoxicity by measuring the expression of TLR4, NLRP3 and pro-inflammatory cytokines including IL-1β and IL-18. The role of cGMP-dependent protein kinase G (PKG) activation and mTOR inhibition with associated downstream signaling pathways in protecting against DOX-induced cardiac dysfunction will be studied. We will also investigate the effect sildenafil and rapamycin treatment in potentiating the anti-tumor efficacy of DOX and DOX with Trastuzumab and improvement of cardiac function in the clinically relevant mouse models of spontaneous and orthotropic breast cancer. Furthermore, we will determine the effect of sildenafil and rapamycin in attenuation of hypertrophy in cardiac specific ErbB2 transgenic mice. Because sildenafil and rapamycin are clinically approved drugs, the proposed studies may help in developing novel combination therapy for treatment of thousands of cancer patients experiencing the lethal and debilitating cardiotoxic effects of DOX and Trastuzumab worldwide.

NIH Research Projects · FY 2025 · 2022-07

The NIH Physician Scientist Workforce Working Group was convened to address a growing demand for and decreasing supply of physician researchers. The Group concluded that MD-PhD programs, including the Medical Scientist Training Program (MSTP), have been successful in promoting the development of physician-scientists and should be continued. The VCU MD-PhD program has been addressing this shortfall since 1986. Our mission is to train physician-scientists to improve human health through discovery in basic and social sciences and biomedical engineering. Our program objectives are Excellence in Clinical Training, Excellence in Research Training, Program Quality and Satisfaction, and Career Success. In the past four years, our recruitment efforts and growing pool of qualified applicants have greatly enhanced our ability to enroll highly qualified trainees. Our uniquely integrated curriculum is tailored to meet the needs of physician-scientist trainees, with clinical and research learning integrated over the entire training period. We promote rigorous, transparent, reproducible research methods, founded in ethical principles of responsible conduct throughout training. Our training program is centered on the trainee, with transparent leadership and trainee input. Our participating faculty members represent a broad spectrum of biomedical science disciplines and are supported by ample research funding. Our program is committed to mentorship training and a safe and supportive environment. Our governance structure has a prominent role for students and a faculty steering committee to assist our experienced leadership team to continuously improve the program. We closely monitor the progress of individual trainees, support their efforts and wellness, and address their concerns. A detailed, trainee-centered evaluation plan guides us to achieve our objectives with specific, measurable, attainable, relevant, and time-bound goals. Our recent trainees have been highly productive, securing individual training grants, publishing original research, and graduating to top research-intensive residency programs. We are on an upward trajectory in virtually every metric that can be used to assess program quality. As our trainees succeed, our ability to attract highly qualified applicants continues to grow, perpetuating a virtuous cycle. The VCU MD-PhD program is the largest physician scientist program in the country that provides full support for all its trainees but is not funded by an MSTP. Support from the VCU School of Medicine has been extremely generous. In addition, our program has benefited from philanthropic outreach that resulted in a $4M endowment and a $100K enrichment fund. With MSTP funding, we seek to leverage this exemplary support and our superior program plan to increase the number of trainees to whom our mission applies, expanding our ability to reduce the physician-scientist shortage.

NIH Research Projects · FY 2026 · 2022-06

The goal of the Virginia Commonwealth University (VCU) Building Interdisciplinary Research Careers in Women’s Health (BIRCWH) Program is to provide a structured environment that promotes the development of junior faculty researchers into independent scientists with a commitment to interdisciplinary research benefitting the health and well-being of women and men across the lifespan. VCU is a national leader in women’s health with robust research on the extent to which sex as a biological variable influences health, and it offers extensive and varied opportunities and support for training and research in these areas. The BIRCWH Program will recruit promising early-career faculty candidates and implement a novel, interdisciplinary mentoring approach matching scholars with a team of mentors who will bring varied perspectives to the scholars’ research and career development; design and implement a structured, personalized education and training plan to develop scholars knowledgeable about women’s health and the influence of sex as a biological variable who are proficient in study design and conduct, data analysis, and publication in accordance with best regulatory and ethical practices; and connect scholars with other researchers and clinicians from across VCU as well as from other universities and with community partners to encourage interdisciplinary, scientifically rigorous, clinically relevant research on women’s health and sex as a biological variable. With a focus on the five areas of Cancer, Maternal-Child Health, Mental Health and Addiction, Neuro-Musculoskeletal Health, and Obesity and Cardiovascular Health, the program will leverage the expertise of VCU’s exceptional women’s health researchers to train junior researchers in areas that are particularly relevant to women’s health and the study of sex as a biological variable. The VCU BIRCWH Program will be directed by an interdisciplinary team of internationally acclaimed women’s health researchers and administratively housed in the VCU Institute for Women’s Health, providing an environment that supports focused training and research that transcends any single school or discipline. Women and men scholar candidates will be recruited from a rich pool of qualified faculty both within and outside VCU. Three scholars at a time will receive salary support, related research and career development funds, and an individual career development plan (IDP) through the BIRCWH Program. VCU has a long-standing commitment to women’s health research and practice and a coordinated agenda to train interdisciplinary researchers. The VCU BIRCWH Program will provide a unique setting to develop a new generation of interdisciplinary investigators trained to improve the health of women and men by better understanding the role of sex as a biological variable in disease risk, clinical manifestations, treatment, and outcomes as well as in health and health care delivery.

NIH Research Projects · FY 2026 · 2022-06

Project Summary The main goal of this grant proposal is to investigate the interaction between regulatory T (Treg) cells and reactive astrogliosis in the context of brain metastatic disease, and their impact on the brain metastatic process. Brain metastasis represents the final stage of cancer, for which very limited treatment is available. Inevitably, patients with brain metastasis succumb to disease in a very short time. There is a strong resistance to the initial development of brain metastasis, and the activation of astrocytes represents one of the earliest events observed during the establishment of brain lesions. Their dual role first opposing and then favoring brain metastatic progression has only started to be investigated. Treg cells colonize and expand in the inflamed brain tissue, and have been shown to inhibit reactive gliosis in a model of stroke. We have demonstrated that Treg cell ablation in early and late brain metastasis results in significant reduction of the brain tumor burden, and leads to extensive expansion of reactive astrogliosis. In this research proposal, we use a combination of in vivo genetic modeling, ex vivo brain organotypic slice cultures, immunohistochemistry, flow cytometry, and single cell RNASequencing to investigate the hypothesis that Treg cells promote the establishment and progression of brain metastasis by modulating the highly heterogenous and plastic reactive astrocyte population. Results from the proposed studies will illuminate the mechanisms of brain metastatic disease, and will provide novel opportunities based on a largely unexplored therapeutic niche.

NIH Research Projects · FY 2026 · 2022-06

Neuroinflammation has been recognized as an essential player in the pathogenesis of Alzheimer’s disease (AD). Recently, the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, a multimeric protein complex that tightly regulates the innate immune responses, has been suggested with critical roles in AD development and progression. Dysregulation of the NLRP3 inflammasome is responsible for the over production of pro-inflammatory interleukin (IL)-1β and IL-18, ultimately leading to inflammatory responses and cell death. Thus, NLRP3 inflammasome represents an attractive drug target for AD and offers promise to provide effective disease modifying potential. Over the past several years, our team has successfully developed novel small molecule NLRP3 inflammasome selective inhibitors (NSIs). We originally reported NSIs with sulfonamide containing chemical scaffolds, and have established a small molecule library containing > 200 compounds with various biological characteristics. Proof of concept studies of our 1st generation lead NSI in transgenic AD mouse models demonstrated target engagement and in vivo efficacy to reduce neuroinflammation and improve cognitive functions. Our recent medicinal chemistry campaign led to the identification of new lead NSIs with significantly improved potency and binding affinity. Furthermore, our accumulated structure-activity relationship (SAR) studies have identified key structural features of the scaffolds for further optimization. The central hypothesis of this proposal is that structural optimization of the current two preclinical lead NSIs will be achieved by designing new viable analogs and isolating potent and orally available NSIs with improved pharmacokinetic (PK) properties (Aim 1), and that pharmacological suppression of the NLRP3 inflammasome by our NSIs will mitigate neuroinflammation and improve cognitive functions in preclinical AD animal models (Aim 2), which will be further evaluated by preclinical Investigational New Drug (IND)-enabling studies (Aim 3) to advance to clinical studies. For our hypothesis, the goal of this application is to accomplish preclinical IND-enabling studies on at least one candidate NSI and prepare for a meeting with the FDA and subsequent IND filing. Three aims are proposed to achieve our objectives. In Aim 1, new analogs of the lead NSIs will be designed, synthesized and biologically characterized to build a dynamic drug discovery and development pipeline. In Aim 2, selected NSIs from aim 1 will be tested for PK/PD properties in various animal models including AD mouse models. In aim 3, the top candidate NSI identified from Aim 2 will be subjected to IND-enabling studies including GMP production, GLP toxicology studies in rodents and dogs, and oral formulation development to prepare for IND filing and clinical trials. The proposed research is highly significant because we are developing a novel class of NSIs that will offer great promise to provide novel and effective therapeutics for AD, a devastating neurodegenerative disorder without cure currently.

NIH Research Projects · FY 2024 · 2022-05

PROJECT SUMMARY/ABSTRACT The focus of this study is on early life factors and their effect on mammary development during puberty and how they relate to increased breast cancer risk. At this time we do not understand what biological changes occur during pubertal mammary development which leads to a greater risk of developing cancer in later life. Identifying the molecular mechanisms that cause aberrant pubertal mammary development may lead to defined strategies to reduce breast cancer burden in later life. As our bodies use the sugars that we consume for energy they generate waste chemicals known as metabolites. One such group of metabolites is known as advanced glycation end products or AGEs for short. Critically apart from their production as a result of the breakdown of sugar, AGE’s are also formed through the ingestion of food and by external environmental factors such as lack of exercise. Changes in this dynamic equilibrium causes protein dysfunction, protein crosslinking, decreased genetic fidelity, altered gene expression profiles and aberrant cell signaling. Our studies have identified in animal models that a diet high in AGEs significantly alters how the breast develops during puberty. The tumor microenvironment is now becoming recognized as having a major role in facilitating both mammary development and cancer progression, and that, alterations in stromal cell signaling can precede epithelial cell alterations and act as drivers of the tumorigenic process. Critically, the high AGE diet produces architecture in the breast that resembles pre-neoplastic lesions with hyper-proliferative structures and increased levels of stromal cells. We also show that AGE levels are significantly elevated in the circulation and tumor tissue of breast cancer patients and that AGE treatment alters cancer associated signaling pathways to promote breast tumor growth. This study aims to define the mechanism by which a high-AGE diet causes the dysregulation of the mammary gland during puberty (SA1) and adulthood (SA2) and will ask if the changes observed lead to a higher risk of breast tumor formation and growth (SA3). A greater mechanistic understanding of the link between AGE intake during puberty and increased breast cancer risk may define novel potential strategies for lifestyle and pharmacological intervention aimed at reducing breast cancer risk at a defined window of susceptibility.

NIH Research Projects · FY 2026 · 2022-05

This project seeks to further the understanding of the genomic etiology of alcohol use disorder (AUD). Genetic studies have identified loci associated with the disorder; however, the genetic architecture of AUD has not been fully explained. Currently, genome-wide variant data of the disorder are available for analysis, and functional genomic datasets are being generated from consortia. Sequencing data from biobanks would allow assessment of the contribution of coding and functional non-coding regions to AUD risk by using a proxy phenotype from the information of the Alcohol Use Disorder Identification Test (AUDIT) report. Prior work has shown that 1) AUD has a high genetic overlap with some neuropsychiatric disorders (NPDs), and 2) common-variant studies identify biological pathways associated with the disorder. Therefore, integrative analyses which incorporate multi-omics datasets and overlapping genetic information can help identify additional loci associated with the disorder. Thus, the candidate plans to use integrative methods to 1) increase power for genetic discovery, and 2) better understand the genomic architecture for AUD. AUD has a high genetic correlation with the AUDIT-based phenotype (AUDIT-P) which assesses the problematic consequences of drinking. AUD and AUDIT-P have similar genetic correlations with other NPDs. Multiple AUDIT-P datasets are publicly available, and a recent meta-analysis of AUD and AUDIT-P datasets shows increased statistical power for risk loci identification. For this reason, this proposal centers on identifying the genomic association for problematic alcohol use which includes AUD itself and/or AUDIT-P. To achieve this research goal, the candidate proposes the following aims. First, he plans to extend his previous methods to jointly analyze rare exonic variants and other omics datasets. Second, he will develop methods to integrate common variants, omics information and genetic overlap information to increase power for multi-trait analysis. Third, he proposes an integrative method to analyze rare variants from whole-genome sequencing data. Fourth, he will apply these methods to analyze large-scale variant and functional-genomic datasets. He plans to use systems biology approaches to elucidate analysis results from these methods. Also, he proposes using genetic model organisms (C. elegans) to better understand the results from computational approaches via RNA interference and CRISPR-Cas9 experiments. Dr. Nguyen has a background in mathematics, statistics and statistical genetics; however, he has not had prior experience in the field of genetics of AUD. The mentor team including leading experts in the field will help him to 1) gain expertise in the basic principles of psychopathology, alcohol related phenotypes, the nosology of NPDs and alcohol related phenotypes; 2) acquire understanding of genetic model organisms, RNAi and CRISPR-Cas9 experiments for validation of computational results; 3) gain expertise in additional types of omics data; and 4) develop needed independence in his career. These training goals will aid him in successfully conducting the proposed work, and building a NIH-funded translational research program focused on AUD and its comorbid conditions.

NIH Research Projects · FY 2025 · 2022-05

ABSTRACT The “magnificent seven” human sirtuins play critical roles in various cellular processes including DNA repair, gene silencing, mitochondrial biogenesis, insulin secretion and apoptosis. They regulate a wide array of protein and enzyme targets through their NAD+-dependent deacetylase activities. Sirtuins are also thought to mediate the beneficial effects of low calorie intake to extend longevity in diverse organisms from yeast to mammals. Small molecules mimicking calorie restriction to stimulate sirtuin activity are attractive therapeutics against age-related disorders such as cardiovascular diseases, diabetes and neurodegenerative diseases. Little is known about one of the mitochondrial sirtuins, SIRT5. SIRT5 has emerged as a critical player in maintaining cardiac health and neuronal viability upon stress, and functions as tumor suppressor in a context specific manner. Much has been debated about whether SIRT5 has evolved away from being a deacetylase because of its weak catalytic activity, especially in the in vitro testing. We have, for the first time, identified a SIRT5-selective allosteric activator, nicotinamide riboside (NR). It can increase SIRT5 deacetylation efficiency with different synthetic peptide substrates as well as its endogenous cognate substrate. However, the deacylase activity of SIRT5 is insensitive to NR activation. Mechanism of activation will be further explored in three specific aims. In aim 1, our effort will be directed at the elucidation of structural determinants required for the differential NR sensitivities and the identification of allosteric binding site. In aim 2, target engagement and activation of SIRT5 in response to activator treatment in the cellular context will be investigated. In aim 3, several series of SIRT5 activators will be synthesized based on our initial screening, structure-activity relationship analysis and docking studies using a combination of chemical and enzymatic strategies. The knowledge gained in the proposed study will not only clarify our understanding of the biological functions of SIRT5, but also lead to new therapeutics for metabolic disorders and age-related diseases.

NIH Research Projects · FY 2026 · 2022-03

Project Summary This application is for a Mechanistic Clinical Study (R01) entitled “Prevention of HF with IL-1 blockade: a mechanistic study” submitted by Antonio Abbate MD, PhD and Benjamin Van Tassell, PharmD. Despite improvements in early diagnosis and treatment, ST-segment elevation myocardial infarction (STEMI) remains a leading cause of morbidity and mortality in the US. Patients with STEMI are significantly increased risk for developing heart failure. While numerous studies have identified inflammation as a risk factor for heart failure, there are currently no anti-inflammatory therapies with a documented benefit in patients with STEMI. Among the different inflammatory mediators, Interleukin-1 (IL-1) occupies a central role, not only because it is a key mediator of systemic inflammation (i.e. fever) but also because IL-1 is sufficient to cause significant depression of cardiac function, impaired cardiac reserve, and worsened cardiac remodeling in acute myocardial infarction. In a recent study, treatment with anakinra (recombinant IL-1 receptor antagonist) in patients with STEMI significantly blunted the acute systemic inflammatory response and fewer patients treated with anakinra developed heart failure during the following year. This application will confirm and expand these findings by studying the mechanism by which IL-1 blockade with anakinra may prevent heart failure. We propose the IL-1 blockade with anakinra preserves cardiorespiratory fitness through cardiac diastolic/systolic reserve, affecting quality of life, and incidence of heart failure in patients with STEMI. We propose to conduct a randomized, double-blind, placebo- controlled, phase II clinical trial (n=84) with 1:1 allocation to anakinra or placebo for 14 days among patients with acute STEMI and state-of-the-art cardiopulmonary exercise testing, cardiac imaging with Doppler echocardiography and cardiac magnetic resonance, biomarkers and quality of life assessments up to 12 months.

NIH Research Projects · FY 2026 · 2022-03

Project Summary Suicidal thoughts and behaviors (STB) are substantially impacted by genetic factors. However, molecular genetic studies of suicidality, and their genetically informative epidemiologic counterparts, have historically been statistically underpowered, precluding substantive interpretation of the effects of genetic influences in a developmental or psychosocial context. Recent advances include well-powered genomewide association studies alongside twin/family modeling of Swedish national registry data on (non-fatal) suicide attempt and death. The clear signals observed in these studies provide initial insight to the genetic etiology of suicidality, including: (i) suicide attempt and death are substantially, but not entirely, genetically correlated, raising the possibility that genetic liability underlying these distinct outcomes may be differentially related to risk pathways; (ii) the qualitative and quantitative nature of genetic liability to suicidality shifts across the life course; and (iii) genetic influences underlying suicidality are likely related to multiple behavioral correlates of risk, notably behavioral disinhibition and depression. Additional gene identification studies are essential to further elucidate the molecular nature of suicidality. However, to fully characterize how genetic liability manifests into STB, gene-finding studies must be complemented by research efforts that address the relationship between aggregate genetic risk and distinct STB outcomes, STB occurring during different periods of development (e.g., adolescence versus adulthood), key behavioral mediators, and environmental precipitants. The current proposal will address this critical knowledge gap through the incorporation of aggregate genetic risk scores for suicide attempt or death into models of psychosocial risk for STB. We will implement our research aims in a range of target samples selected for the unique perspectives they enable: (i) They span the life course, from childhood to late adulthood (and through death in the case of national Swedish registries); (ii) several include longitudinal assessments; (iii) they are densely phenotypically characterized, with data available on multiple STB (e.g., ideation, plans, attempts), behavioral mediators, and environmental risk factors; and (iv) they include five population-based studies, enabling us to expand our understanding of STB etiology outside of highly selected samples, along with two samples ascertained for history of major depression, enabling us to assess whether pathways of risk to STB are consistent across groups, and whether genetic liability to suicidality is superseded by the powerful clinical context of depression. The assembled team’s complementary areas of expertise are ideally suited to successfully implement the research aims. The proposed analyses leverage the aforementioned recent advances in the genetics of suicidality while enabling unparalleled and critical context for understanding the complex and dynamic pathways to suicidal thoughts and behaviors.

NIH Research Projects · FY 2026 · 2022-02

Scrub typhus is an emerging and potentially fatal global health threat. Approximately one million new cases are reported annually. The etiologic agent is Orientia tsutsugamushi, an obligate intracellular bacterium that infects leukocytes and endothelial cells resulting in vascular collapse, organ failure, and death. Treatment options are limited and no preventative vaccine exists. The success of O. tsutsugamushi as a pathogen lies in its ability to modulate host immunity and other pathways. The responsible mechanisms are unknown, highlighting the need for a better understanding of scrub typhus host-pathogen interactions. The ankyrin repeat (AR) is a protein- protein interaction motif that is prevalent throughout nature. O. tsutsugamushi has one of the largest arsenals of AR-containing effectors (Anks) among bacteria and expresses all of them during infection, underscoring their importance for intracellular survival and virulence. Most Orientia Anks carry a C-terminal F-box motif that co-opts host ubiquitin ligases. We discovered that O. tsutsugamushi Ank1 and Ank6 impede the NF-κB pathway in an AR- and F-box-dependent manner. Both bind and prevent the degradation of host NF-κB inhibitor, p105. Ank1 and Ank6 ARs mimic those of EPRAP, a host protein that stabilizes p105, and ubiquitinate Crybg3, a host kinase that influences p105 stability. Further screening revealed that a total of 13 Anks antagonize NF-κB, some of which bind p105 and others do not. Thus, multiple Anks inhibit NF-κB by distinct, overlapping mechanisms. We found that O. tsutsugamushi lowers MHC-I levels by orchestrating proteasomal degradation of NLRC5, a transactivator of MHC-I gene expression, and linked this phenomenon to Ank5. How Ank1, Ank5, and Ank6 inhibit innate and adaptive immunity is poorly characterized. We established that Orientia Anks alter the host cell ubiquitome, but the extent of this strategy, identity of modified targets, and infection outcomes are unexplored. Finally, other Anks target unknown eukaryotic pathways that also likely influence O. tsutsugamushi pathobiology. To fill these knowledge gaps, we will decipher the mechanisms by which Anks inhibit NF-κB and use two innovative screens that circumvent O. tsutsugamushi genetic intractability as part of our approach (Aim 1); dissect how Ank5 promotes NLRC5 degradation to block MHC-I expression (Aim 2); and identify new host cell pathways and ubiquitome changes that Anks modulate (Aim 3). The contribution of each newly discovered host- Ank interaction to O. tsutsugamushi pathogenesis will be interrogated. Overall, we will advance fundamental understanding of O. tsutsugamushi-host interactions, define novel mechanisms by which intracellular pathogens modulate immunity, identify new scrub typhus therapeutic targets, and benefit the bourgeoning concept of designed AR proteins as biomedicals to have a broad and powerful impact.

NIH Research Projects · FY 2026 · 2022-01

This new R25 program is designed to engage undergraduate students in multi-disciplinary translational cardiovascular research directed toward the diagnosis, treatment and prevention of cardiovascular disease (CVD). Broadly, there is a general decline in individuals pursuing CVD research careers with fewer individuals seeking post-doctoral positions and ½ of CVD researchers leaving science within five to 10 years of their first publication – as recognized by the NHLBI task force review of research training and career development programs. This program is designed to involve undergraduate students in multi-disciplinary research activities to reduce the burden of CVD. Our 5-year proposal will enroll 12 sophomore students each year into a multi-year commitment that combines the summer research stipend from this proposed NIH award with an educational curriculum supported by each student’s undergraduate institution of higher learning in Virginia and the research strengths of Virginia Commonwealth University (VCU) – including an NIH Clinical and Translational Science Award and the VCU Pauley Heart Center. Key features of this proposed R25 program include: 1) pairing each trainee with a funded research mentor whose research focuses on CVD; 2) outstanding multidisciplinary faculty who are seasoned mentors; 3) access to multiple phenotypic and biologic materials from major NIH-funded basic science, prospective cohort, or clinical trials at VCU through the supporting program faculty; 4) courses provided by the existing undergraduate, graduate, and medical school faculty to supplement areas of CVD research not previously experienced by students; and 5) two institutional seminar series that enhance interactions with other students and individuals from multiple disciplines. Motivated teaching faculty with exemplary qualifications from six (6) universities will be a part of the proposed program each already having experience mentoring 12 students in a successful and comparable program in the prior year. All faculty have NIH or VA extramural or other peer-reviewed funding; strong institutional support (financial resources, facilities, and equipment); robust integration with VCU for recruiting and training undergraduate students; and support for key professional development activities such as presentations and grant and manuscript writing. The ultimate goal of this R25 program is to attract and train a cohort of outstanding young students from undergraduate institutions within Virginia to become fluent in the latest developments of CVD multidisciplinary translational research, who will be well prepared to pursue future careers in cardiovascular health. Accomplishing this goal would augment the number of undergraduate students that will enter into graduate programs focused on developing new advances in multi-disciplinary translational research to treat and prevent cardiovascular disease, a major public health issue.

NIH Research Projects · FY 2025 · 2021-12

PROJECT SUMMARY It is a common occurrence in human that pain is perceived at a remote location away from the diseased organ. This is also true with bowel dysfunction. Patients with inflammatory bowel diseases (IBD) and/or irritable bowel syndrome (IBS) often experience bladder hyperactivity and somatic pain. Understanding the peripheral mechanisms of pain generation and sensory cross-sensitization helps development of therapeutic approaches with minimum central adverse effects to treat pain comorbidity. Peripheral glial cells are gaining increased recognition for their roles in modulating sensory neuron activity. Satellite glial cells (SGCs) of dorsal root ganglia (DRG) reside around sensory neurons and connect sensory neurons through SGC networks. Using Cre-based expression of hM3Dq to activate glial cells by clozapine-N-oxide (CNO), we show that activation of glial cells leads to an enhanced calcitonin gene-related peptide (CGRP) release to the spinal cord, an essential process in spinal central sensitization. Activation of glial cells also facilitates hypersensitivity of the colon, urinary bladder and hind paw in mice. In DRG, TrkB.T1 is expressed by SGCs but not neurons. Calcium (Ca2+) activity is a common pathway mediated by hM3Dq and TrkB.T1 in SGCs. Importantly, using a unique SGC- sensory neuron co-culture system we show that activation of SGCs mediated by TrkB.T1 leads to activation of adjacent sensory neurons that participate in pain processing. We therefore hypothesize that TrkB.T1 mediates glia-neuron interaction and participates in sensory neuron cross-activation and cross-organ sensitization. To test this hypothesis, we will use mice with inducible conditional TrkB.T1 deletion (TrkB.T1cKO) from peripheral glia mainly from SGCs and mice with hM3Dq or hM4Di expression in peripheral glia. We will perform molecular and functional analysis of colon-bladder sensory neuron cross-activation and cross-organ sensitization in these unique mouse lines (Aim 1). The functional roles of TrkB.T1 in SGCs are to increase the levels of Ca2+ to promote gliotransmitter release. We have identified a number of glial mediators that are regulated by TrkB.T1 in SGCs through proteomic screening and transcriptional analysis. We will characterize TrkB.T1-mediated gliotransmission and gliotransmitter-facilitated sensory neuron activation in the context of cross-organ sensitization (Aim 2). Central sensitization not only contributes to colon-bladder cross-sensitization but also underlies viscero-somatic cross-sensitization. We therefore will examine whether TrkB.T1-mediated SGC- sensory neuron crosstalk contributes to CGRP central release and leads to viscero-somatic cross-sensitization (Aim 3). Throughout the three aims, we will use more than one animal models and apply in vivo and in vitro approaches for functional and mechanistic studies. Interestingly, our preliminary data show that TrkB.T1 is sexually dimorphic. We therefore will perform our experiments in both genders. We anticipate revealing the role of TrkB.T1 in glia-neuron interaction to provide insights in understanding the development of cross-organ sensitization and suggest therapeutic targets.

NIH Research Projects · FY 2026 · 2021-12

An Integrative Approach to the Etiology of Internalizing Disorders in the Lifelines Cohort Internalizing Disorders (IDs) account for a substantial proportion of global disease burden, are highly comorbid and share common etiologic pathways. However, progress in understanding the causal mechanisms underlying IDs has been slow. The overall aim of this project is to clarify the etiology, course and comorbidities of five major internalizing disorders (Major Depression [MD], Dysthymia [DYS], Generalized Anxiety disorder [GAD] and Panic Disorder [PD], Social Phobia [SPH] in Lifelines, a prospective population-based cohort in North-Eastern Netherlands following 167,729 adult subjects with assessments of psychiatric and general medical health every five years. Lifelines includes high quality data on the phenotypes, environments, genotypes, and microbiome of multiple generations of family members and detailed assessments of the IDs as well as the three major functional disorders (FDs) (Chronic Fatigue Syndrome [CFS], Fibromyalgia [FM] and Irritable Bowel Syndrome [IBS]) which are highly comorbid with IDs. The richness of this data allows for an in-depth analysis of disease mechanisms. We will build multivariate models that include the phenotypic, environmental, familial, and molecular genetic levels to understand which of the mechanisms are shared amongst versus specific to the 5 IDs and 3 associated FDs. To meet these goals, we propose three specific aims. In our first aim, we will investigate, utilizing a range of causal inference and multivariate methods, the etiologic relations between IDs and between IDs and FDs, leveraging the rich longitudinal and family structure of Lifelines. Our second aim will be to use advanced genetic epidemiologic and molecular genetic methods applied to both family structure and genome wide SNP data to clarify the shared and unique risk factors for IDs and between ID and FDs. We will re-look at causal inter-relationships among our disorders using Mendelian Randomization. Building on aims 1 and 2, our third aim will investigate the joint action and interaction of genetic and environmental risk factors on the development(s) of IDs and FDs. This will include examining the effects of genetic nurture. We will again be using complimentary methods to examine gene x environment interactions utilizing methods from both genetic epidemiology and molecular genetics. To conduct this cross-disciplinary research, we have assembled, over the last 5 years, a broad collaborative team from the Virginia Institute for Psychiatric and Behavioral Genetics at VCU and the departments of Psychiatry and Genetics at the University Medical Center Groningen, Netherlands.

NIH Research Projects · FY 2025 · 2021-09

Abstract The goal of this project is to support a National Center of Excellence in Youth Violence Prevention to implement and evaluate a comprehensive prevention strategy to reduce and prevent community rates of youth violence in Richmond, Virginia and similar communities across the United States. The project’s specific objectives are: (1) To implement a comprehensive approach to youth violence prevention at the community-level with the following violence prevention strategies: (a) two complementary participatory action research prevention strategies including Youth Voices, a culturally responsive curriculum for African American adolescents, and the SEED Method, an evidenced-based process where youth and adults join together to identify strategies and develop an action plan to address social and structural conditions that create inequities in positive youth development opportunities, (b) a hospital-based prevention strategy, Emerging Leaders, that offers a brief hospital-based violence intervention followed by 6-months of wrap-around community case management, a firearm safety counseling program, and a psychoeducational workshop series for youth who have experienced an intentional or violence-related injury, and (c) stakeholder education strategies to build funding and resource capacity for youth-serving grassroots organizations through workshops and technical assistance in grant-writing, to expand the Walker-Talker community engagement model to increase community members’ knowledge of and access to positive youth development opportunities, and to offer evidenced-based workshops for organizations to promote youths’ developmental assets; (2) To evaluate the community-level impact of this comprehensive approach through continuous collection of surveillance data on community-level indicators of youth violence exposure using a multiple baseline design in three economically disadvantaged communities; (3) To evaluate the effectiveness of each prevention strategy with this comprehensive approach by assessing their impact on specific risk and protective factors they address; (4) To develop a Youth Advisory Council that will be actively involved in the development, implementation, and evaluation of the prevention strategies, and (5) To mentor and provide training to doctoral-level students, postdoctoral fellows, and faculty in the area of youth violence prevention. The project focuses on three economically disadvantaged communities in the City of Richmond, Virginia that were selected based on community input and review of surveillance data indicating high rates of community youth violence. Youth homicide accounted for the majority of all homicides and intentional injury deaths (96%) between 1999 and 2019 (CDC-WISQARS) – a rate that is nearly two times to 10.5 times greater than the national average (CDC-WISQARS, 2020). Violence in Richmond disproportionately impacts African American youth, and 92% of all youth who died from intentional and violence-related injuries were African American (Bishop & Chapman, 2019). Given these statistics, is essential to identify strategies that prevent and decrease community rates of youth violence in Richmond.

NIH Research Projects · FY 2024 · 2021-09

OVERALL: PROJECT SUMMARY Investigators from Virginia State University (VSU), a Historically Black College/University, and the NCI- designated Virginia Commonwealth University (VCU) Massey Cancer Center (MCC) recognized a need to collaborate and leverage the expertise and resources of both institutions to educate and train promising individuals who will ultimately contribute to diminishing cancer disparities in Virginia. The outcome of this collaboration resulted in the formation of the VSU-MCC PartnErship for CancEr Disparities Research and Training (SUCCEED) program. The overarching goal of SUCCEED is to lead in the transformation of cancer- related outcomes for Virginians and to serve as a model of transdisciplinary disparities research and education. Guided by the NCI framework, our preliminary data, and the expertise of our multidisciplinary team, we will employ a multilevel approach to develop a robust collaborative infrastructure that will build on the strengths of the partnering institutions to enhance their capacity to conduct cancer health inequities research that is driven by local data and informed by the cancer-related needs of local communities. Specific aims are to: Aim 1: Establish a mutually beneficial collaborative partnership between VSU and MCC in cancer disparities research and training; Aim 2: Conduct collaborative, locally focused liver/gastrointestinal (GI) cancer pilot research studies by investigators at MCC and VSU; Aim 3: Provide an integrated cancer research training and career development experience to VSU faculty; Aim 4: Support underrepresented minority undergraduate students from VSU to pursue careers in disparities research; Aim 5: Conduct an ongoing evaluation that reflects the progress of the collaborative partnership in meeting its goals and objectives. To our knowledge, this is the first targeted effort of this nature to address cancer disparities in the state of Virginia.

NIH Research Projects · FY 2025 · 2021-09

The population burden of cirrhosis is rising especially related to nonalcoholic steatohepatitis (NASH), alcohol- induced liver disease (ALD) and in those living with HIV. The progression of cirrhosis to liver-associated clinical events (LACE) and death is related to a diverse set of systemic and hepatic factors which may be etiology- specific or agnostic. There remain gaps in knowledge in assessing how these factors interact to cause cirrhosis- progression to outcomes. This limits rational development of non-invasive tools for risk-stratification and disease-monitoring purposes as well as the ability to holistically model the development of outcomes. There is also no established etiology-agnostic approach to reduce the risk of outcomes and death. This proposal, in response to RFA-DK-20-003, addresses these unmet needs with two specific aims: Aim 1: To conduct a prospective, multicenter, observational study of patients with cirrhosis of varying etiology that serves as the foundation for conducting novel mechanistic and therapeutic studies. Patients with compensated cirrhosis of varying etiology inclusive of NASH, ALD with and without HIV will be enrolled and followed prospectively with protocol-driven data and bio-sample collection. Outcomes will be assessed prospectively by a pre-specified adjudication process. Through collaboration with external partners, we will evaluate several promising tools (e.g. spleen-stiffness measurement), circulating biomarkers (PROC3-6, ELF test) and machine-learned approaches to obtain novel insights on fibrosis, factors driving outcomes and to model outcomes. The cohort data and bio-samples will further support mechanistic studies of factors driving fibrosis and outcomes. Aim 2: To perform a multi-center prospective randomized, double-blind placebo-controlled clinical trial to evaluate the clinical utility of atorvastatin (10 mg/day x 2 yrs) in patients with compensated cirrhosis. Patients with compensated cirrhosis of varying etiology, stratified by varices and CTP score (5 or 6) will be enrolled. The trial design uses the estimand framework proposed by the FDA (ICH E9 R1). The primary endpoint captures benefit from a patient-perspective and is defined by survival without LACE or major adverse cardiac event or need for drug withdrawal for toxicity. The primary analysis will be a comparison of proportions of patients meeting the primary endpoint. The secondary analysis of benefit is a time-to-event analysis of clinical outcomes. Several measures to track safety and de-risk the study are proposed. A benefit-risk analyses using state of the art approach is proposed. Together, they will provide robust information on the utility of atorvastatin to improve outcomes in compensated cirrhosis. The feasibility of the studies is supported by a strong and extensive referral network, a robust tele-medicine program for liver disease and research infrastructure. The studies will have a major positive impact by: (1) providing robust outcomes data, (2) supporting mechanistic studies, (3) use of innovations to refine application of NITs, (4) model clinical outcome risk to inform future monitoring strategies, and (5) provide a treatment to slow this progression, thereby providing a way to reduce the burden of cirrhosis.

NIH Research Projects · FY 2024 · 2021-09

Project Summary Multiple genetic risks cause alcohol, nicotine and cannabis substance use (SU) and substance use disorders (SUDs). However, genetic studies alone cannot explain the cascade of molecular changes between SNPs and SU and SUDs. Nor can current approaches correctly measure the causal impact of genetic differences on parental and home environments linked to SU and SUDs. Molecular studies that link GWAS results to gene expression data via eQTL findings have increased our understanding of the etiology of SU and SUDs. Yet, they fail to capture complex gene interactions that are the hallmark of complex traits including SU and SUDs, or are mostly underpowered (especially from brain tissues). Another limitation is that genetic and molecular studies neglect environmental confounding. We know that parents create and influence children’s environments and that certain parental and home environments are more associated with SU and SUDs. Not only do genetic risks vary with environments, but environments themselves are also heritable, and are thus confounded by parental genetics. We and others argue that unconfounding the impact of parent-to-offspring molecular genetics on SU and SUDs from the parental and home environments is the central task of genetics. Here, we rely on recent methodological advances to address these limitations. First, we have developed a novel and proven method of measuring the impact of untransmitted parental genomes. This method identifies the indirect impact of untransmitted parental genomes on complex behaviours. A significant impact of untransmitted genomes is evidence of genetically nurtured environments that are unconfounded by the direct parent-to-offspring genetics. Second, we can now perform gene expression (GE) imputation using existing GWAS. We can, therefore, estimate heritable, genome-wide individual differences in imputed GE networks in very large samples. This substantially increases our power to identify molecular pathways underlying SU and SUD aetiology. In summary, we are proposing to i) use existing GWAS data from large population-based family samples, ii) apply our method of assembling untransmitted parental genomes, iii) impute parentally transmitted and untransmitted GE, iv) apply network analyses to identify transmitted and untransmitted GE networks that are associated with SU and SUDs, and v) identify parental and home environments mediating these networks. This will enable us to identify the GE networks involved in SU and SUDs while identifying risky and protective parental and home environments that are genetically ‘nurtured’ within a unified theoretical framework.