Virginia Commonwealth University

NIH Research Projects · FY 2026 · 2008-09

SUMMARY Lyme disease bacterium Borrelia burgdorferi (Bb) is highly motile and can traverse complex environments inside mammalian and arthropod hosts during its infectious cycle. The central hypothesis of this application is that the motility and chemotaxis of Bb constitute a distinct paradigm and play a pivotal role in the host-vector cycle as well as in the disease process, including invasion, dissemination, tissue tropism, and immune evasion. During the last two funding cycles, we revealed several unique aspects of Bb motility and chemotaxis; however, their underlying molecular mechanisms and precise roles in the disease process remain largely unknown. Building upon our previous findings, this renewal aims to fill this knowledge gap by addressing three key questions: (1) How does Bb control asymmetrical flagellar rotation? Due to its unique cell shape and geometry, Bb must rotate its bipolar periplasmic flagella (PF) asymmetrically in order to run: the anterior PF rotates counterclockwise, and the posterior PF rotates clockwise. Without asymmetrical rotation, the cells become distorted. This is a hallmark feature of spirochete motility; however, its underlying molecular mechanism remains elusive. Aim 1 seeks to unravel this longstanding conundrum by determining the function and structure of FliG1, a noncanonical flagellar motor switch protein, using an integrative approach of genetics, biochemistry, cryo-electron tomography, and crystallography. (2) Has Bb evolved swarming motility to facilitate its invasiveness and virulence? During the enzootic cycle, on several occasions, Bb swims in highly viscous gel-like environments, such as mammalian dermis tissue and the tick-gut basement membrane, which are reminiscent of the environments in which bacteria swarm, a form of movement that allows bacteria to crawl over solid and semi-solid surfaces. It has been speculated that Bb has evolved swarming motility to empower its invasiveness. Aim 2 plans to delineate the underlying mechanism of swarming motility and its role in the pathogenicity of Bb, using a comprehensive approach of genetics, biochemistry, structural biology, and in vivo animal models along with intravital imaging. (3) Does CheA1 control Bb virulence and, if so, how? Bb has evolved unique chemotaxis to accommodate its distinct motility and enzootic cycle, e.g., its genome encodes multiple chemotaxis proteins such as two CheA histidine kinases (HK): CheA1 and CheA2. A longstanding question is why Bb needs multiple chemotaxis proteins. CheA2, but not CheA1, is essential for Bb chemotaxis. The role of CheA1 remains unknown. Interestingly, we recently found that CheA1 is required for Bb hematogenous dissemination in mice and expression of several key virulence factors of Bb. Building upon these results, Aim 3 proposes to elucidate the role and underlying molecular mechanism of CheA1 in Bb pathogenicity, using a multidisciplinary approach of genetics, biochemistry, RNA-seq, and animal models. Achievement of these aims will lead to a better understanding of Bb motility and chemotaxis as well as their precise roles in the pathogenesis of Lyme disease. Moreover, the fundamental knowledge to be gained is highly impactful and likely to aid understanding of these processes in other pathogenic spirochetes as well.

NIH Research Projects · FY 2025 · 2008-07

Project Summary Impulsivity has gained prominence as one of the cardinal etiological risk factors for the development and maintenance of addictive disorders. However, both impulsivity and addiction are highly heterogeneous, which has hampered progress in understanding the link between the two. To address this heterogeneity, we have developed a program of addiction research in Bulgaria, a major European center for production of synthetic amphetamine-type stimulants and a key transit country for heroin trafficking, due to its strategic geographical position on the Balkan Drug Route. Through our 17-yearlong collaboration with Bulgarian colleagues, we have accessed rare populations of predominantly monosubstance-dependent (‘pure’) heroin and amphetamine users, many in protracted abstinence. In the parent DA021421 study, we have tested >800 participants with a comprehensive assessment battery of clinical, personality, and neurocognitive tasks of impulsivity and related externalizing and internalizing phenotypes. We genotyped participants with the Smokescreen array and enrolled siblings discordant for opiate and stimulant addictions. We combined theory-driven (e.g. cognitive modeling, joint modeling) with data-driven (e.g. machine learning (ML)) computational approaches, which proved particularly informative and revealed distinct multivariate risk profiles characterizing opiate and stimulant addictions with high degree of accuracy. Findings from the parent study significantly informed our integrative multidisciplinary framework (Vassileva & Conrod, 2019), which highlights the potential for distinct dimensions of impulsivity to inform clinical assessment and intervention development for different types of addictions. Impulsivity also figures prominently in the neuroscience-based heuristic framework for the neuroclinical assessment of addictions (ANA; Kwako et al., 2016), which proposes that successful addiction treatment must accommodate the heterogeneity and different etiological mechanisms implicated in addictions, by performing multidimensional assessments focusing on three neurofunctional domains of impulsivity and compulsivity: executive function (EF), incentive salience (IS), and negative emotionality (NE). However, because the ANA framework is based primarily on findings in alcohol use disorder, it is not well understood how these domains might generalize to other SUD, such as opiate and stimulant use disorders. The current competing renewal application aims to address this critical gap with the following specific aims: Aim 1: Identify key personality, neurobehavioral, polygenic, and computational markers of opiate and stimulant addiction following the ANA framework, using the comprehensive assessment battery and computational methods developed in the parent DA021421 with 250 participants (100 with opiate use disorder, 100 with stimulant use disorder, and 50 healthy controls); Aim 2: Identify the brain signatures of the 3 ANA domains (EF, IS, NE) in opiate and stimulant addictions; Exploratory Aim 3: Combine data from Aims 1 and 2 to identify addiction biotypes based on neurocircuitry implicated in the ANA domains.

NIH Research Projects · FY 2025 · 2007-07

Human granulocytic anaplasmosis (HGA) is a potentially fatal infection and the second-most common tickborne disease in the United States. Its incidence is increasing at an alarming rate. Indeed, the 39% rise in the number of cases from 2016 to 2017 is greater than for any other tickborne infection. Even more concerning, the true incidence of HGA in this country is estimated to be 10- to 50-fold higher. The causative agent of HGA is Anaplasma phagocytophilum, an obligate intracellular bacterial pathogen that exhibits an unusual tropism for neutrophils. Like all obligate intracellular bacteria, Ap must invade cells to survive and cause disease. Identifying the adhesins and their host cell receptors that facilitate this essential step is fundamental to understanding Ap pathogenesis and preventing HGA. During the prior funding period, we identified three adhesins called Asp14, AipA, and AipB that Ap expresses when it converts to the infectious form and during tick transmission feeding on mammalian hosts. Hence, they are ideal targets for neutralizing infection. The adhesins’ receptor binding domains are Asp14 residues 113-124 (Asp14113-124), AipA residues 9-21 (AipA9-21), and AipB residues 80-94 (AipB80-94). An antibody cocktail against all three domains robustly inhibits Ap infection of host cells, whereas targeting only one or two is less effective. Therefore, they function cooperatively, are compensatory, and maximal blockade of Ap infection is achievable by disrupting the full cohort of adhesin-receptor interactions. Asp14 binds protein disulfide isomerase (PDI) on the neutrophil surface, which brings Ap in sufficient proximity to PDI such that it reduces bacterial surface thiols as a key step in infection. AipB is a PDI substrate that potentially binds CD18, a 2 integrin component and newly discovered Ap receptor. AipA and CD13 are a third Ap adhesin- receptor pair that is critical for invasion. PDI, CD13, and CD18 cluster in lipid rafts, which are essential platforms for Ap entry. Moreover, signaling events that CD13 and CD18 elicit are associated with Ap infection. Mice immunized against Asp14113-124 and/or AipA9-21 are significantly, but incompletely, protected from Ap challenge. Thus, Asp14 and AipA are important for Ap infection in vivo and their receptor binding domains are protective antigens. For our competitive renewal, we will build on these compelling data. We will dissect how the AipA- CD13 and AipB-CD18 interactions orchestrate Ap uptake into host cells and define the relevance of AipB to Ap infection in vivo. We will determine the protective capacity of AipB alone and in cooperation with AipA and Asp14 against syringe-mediated and tick-transmitted Ap challenge. Completing the proposed aims will yield the most comprehensive understanding of adhesin-receptor interactions for any rickettsial agent and one of the most refined models for the molecular basis of infection among intracellular bacterial pathogens. This fundamental knowledge will benefit design of approaches for protecting against HGA and significantly advance the field.

NIH Research Projects · FY 2025 · 2005-03

The overarching aims of this Center are to help advance the clinical, research, and educational goals of the ChiLDReN grant with a particular emphasis on engaging cutting- edge genome studies as a basis for discovery, innovation, and improvements in outcomes and care. As such, the aims of this application are not only to provide comprehensive research opportunities for children at the Atlanta sub-site, but to continue the important, unique, novel and ongoing Genomics work for ChiLDReN. Aim 1: Continue robust Clinical Center participation in all aspects of ChiLDReN. The Atlanta site at Emory/Children’s Healthcare of Atlanta is one of the largest enrollers in ChiLDReN studies and is the only ChiLDReN site in the SouthEast. The infrastructure is in place to continue and build upon the history of successful enrollment and retention of participants. The PI and subsite PI will continue close collaboration to ensure compliance and optimal enrolment and collection of data and biospecimens. Aim 2: Continue Genomics WorkGroup leadership for consortium-wide collaborative analyses and stewardship of genetic data for ongoing and future ChiLDReN studies. The Genomics WorkGroup, led by the site PI, will be able to continue novel paradigm-shifting work on understanding the direct causes and exacerbants of cholestatic disorders of childhood, with a specific focus on biliary atresia (BA). Application of modern genetic analytical technologies in this large group of participants are likely to lead to novel discoveries for etiology, disease modification, and therapeutic targeting.

NIH Research Projects · FY 2025 · 2002-05

This proposal, in response to RFA-18-505, is an application for the fourth competitive renewal of the VCU-Emory clinical centers of the NIDDK NASH Clinical Research Network (CRN). It has three specific aims that are aligned with the planned objectives of the renewal of the NASH CRN. Specific aim 1 is to complete recruitment and retain adult and pediatric subjects in the NAFLD Database 3 (DB3) study to support execution, analysis and publication of data to address unmet needs in the field. We will continue enrollment and follow up of participants in the NAFLD Database 3 (DB3) cohort study with collection of bio-samples and clinical data according to the protocol and leverage this data-set to obtain novel insights in to disease biology and validate biomarkers including measurements of spleen stiffness in this population. We already have met our recruitment target and will over-enroll in this study where we have over 90% retention. Specific aim 2 is to fully enroll and complete the ongoing vitamin E dose ranging study of metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD). We are close to completing recruitment and expect to meet our enrollment goals by the end of the current funding cycle and have 100% retention in the study. Specific aim 3 is to leverage the transcriptomic dataset generated as part of the NASH CRN ancillary study linked to the CRN database-2 study to validate molecular subclasses of MASLD and their relationship to disease course and outcomes. It builds on our previously published findings that there are distinct transcriptomic profiles within patients with similar histological severity of MASH. Specifically, we will generate novel data on their relationship to histological progression of disease and in those with advanced fibrosis, relate them to time to decompensation and clinical outcomes. A key focus will be to evaluate metabo-inflammation, accelerated aging and fibrogenesis related pathways to disease progression and outcomes. The proposed studies will be highly significant and impact the field as follows: (1) improved understanding of disease evolution including bi- directional interactions in liver and other metabolic dysfunction associated end-organ disease and impact of social and economic determinants of health, (2) acceleration of regulatory qualification of non-invasive tests for clinical use via collaboration with the FNIH NIMBLE project, (3) validation of spleen stiffness measurements and development of other biomarkers, (4) novel insights on disease heterogeneity via the proposed transcriptomic studies and (5) generating foundational data to support future applications for a fully powered trial of vitamin E for metabolic dysfunction associated steatohepatitis (MASH). The VCU and Emory clinical centers have played a robust role in advancing the mission of the NASH CRN and are fully committed to the proposed requirements of the RFA and have the resources to complete the proposed studies. As encouraged by the RFA, we are also collaborating with both internal and external partners to fully leverage the data resources of the CRN. Together, these provide a rationale for the fourth competitive renewal of the VCU and Emory clinical centers of the CRN.

NIH Research Projects · FY 2025 · 2001-09

This is a competitive renewal of the NCI T32 Cancer Prevention and Control (CPC) Training Program at the Massey Comprehensive Cancer Center (Massey) at Virginia Commonwealth University (VCU). The training program has been active for three 5-year cycles – first as an R25 and, in 2018, successfully transitioned to a T32. The present training application has a renewed focus on reducing the cancer burden to meet the needs of Massey's catchment area and align with the center-wide theme. Massey's catchment area includes “hot spots” of elevated cancer risk, with several counties having elevated age-adjusted cancer rates. This unique catchment area serves as a backdrop for research and training being conducted within communities and among a wide range of residences in the population. As the longest-standing NCI-funded T32 training program at Massey, the CPC program is highly valued by the institution and supported in matching funds by VCU, Massey and the School of Medicine. The program brings together 25 primary and 6 secondary mentors from 12 departments across three schools/colleges. One hundred percent of the predoctoral trainees secured postdoctoral training positions and four out of five postdoctoral trainees who have completed the program are in academic/research faculty positions and the other is working in a non-profit research-related career. The proposed T32 has four objectives: 1) offer an integrated training program with a broad range of research opportunities in cancer prevention and control, including an option to complete a concentrated Master of Science or public health degree; 2) provide structured didactic training in cutting-edge research methods to support career advancements in cancer prevention and control; 3) cultivate a collaborative community that will form the foundation for effective professional development and career readiness; and 4) provide training to emerging scholars through intensive mentoring. The program requests support for two predoctoral and five postdoctoral trainee slots. The selection of seven scholars will allow for an approximate 4:1 mentor/trainee ratio.

NIH Research Projects · FY 2025 · 1999-08

Revised Project Summary/Abstract This application requests five further years of support for an Institutional National Research Service Award to cover multidisciplinary training in Psychiatric, Behavioral and Statistical Genetics. We request support for three pre-doctoral and three postdoctoral students for primary training in: i) statistical, quantitative, behavioral and molecular genetics; ii) psychiatric nosology; iii) neuroimaging genetics and neurobiology; iv) clinical psychology; v) biostatistics and vi) epidemiology. In addition to specializing in one of these areas, trainees will be exposed to all others and encouraged to study at least one other with sufficient detail to broaden their scope for future career development and interdisciplinary research. Training will usually be 2-3 years in duration for both pre-doctoral and postdoctoral students. Applications for positions are expected to continue from a wide variety of disciplines, including medicine, psychiatry, psychology, biostatistics, neuroscience, molecular genetics and biology. Trainees are housed in the Virginia Institute for Psychiatric and Behavioral Genetics at Virginia Commonwealth University, a modern custom-built facility with private offices, state-of-the-art computational facilities, integrated molecular genetics and experimental laboratories, and an associated neuroimaging facility. Major strengths of the program include: i) broad expertise of faculty in psychiatry, psychology, genetics, neuroscience and statistics; ii) highly productive research environment with well-funded faculty who are among the most highly cited researchers in the field; iii) extensive experience and excellent track record of faculty in training at this level; iv) potential for trainees to take part in active data collection and data analysis projects; v) access to large genetically informative datasets collected at VCU and elsewhere; vi) direct access to genome sequencing, experimental study and neuroimaging facilities; vii) pairing with clinical psychiatrist to attend rounds; and viii) face-to-face instruction in responsible conduct of research.

NIH Research Projects · FY 2026 · 1995-12

The Massey Cancer Center (MCC) at the Virginia Commonwealth University (VCU) seeks the renewal of its National Cancer Institute (NCI) Cancer Center Support Grant (CCSG), an award it has continuously held since 1975. As a leading academic medical center within the Commonwealth of Virginia, the MCC serves a 66-locality catchment area spanning central, southern, and eastern Virginia. This region is home to more than four million residents and is characterized by communities with substantial racial, geographic, and socioeconomic variation that contributes to a higher overall cancer burden and significant health disparities than reported nationally. The MCC is home to an interdisciplinary cohort of 147 cancer investigators from six VCU Schools and Colleges. These investigators are organized into three, highly productive research programs – Cancer Biology, Developmental Therapeutics, and Cancer Prevention and Control. To provide these cancer scientists with access to the latest technologies and highest-quality methodologies, MCC requests CCSG support for six shared resources: Biostatistics, Flow Cytometry, Lipidomics and Metabolomics, Microscopy, Tissue and Data Acquisition and Analysis, and Transgenic/Knockout Mouse. As part of its overall organizational strategy, the MCC also provides its membership direct supportive services through an Office of Cancer Research Training and Education Coordination; Office of Community Outreach and Engagement; Office of Research Development within the MCC Administrative Core; and a centralized, full-service Clinical Trials Office (CTO). Of note, the MCC is one of 14 NCI Community Oncology Research Programs in the US charged to facilitate access to and implementation of clinical research throughout its catchment area in partnership with 11 community-based cancer practices. The MCC has invested $33.4M since its last competing renewal in 2016, in the strategic recruitment of a group of 38 cancer scientists to VCU. Other evidence of MCC’s success includes marked positive trajectories of growth – since 2016 a 32% increase in annual direct NCI research funding, 70% increase in the number of collaborative team science awards, and membership (6% to 12%). Further, MCC members reported their research discoveries and outcomes in 990 peer-reviewed publications with 43% reflecting inter- and/or intra-programmatic collaborations. After significant health system investments in a new electronic medical record system and a CTO restructuring, there has been a 51% growth in interventional trial accruals since 2019. Guided by the 2021-2025 Strategic Plan, MCC’s overarching focus for research, education, and community outreach and engagement efforts will be to reduce cancer health disparities and improve survivorship for all with priorities placed in developing innovative approaches to the prevention and treatment of lung, gastrointestinal, breast, and prostate cancers as well as two key behavioral factors, tobacco and obesity control.

NIH Research Projects · FY 2025 · 1976-07

During the current funding period, this program has continued its outstanding record of educating scholars as independent investigators and leaders in drug-abuse research. Since the submission of our last competitive application in 2015, competition for support from this program has been robust, and all slots have been filled. Twenty-five pre-doctoral and 14 post-doctoral trainees have received support from the grant, these trainees have published 149 papers, and 10 pre-doctoral and 5 post-doctoral trainees have earned individual NIH fellowships. Looking forward, we are poised to continue this record of success. We have recruited 2 new drug-abuse faculty in pharmacology as well as 5 new faculty members with relevant skills and interests from other departments. Moreover, recognizing the many strengths of the Department of Pharmacology and Toxicology, the dean has authorized the recruitment of up to 10 additional well- established faculty to join our team of 22 drug-abuse faculty. Additionally, a large increase in the number of clinical faculty in recent years justifies our request to increase the number of both pre and post-doctoral trainees by 2. Further support for this requested increase comes from the fact that there are more than 90 research grants from NIDA at this institution, and this is the only institutional training grant. Our preceptors provide trainees with “cutting edge” expertise in molecular, cellular, behavioral, clinical, and translational research. The program continues to emphasize pharmacology, but it has truly developed into a university- wide program open to trainees from all schools and incorporating multiple disciplines. The broad academic scope of the program is accomplished through rigorous core courses and a wide variety of advanced electives, a high level of collaboration among mentors to include reciprocal service on thesis committees, and multiple excellent seminar series. Additional initiatives are proposed to enhance mentor training. These academic opportunities complement a research infrastructure supported by a NIDA P30 grant that provides for the development of genetically altered animals, sophisticated bioanalytical technology, and expertise in advanced gastrointestinal and neuropharmacology research methodologies. Academic and research training is further supplemented by guidance on teaching, professional development for a career in drug-abuse science, and all aspects of becoming a productive, independent researcher. Our goal is to build on the program’s established record of success by continuing to provide a rigorous and supportive atmosphere for training leading scholars in the drug-abuse field for the future.