Vanderbilt University Medical Center

NIH Research Projects · FY 2026 · 2012-09

There is a critical need to increase the recruitment of a workforce and develop next-generation scientists who can conduct research in areas relevant to the NIH mission, particularly that of the NIDDK. Science, technology, engineering, and mathematics (STEM) careers are the fastest-growing occupation in the United States, with around 70% of jobs requiring a post-secondary degree with STEM comprehension. Yet less than 20% of college graduates earn degrees in a STEM-related field, the initial step in accessing a research career. To address this shortfall, we developed a holistic training program titled “Aspirnaut™ K-20 STEM Pipeline” at Vanderbilt University Medical Center (VUMC). Since the inception of the program in 2009, 171 undergraduate students from 28 states have matriculated into the pipeline. Notably,146 undergraduates have graduated college, and 90% of these students entered advanced degrees in STEM or directly entered the STEM workforce. In this project, we will leverage our success over 16 summers with the Aspirnaut training pipeline. In Aim 1, we will engage undergraduate students in discovery science experience on the topic of “Renal Biology and Disease”. In Aims 2 and 3, we will augment the discovery science experience with professional skills development and wellness training. Additionally, we will implement several innovations, piloted over the previous funding cycle, to perfect a holistic model of the training pipeline. These include science communication, Kidney 101, and a comprehensive wellness program. The anticipated outcomes will increase the number of undergraduates entering STEM disciplines of relevance to the NIDDK mission.

NIH Research Projects · FY 2025 · 2012-09

SUMMARY / ABSTRACT The overall goals of the research proposed are to verify whether inter-regional correlations in resting state fluctuations of MRI signals (rsfMRI) reliably measure functional connectivity (FC) between brain regions, to quantify factors that modulate rsFC derived from MRI, and to validate the neurobiological and behavioral relevance of changes in rsFC following specific interventions. We aim to continue our studies of the functional architecture of the sensorimotor system in non-human primates (NHPs) using multi-modal measurements of neural activity before and after perturbations of neural circuits. We will establish how fMRI data correlate with other metrics of connectivity obtained using optogenetic and electrophysiological techniques, and quantify changes in neural circuits that result from specific, targeted interventions, along with their functional consequences. These studies are important for the interpretation of fMRI studies in humans that are in widespread use but which have not previously been properly validated. Such studies can be performed using only invasive techniques in animals whose brain architecture resembles humans. We will use high resolution (sub-millimeter) fMRI at 9.4T to assess mesoscopic scale networks within a well defined functional region of somatosensory cortex in monkeys, where we can measure spatial patterns of resting state correlations in cortical layers and validate their interpretation with electrophysiological signals and anatomic tracers. We will: (1) Quantify laminar-resolved patterns of rsFC in sub-regions of S1, S2, thalamus and inter-hemispheric regions, and compare networks engaged by vibrotactile and layer-specific microelectrode stimulation with rsFC data. Cerebral cortex exhibits a laminar structure, but the laminar distribution of rsFC is poorly understood. We will confirm that CBV provides more faithful metrics of fine-scale connectivity than BOLD: (2) Quantify effects of selective deafferentation of inputs from (i) spinal cord (ii) thalamus, and (iii) area 3b of S1, on the patterns and strengths of rsFC and behavior. We will show how disruption of driver inputs alters rsfMRI correlations between regions in a layer-specific and functionally-relevant manner: (3) Identify and compare networks engaged by optogenetic stimulation of different cell populations with rsFC data. By comparing optogenetic vs fMRI responses for different transfection viruses we can assess the relative contributions to rsFC of selective activation of excitatory pyramidal or inhibitory interneurons, or inhibition of excitatory neurons, locally at the S2 site and at the network level at interconnected brain regions. For each set of experiments we will acquire rsfMRI and invasive multi-electrode measurements in the same animals to quantitatively compare different metrics of neural activity and anatomical connections. We will also measure animal behaviors in skilled hand use to identify specific effects of changes in rsFC after intervention and with recovery. We believe that the proposed studies have considerable importance for validating the neural basis of resting state functional connectivity measures, and have direct implications for human fMRI studies and their applications.

NIH Research Projects · FY 2025 · 2012-09

WNK-SPAK kinases are integral components of a potassium-dependent signaling system, coined the “potassium switch,” that adjusts the activity of the thiazide-sensitive sodium chloride cotransporter (NCC) in the distal convoluted tubule (DCT) and shapes the structure of the entire distal nephron to maintain sodium and potassium balance over a wide range of dietary potassium intakes. Low potassium consumption, common in modern diets, presses the pathway to conserve potassium at the expense of increasing sodium absorption and increasing blood pressure. A decrease in plasma K+, leads to a decrease in intracellular Cl- which stimulates the WNK/SPAK pathway, leading to activation of NCC and hypertrophy/hyperplasia of the DCT. The molecular details of the signaling pathway are still mostly unknown or are controversial, especially the specific role of a kidney-specific isoform of WNK1 and Cab39 (MO25), a kinase adaptor protein. How Na+ transport signals to increase DCT mass remains another great mystery. Here, we tackle these pressing unknowns, challenging prevailing views, and pushing the boundaries of the field with an innovative, stepwise multidisciplinary approach, combining molecular genetics, genomics, cellular biology, imaging, state-of-the-art physiological phenotyping in novel mouse models, and, mechanistically in innovative in vitro systems Aim 1: Newly published and preliminary data challenges the view that KS-WNK1 is an inhibitor of WNK4 and suggests that it acts to enhance WNK4-SPAK signaling in the DCT. We test this idea by specifically targeting KS-WNK1 gene knockout in the DCT and performing a molecule- to-physiology phenotyping analysis; characterize the KS-WNK1 transcript and protein, which our preliminary data indicate are different than previously believed; and define mechanistically how KS-WNK1 modulates NCC function. Aim 2: Recent data, including our preliminary data, indicate that kinase adaptor proteins, Cab39/Cab39l, enhance WNK-SPAK signaling in the DCT. Here, we have engineered a new mouse model, overcoming a roadblock in the field, to test this idea in a mammalian system for the first time, and have developed a new system to understand mechanistically how the adaptor proteins interact with WNK4 and SPAK, and modulate their function. Aim 3: Our RNAseq analysis on our DCT-specific constitutively active SPAK mouse, which is sufficient to activate DCT hypertrophy and hyperplasia, identified a network of DCT-specific transcription factors. We hypothesize that one of these Spalt like transcription factor-3 (Sall3) is the master regulator of the transcription network that defines the epigenetic fingerprint of the DCT and maintains the DCT lineage as it expands. To test this novel idea, we will define how Sall3 is induced in response to activation of SPAK and/or NCC; establish the impact of specifically targeting Sall3 knockout in the DCT on the remodeling response using a innovative new imaging approach; and determine if Sall3 represses gene methylation of DCT-specific gene networks. Together, we expect these studies to have a major impact and push the field forward.

NIH Research Projects · FY 2025 · 2012-09

A critical barrier to the development of new strategies for preventing costly fractures of the hip, spine, and proximal humerus is an incomplete understanding of the key age- and disease-related changes occurring in bone tissue. In particular, little is known about the pathogenic mechanisms by which the deterioration in the extracellular matrix (ECM) reduces the fracture resistance of bone or increases fracture risk. Non-enzymatic post-translational modifications (NE-PTMs) are potential contributors to poor ECM because they accumulate in matrix proteins as fracture risk increases. Therefore, the overall goals of this project are i) to determine which NE-PTMs of collagen I, the predominant ECM protein of bone, predict bone fracture resistance and are clinically relevant in osteoporosis and ii) to establish whether non-crosslinking or crosslinking NE-PTMs contribute to a decrease in fracture resistance of bone and whether they do so via alterations in the structure and hydration of collagen I. To achieve our goals, we will first generate specimens of cortical bone (dense) and trabecular bone (spongy) using cadaveric femurs collected from both female and male donors between 50 years and 100 years of age (Aim 1a). These specimens will be comprehensively analyzed to quantify: bone mineral density, bone volume fraction, ECM-bound water, secondary structure of collagen I, mature enzymatic & non-enzymatic collagen crosslinks, integrity of collagen I fibrils, the resistance to yielding (strength), the ability to deform after yielding (toughness), the resistance to crack growth (fracture toughness), and the resistance to damage accumulation (fatigue). From adjacent bone samples, we will also extract ECM proteins including collagen I and quantify NE-PTMs at specific amino acid residues that form its triple helix using mass spectrometry. By fitting the data to statistical models, we will determine whether the levels of certain NE-PTMs help explain differences among the donors in fracture resistance, collagen fibril integrity, ECM-bound water, and spectroscopic markers of helical structure. We will also generate bone specimens from proximal femurs acquired from cadavers without osteoarthritis (OA) and two types of orthopaedic surgical cases: total hip arthroplasty (THA) for OA and hemi- arthroplasty (HA) to fix a fragility fracture (Aim 1b). The specimens will be analyzed as in Aim 1a to determine whether NE-PTM levels are significantly higher while ECM-bound water and fracture resistance are significantly lower in HA (osteoporosis) vs. THA (OA) or the cadaveric controls. To identify a mechanism whereby NE-PTMs lowers fracture resistance of bone, we will treat bones ex vivo to accumulate specific types of NE-PTMs (Aim 2a). Following treatment, we will assess the bones to determine which specific NE-PTMs significantly affect the fracture resistance of bone in a manner similar to that of aging as determined in Aim 1. Lastly, we will perform molecular dynamics simulations and molecular modeling of collagen I to determine how relevant NE-PTMs affect the triple helix structure and hydration (Aim 2b). Successful completion of the project would shift the paradigm of bone health from a focus on bone mass to the inclusion of pathogenic contributions from bone ECM.

NIH Research Projects · FY 2025 · 2011-09

Cancer health differences across populations are the result of a combination of socioeconomic, environmental, behavioral, and biological factors. These differences impact cancer incidence, prevalence, mortality, survivorship, financial burden, and screening rates. The long-standing and mature Meharry Medical College (MMC), Vanderbilt-Ingram Cancer Center (VICC), Tennessee State University (TSU) Cancer Partnership (MVTCP), continues to provide and expand upon an exceptional cancer research and training environment to support the efforts of all investigators in addressing population differences. These efforts span across multiple disciplines to study the health determinants at an NCI-designated comprehensive cancer center (VICC), along with enhancing research infrastructure, capacity-building, and impact at MMC and TSU. Collectively, over the past twenty years of partnership, these collaborative efforts provide a robust infrastructure to improve cancer-related health outcomes while expanding research opportunities, recruitment, and training. Our triad has benefited from sustained and strong collaborative interactions between the three partner institutions, resulting in robust community and educational outcomes. Moreover, the geographical placement of this triad in Tennessee, a region with some of the highest cancer incidence and mortality rates in the United States, also provides a unique opportunity for our Partnership to positively impact outcomes for cancer patients in this geographical region. This region continues to have significant differences in lung, breast, prostate, and colorectal cancers across populations. Our ultimate goals are to improve cancer outcomes across all populations while simultaneously strengthening research impact.

NIH Research Projects · FY 2025 · 2011-09

PROJECT SUMMARY/ ABSTRACT Revision anterior cruciate ligament (ACL) reconstruction represents an infrequent but clinically important challenge in orthopaedic practice. It is commonly reported that the results of revision surgery remain inferior to primary ACL reconstructions, while the etiology of these poorer outcomes compared with primary reconstructions remains unknown. With this in mind, the Multicenter ACL Revision Study (MARS) group was established as an 83-surgeon multicenter consortium to perform a prospective longitudinal cohort analysis of revision ACL reconstruction outcomes. This is a mixed group of academic and private practice physicians and has been supported and endorsed by the American Orthopedic Society for Sports Medicine (AOSSM). Over 1,200 patients were enrolled and have now been followed beyond ten years. Our previous grant built on previous 2 and 6-year follow-up and obtained 10-year follow-up on the entire cohort (patient-reported outcome measures and incidence of subsequent surgeries), as well as collecting 10- year onsite follow-up within a nested cohort for radiographic and clinical measures. Radiographic onsite follow-up demonstrated structural post-traumatic osteoarthritis (PTOA; Kellgren-Lawrence grades 3-4) in 56% of the onsite cohort. Previous meniscectomy proved to be a predictor for this severe structural OA, but 60% did not have a previous medial or lateral meniscectomy. Thus, this proposed grant will utilize genomics targeted for OA predictors to seek to determine a more comprehensive risk profile for patients for symptomatic and structural PTOA. Predictors of risk will guide revision surgical decisions and post-surgical activity and lifestyle guidance, as the spectrum of resulting PTOA may be influenced by genetic variation. Additionally, predictors and outcomes for total knee arthroplasty in these young active patients will be assessed. Validated patient-reported outcome measures will assess outcome at 20 years with analysis for predictors to continue to build upon 2, 6 and 10-year follow-up in order to shape the care of these challenging patients.

NIH Research Projects · FY 2025 · 2011-08

The overall goal of the ‘Childhood Infections Research Program’ T32 (CHIRP) is to prepare MD Fellows and PhD postdoctoral scientists for careers as investigators in basic and clinical / translational research related to infections in children. The objectives of CHIRP are: 1) to identify outstanding MD and PhD candidates committed to a research career related to infections of children; 2) to support mentored research training with experienced senior mentors and productive emerging mentors; 3) to implement a “career design by objective” program that establishes individualized timelines and pathways for training and long-term career development; 4) to utilize courses and degree programs relevant to the individualized training plan; and 5) to incorporate novel interdisciplinary training programs among MD and PhD trainees to create broad understanding of important questions and issues in childhood infections. CHIRP has identified 23 senior mentors in Pediatric Infectious Diseases, Pediatrics, Medicine, and Pathology, Microbiology & Immunology with sustained NIH funding coupled with a successful track record of mentoring early career scholars. Also, we have selected 8 ‘emerging mentors’, with funding and established trainees and productivity. Mentor research and training programs are in virology, bacteriology, vaccines, hospital infections, epidemiology, and outcomes. MD trainees will be identified from Pediatric Infectious Diseases and other pediatric and adult subspecialties. PhD applicants will be identified by application of externally and internally recruited PhD candidates of CHIRP mentors and broadly across Vanderbilt. A Program Director, Associate Directors, and Steering Committee will direct the selection and ongoing evaluation of trainees and program progress. An Advisory Committee of three national leaders in Pediatric Infectious Diseases will review the program and provide recommendations for changes and improvements, including approaches to increase the applicant pool. Evaluation of trainees will be based on required scholarship oversight committees, individual development plans, trainee progress reports, and compliance with requirements for training in responsible conduct of research and reproducibility. Ongoing program evaluation has led to improvements including the advisory committee and a monthly “T32-Club” for trainees with discussions of RCR, reproducibility, research-in-progress, and trainee-selected topics relevant to success and challenges of research careers. Long-term program success will be based on outcomes of trainees in publications, career progress, and follow-on funding and will be assessed using trainee evaluations and formal review by the steering and advisory committees. CHIRP has been highly successful in recruiting, mentoring and establishing investigators in childhood infections, and we request support to continue the program success.

NIH Research Projects · FY 2026 · 2011-08

OVERALL PROGRAM – ABSTRACT This AADCRC application focuses on the airway, the primary organ affected in asthma, to address key questions that will support biologically targeted prevention and treatment strategies. Understanding the heterogeneity of asthma requires studying airway development from birth and assessing how environmental risk factors influence epithelial development. Asthma is characterized by a dysfunctional airway epithelium, where the cell community lining the airways contributes to mucociliary clearance, acts as an immunologically active barrier, and interacts with the immune system to defend against pathogens, aeroallergens, and pollutants. How it becomes dysfunctional during the development of childhood asthma is the focus of this program. Our program in its current funding cycle developed novel data on an early life airway epithelial phenotype that predates asthma development, the role of RSV in asthma development, and data on pathways through which RSV may alter airway epithelial development. Our program also initiated a novel birth cohort using a longitudinal multi-modal approach to study airway development, and the children will turn 5 during this renewal application period and will serve as the study population for the scientific projects. Relevant to this program, the cohort includes: (1) specialized preservation of airway epithelial cells for single-cell RNA- sequencing to reveal cellular heterogeneity, molecular signatures, differentiation trajectories, and functions in health and asthma; (2) culturing airway epithelial cells to investigate development, differentiation, and experimental infection in vitro; and (3) collecting nasal brush samples for RNA and DNA extraction to perform bulk RNA-seq and DNA methylation analyses. Our overarching hypothesis for this proposal is that t here are distinct airway epithelial developmental defects present at birth (endotypes) that give rise to specific asthma phenotypes. These airway endotypes exhibit unique responses to environmental exposures, such as response to RSV infection during infancy, that contribute to asthma inception and virally mediated exacerbations. Defects in postnatal differentiation of the airway epithelium driven by aberrant developmental, metabolic and epigenetic programs lead to abnormal pre-asthmatic changes in the airway barrier. These changes play a critical role in the airway's response to viral infections and the onset of asthma. To test this hypothesis Project 1 utilizes multi- omic analyses of longitudinal cell-specific transcriptomic, metabolic, and epigenetic data to understand the development of the airway epithelium in health and asthma. Project 2 similarly focuses on the differentiation of the airway epithelium by utilizing airway epithelial cells cultured from infants, starting at birth, as an ex vivo developmental biology model to evaluate the effects of experimental RSV and HRV infection to understand the enhanced susceptibility of asthmatic airway epithelium to respiratory viral infection. A clinical core will manage the study population and biospecimens, and a data/systems biology core will be the center for the analyses to support the scientific projects. An administrative core will support the entire program.

NIH Research Projects · FY 2026 · 2011-05

ABSTRACT Many important variables in biomedical studies of HIV/AIDS are skewed, ordinal, or a mix of the two (e.g., data with detection limits). Rank-based statistical methods for ordered categorical data can be applied to these types of data, providing robust analysis approaches that make fewer assumptions than standard approaches. In past cycles of our grant, we developed semiparametric cumulative probability models (CPMs) to analyze skewed, ordinal, or mixed response data; we demonstrated good properties of these approaches theoretically, via simulations, and in real-world data; and we extended these approaches to settings with clustered data. In this renewal application, we focus on novel and exciting extensions of these methods that could have a large impact on the analysis of biomedical data. First, we will develop distribution prediction models by extending CPMs to allow flexible inclusion of predictor variables via penalization (e.g., ridge regression, lasso, and elastic net) and tree-based approaches (e.g., random forests and boosting). Second, we will develop rank-based methods to estimate robust causal population parameters (i.e., estimands) that quantify the effect of a treatment in observational studies with skewed, ordinal, or mixed response outcomes. Our robust estimands include the quantile treatment effect, the probability treatment effect, and the Mann- Whitney/Wilcoxon/probabilistic index treatment effect, and variations of these estimands conditional on covariates. These causal estimands will be estimated in a robust, rank-based manner using CPMs. Third, we will use CPMs to extend modern difference in differences (DID) methods to permit estimation of robust estimands using rank-based methods in simple two-group two-time period settings and more complicated settings with staggered treatment adoption. Fourth, we will develop simple and unifying sample size formulas and analysis methods for cluster randomized controlled trials with skewed, ordinal, or mixed response data. We will package our methods in freely available software and apply our analyses to important studies of HIV/AIDS.

NIH Research Projects · FY 2025 · 2011-05

Summary Clostridioides difficile is a Gram-positive, spore-forming anaerobe that infects the colon, causing a range of human disease including diarrhea, pseudomembranous colitis, and toxic megacolon. The United States Centers for Disease Control reports that, in 2017, there were 223,900 estimated cases of C. difficile infection (CDI) in hospitalized patients in the United States with an estimated 12,800 deaths. The incidence of community- acquired CDI is also common making C. difficile a significant public health concern. The bacterium makes a toxin, TcdB, which is responsible for the majority of CDI symptoms. The goal of the proposed project is to define the structural basis and physiologic consequences of TcdB binding to receptor proteins on the host cell surface. In Aim 1, we will define the structures and key residues involved in TcdB-receptor interactions using a combination of structural biology, mutagenesis, and quantitative binding approaches. We will use this information to generate C. difficile strains with defined mutations in TcdB receptor binding sites. In Aim 2, we will evaluate the cellular tropism of the toxin in the context of a human explant intoxication model, taking advantage of significant technological advances in high resolution light microscopy imaging. These studies will be paired with mechanistic studies in a novel cellular model of TcdB intoxication as well as the mouse model of CDI. Collectively, these studies will define the physiologic consequences associated with defined TcdB-receptor interactions and are expected to provide a mechanistic framework for advancing novel therapeutic and CDI prevention strategies.

NIH Research Projects · FY 2025 · 2011-03

PROJECT SUMMARY As the population ages, Alzheimer's disease and dementia are becoming a public health crisis. In our initial cycle, the Vanderbilt Memory & Aging Project was established to examine cardiovascular function in relation to structural neuroimaging changes and cognition. We also tested whether associations were more prominent in clinically symptomatic individuals. We successfully enrolled several hundred participants age 60 and older, our data successfully supported multiple training grant opportunities (e.g., National Research Service Awards, Career Development Awards), and we published numerous papers. Our results suggest subclinical cardiovascular changes relate to worse cognition, white matter changes, and cerebral atrophy, especially in the hippocampus and other cortical regions primarily affected in Alzheimer's disease. Evidence to date supports our central hypothesis that well-established homeostatic mechanisms designed to protect cerebral blood supply become less effective with age, altering the integrity of cerebral hemodynamics, and lowering the threshold for neurodegenerative and cognitive changes. Interestingly, our preliminary associations between subclinical cardiovascular integrity and cerebral hemodynamics are stronger among carriers of the apolipoprotein E ε4 (APOE-ε4) allele, an Alzheimer's disease genetic risk factor. Furthermore, findings are more prominent in cognitively unimpaired participants, suggesting subtle cardiac hemodynamic changes may act as an underrecognized precipitating contributor of neurodegeneration and corresponding cognitive decline, distinct from the exacerbating effects of overt cerebrovascular disease. In the next cycle, we propose to better characterize underlying mechanisms linking early cardiac hemodynamic changes to abnormal brain aging in cognitively unimpaired participants, and test whether APOE-ε4 moderates the effect of vascular damage on brain health. We will follow the existing cohort and supplement it with enrollment of several hundred cognitively unimpaired participants to increase statistical power for more comprehensive analyses. The new participants will complete serial longitudinal assessments with identical procedures plus lumbar puncture for cerebrospinal fluid acquisition. Innovative translational efforts leveraging sophisticated neuroimaging and molecular biomarkers are critical to better detect early, asymptomatic cardiac hemodynamic changes, which may be more influential in initiating downstream cerebrovascular and neurodegenerative processes than previously recognized.

NIH Research Projects · FY 2025 · 2010-09

Glaucoma is the leading cause of irreversible blindness that is due to degeneration of retinal ganglion cells (RGCs) and their axons. Biomechanical stability of the optic nerve head (ONH) which is composed of the lamina cribrosa (LC) and peripapillary sclera (PPS) and is rich in elastic fibers, has been postulated to play an important role in maintaining normal function of RGC axons. In our previous grant cycle, stemming from our initial discovery of a glaucoma-causing mutation in a microfibril-related gene, ADAMTS10, we focused on microfibrils and established their important role in glaucoma pathogenesis. Microfibrils are primarily composed of fibrillin-1 (encoded by FBN1) and required for proper elastic fiber assembly, contributing to their biomechanical properties. Elastin undergoes crosslinking by Lysyl Oxidase Like 1 (encoded by LOXL1), another key element for proper elastic fiber formation. Mice lacking LOXL1 (Loxl1-/-) develop pelvic floor organ prolapse (POP) due to malformation of elastic fibers, demonstrating the essential role of LOXL1 in normal elastic fiber formation. Our preliminary data with Loxl1-/- mice demonstrated ocular pathologies, including abnormal biomechanics as determined by Atomic Force Microscopy (AFM) and ultrastructural changes of collagens and elastic fibers in the PPS. A landmark study discovered the association of LOXL1 genomic variants with exfoliation glaucoma (XFG) caused by exfoliation syndrome (XFS) which is a disease with systemic manifestations of elastic fiber defects, including higher prevalence of POP. The association of LOXL1 with XFG/XFS has been replicated in many populations, however, it is also recognized that while defective LOXL1 is necessary, it is not sufficient to cause disease, suggesting that other factors must be involved. We hypothesize that microfibrils are a key additional factor, in part because of their indispensable role for proper formation of elastic fibers. Our central hypothesis is that alterations in the biomechanics and structure of the ONH caused by defective elastic fibers result in RGC axon pathology. This hypothesis suggests that directly targeting biomechanical abnormalities may prove to be an effective novel treatment for glaucoma patients. To test our hypotheses, we will use our newly created double mutant (Fbn1C1039G/+/Loxl1-/-) and Loxl1-/- mice to investigate biomechanical and ultrastructural changes caused by elastic fiber defects in SA 1 and to determine the effect of these changes on RGC axon pathology relevant to glaucoma in SA 2. Based on the findings, we will test the effectiveness of targeting biomechanical abnormalities for protection against RGC axon pathology. Success of this investigation would provide mechanistic insight into the role of biomechanics of the ONH in glaucoma and, more importantly, it would lead to a much-needed novel treatment approach for glaucoma patients.

NIH Research Projects · FY 2025 · 2010-08

Lung cancer remains the number one cancer killer in the United States and clinically useful biomarkers are needed to improve early detection and diagnosis. The objectives of this proposal for our continuing Clinical Validation Center are to push early lung cancer detection biomarkers into clinical practice while continuing to serve as a core resource to the EDRN, as well as to our academic and industry partners. Our overall objective is to demonstrate that biospecimen and imaging biomarkers will provide clinical utility to diagnose lung cancer by reducing the number of invasive procedures performed for benign disease and the time to diagnosis for cancer. Aim 1 will seek to demonstrate clinical utility of a combined biomarker and radiomic approach for providing IPN diagnoses. We will expand the existing IPN specimen and imaging biorepository available to the NCI and scientific community, demonstrate the clinical utility of combination biospecimen and radiomic biomarkers, and validate additional candidate lung cancer risk biomarkers.  We hypothesize that a cancer, benign, and radiomic biomarker approach will decrease invasive procedures and the time to diagnosis in an IPN population.  In Aim 1a we will validate the combined approach of Histoplasmosis EIA benign biomarker (MiraVista), hs- CYFRA 21-1 cancer biomarker and radiomic biomarker (HealthMyne) in the EDRN Lung Team Project 2 (LTP2) and National Lung Screening Trial (NLST) cohorts.  In Aim 1b we will validate candidate blood and epithelial biomarkers in Phase 2 and 3 prospective-specimen collection and retrospective-blinded-evaluation (PRoBE) design studies for the early diagnosis of lung cancer and determine suitability for a clinical utility trial.  In Aim 2 we will validate radiomic risk assessment platforms in IPNs and conduct a pilot clinical implementation trial in screening discovered IPNs. We will leverage the robust bioinformatics infrastructure at Vanderbilt University Medical Center to capture and deidentify 800 thoracic CT scans in patients with IPNs. A Lung Cancer Prediction Convolutional Neural Network (LCP-CNN) and the HealthMyne radiomic model will be compared to each other and against the Lung-RADS categories. We will perform a prospective pilot evaluation of the best performing model in Lung-RADS category 3 and 4 IPNs. To accomplish Aim 2 we will: 1) compare the accuracy of LCP-CNN and HealthMyne radiomics 2) determine the LCP-CCN’s ability to reclassify nodules in screening patients in a prospective clinical implementation pilot study. In aim 3 we will test the hypothesis that the addition of a radiomic machine learning- based biomarker for pulmonary nodule lung cancer risk prediction compared to usual care improves patient management in a pragmatic, prospective randomized clinical trial at VUMC, Meharry, and Washington University in St. Louis. At the completion of this proposal, we will have 1) evaluated clinical utility of combining lung cancer biospecimen and imaging biomarkers, 2) developed a platform within current practice to present an imaging biomarker approach to improve IPN risk assessment, and 3) enhanced the biorepository resource for the EDRN and collaborative use.

NIH Research Projects · FY 2026 · 2009-09

Summary Contemporary cohort studies and randomized clinical trials are regularly linked to biorepositories and electronic health records systems. These secondary resources often contain exposure and/or outcome data that are crucial for addressing novel study questions. However, exposure/outcome ascertainment costs are often prohibitive. For example, assaying biospecimen from biobanks to measure blood markers or manually reviewing health records to accurately ascertain medical history information are both costly and restrict sample size. A solution to high ascertainment costs is the two-phase study that uses available participant information to identify those who are most informative for addressing study questions. Restricted study resources are then concentrated on the sub-cohort of informative participants. Outcome dependent and outcome related sampling designs are examples of two-phase studies. They are highly efficient compared to standard random sampling because they use outcome and/or auxiliary variable data to identify the informative participants and then enrich the observed sample with them. However, analyses must correct for the non-representative sample. In this competing renewal, we propose highly efficient outcome dependent and outcome related sampling designs as well as ascertainment correcting analysis procedures for ordinal and longitudinal data. This is a natural extension of the research conducted during the prior funding cycles which focused on longitudinal binary and normally distributed response data. In the current proposal our focus is on generalized ordinal (from a few ordered categories to non-normal, continuous) and longitudinal ordinal responses, on novel semiparametric models, and on robust variations of likelihood-based estimation strategies. Aim 1 regards outcome dependent sampling and outcome related sampling designs and analysis procedures for scalar generalized ordinal response data; Aim 2 regards outcome dependent sampling and outcome related sampling designs and analysis procedures for ordinal, longitudinal data; and Aim 3 extends a new class of semi-parametric generalized linear models (SPGLM) to correlated multi-outcome dependent sampling designs, to longitudinal data settings, and then proposes outcome dependent sampling designs for longitudinal data.

NIH Research Projects · FY 2026 · 2009-01

PROGRAM PROJECT GRANT OVERALL SUMMARY Helicobacter pylori is the strongest risk factor for gastric adenocarcinoma, the fourth leading cause of cancer- related death. One H. pylori determinant that increases gastric cancer risk is the cag type IV secretion system (T4SS) which exports a bacterial oncoprotein, CagA, into host cells. Our entire group has collaboratively shown that cag+ strains selectively activate a gastric stem cell population marked by Lrig1, as well as the EGF receptor, ornithine decarboxylase, and spermine oxidase, host effectors that influence carcinogenesis. Project 2, Core A, and Core B have additionally made the discovery that a pathway contributing to gastric carcinogenesis involves reactive electrophiles and developed a novel intervention strategy using a clinically available electrophile scavenger. Projects 1 and 3 demonstrated with Cores A and B that environmental components of the exposome associated with gastric cancer, such as iron deficiency or a high salt diet, positively select for H. pylori variants linked to increased cancer risk and augment the ability of cag+ strains to induce disease. Finally, all Projects used unbiased approaches (Core B) to identify novel host effectors that increase cancer risk, including bile acids. Our overarching Hypothesis is that differences in infecting strains, host responses, and environmental exposures such as diet affect the risk of developing gastric cancer as a consequence of H. pylori infection. To address this, our PPG integrates studies of host-pathogen interactions and oncogenic signaling initiated by biomedical researchers who have made a strong commitment to research within the fields of carcinogenesis, immunobiology, gastroenterology, and microbiology, and will generate results that would not be attainable through independent investigation. The Projects below are driven by discrete hypotheses, yet are cohesive in their focus on H. pylori-host interactions that induce cellular responses with carcinogenic potential. Project 1. Effect of iron deprivation on H. pylori-induced gastric carcinogenesis (PI-Richard Peek) Project 2. Polyamines and electrophiles in gastric cancer (PI-Keith Wilson) Project 3. Regulation of H. pylori virulence by dietary factors that impact gastric cancer (PI-Tim Cover) The efforts of each Project will be further unified by dynamic interactions with specific Core facilities, consisting of Gastric Histopathology Core A, Proteomics and Metabolomics Core B, and Administrative Core C, which includes sophisticated bioinformatics and statistics. By maintaining a grounded focus on interactions that occur at the H. pylori-host interface, results from this proposed work will not only improve our understanding of gastric cancer, but will also identify targets for prevention and more effective treatment of this devastating disease.

NIH Research Projects · FY 2025 · 2008-12

SUMMARY Staphylococcus aureus and Bacillus anthracis are pathogenic members of the order Bacillales that each represent a considerable threat to global public health. The rise of S. aureus strains resistant to all known antimicrobials has the potential to eliminate available treatment options whereas the successful use of B. anthracis as an agent of bioterror threatens national security. Identifying novel therapeutic targets against these organisms is critical to our continued ability to protect against these infections. Promising antimicrobial targets include bacterial stress sensing and detoxification systems as both processes are required for infection. Alterations in gene expression in response to stress can be orchestrated by signal transduction proteins known as two-component regulatory systems (TCSs). Bacteria typically encode many TCSs that are responsible for recognizing and responding to distinct signals, enabling adaptation to diverse environments. We have identified and functionally characterized two TCSs named EdsRS and HitRS that trigger the response to cell envelope damage as a strategy to defend against phagocyte-dependent killing. EdsRS is conserved in both S. aureus and B. anthracis whereas HitRS is only present in B. anthracis, suggesting that HitRS may have evolved to enable the intracellular lifecycle of this organism. In this proposal, we describe the discovery of additional regulatory factors that govern signal transduction through EdsRS and HitRS, including known enzymes as well as previously unstudied factors involved in RNA expression and stability. The combined activities of these regulatory factors enable transcriptional, post-transcriptional, and post-translational control of TCS signaling. Based on these discoveries, we propose a model whereby HitRS and EdsRS signal transduction is controlled by accessory proteins that enable a coordinated and tightly controlled response to host-mediated barrier damage. We propose that tight regulation of EdsRS and HitRS is required for survival within macrophages and subsequent pathogenesis. This model uncovers new regulatory proteins that control TCS signal transduction, expanding the small but rapidly growing catalogue of known TCS accessory proteins. We will test this model through a series of interconnected specific aims that define the mechanism of control of HitRS and EdsRS signal transduction, elucidate the cascade of events leading to HitRS and EdsRS activation during infection, and uncover host factors that target the cell envelope of Gram positive bacteria and trigger HitRS and EdsRS signaling. Due to the fundamental requirement for TCS in bacterial stress sensing, these studies will be universally relevant to the field of microbial signal transduction.

NIH Research Projects · FY 2025 · 2008-07

PROJECT SUMMARY Approximately 1.2 million individuals in the United States and 38 million worldwide are living with HIV. Priorities for HIV research include cure, mitigating associated inflammation and immune activation, novel therapeutics, and optimizing current management. In addition, there remains detrimental interindividual variability in HIV treatment responses regarding toxicities and immune recovery. Efforts to decipher relationships between the human genome and responses to therapeutic interventions in people living with HIV will help drive continued progress in the field, and involve complementary methodologies. The well-established value of the genome- wide association study (GWAS) is expanded by considering the polygenic risk score (PRS), which considers numerous polymorphisms that, in combination, affect risk for a phenotype, and by the integrated risk score (IRS), which combines PRS with non-genetic exposures. It is further expanded by the transcriptome-wide association study (TWAS), which relies on heritable gene expression in over 40 tissues throughout the body, inferred from genome-wide genotype data, and by the phenome-wide association study (PheWAS), which simultaneously interrogates genotype-phenotype associations across vast numbers of phenotypes. Complementing these variant-based and gene-based approaches are powerful wet-lab direct bulk and single- cell transcriptome analyses (TA) that decipher underlying biology by comparing patterns of gene expression between different experimental conditions or phenotypes. Building on progress to date, we will apply these complementary approaches to decipher genetic underpinnings of HIV-relevant clinical and endophenotypes, largely through analyses of available data and specimens from numerous different AIDS Clinical Trials Group trials and cohorts. We will consider interventions that target inflammation, the HIV reservoir, viral replication, and beyond. This work is facilitated by extensive groundwork laid by the proposing investigators to create and implement efficient, robust systems for variant-based, gene-based, and RNA expression-based genomic data generation and data analysis, as well as interpretation and visualization of results. Our ultimate goal is to improve the lives of people living with HIV through accelerated discovery based on state-of-the-art genomic approaches.

NIH Research Projects · FY 2025 · 2008-07

Acute and chronic lung diseases are major causes of morbidity and mortality throughout the world. For many of these diseases, the fundamental pathobiology is not well understood and effective disease-modifying treatments are not available. This training program titled “Interdisciplinary Training Program in Lung Research” focuses on training researchers in basic mechanisms of lung disease and is committed to equipping young investigators with the skill set necessary to develop into successful scientists and academic leaders. The Division of Allergy, Pulmonary, and Critical Care Medicine (APCCM) at Vanderbilt University Medical Center (VUMC) has a long, successful history in developing well-trained researchers who have the vision and the skills with which to embark on successful research careers. This program is associated with the newly formed Vanderbilt Lung Institute (VLI), which was developed to enhance collaborative multi-disciplinary clinical care and research related to respiratory disease. Dr. Timothy Blackwell (Director of APCCM and VLI) serves as Program Director. This training program, now in its 14th year, was designed to support 5 post-doctoral trainees per year (both MD. and PhD.) who show exceptional aptitude for successfully pursuing an academic research career. Trainees concentrate on one of five disease focused areas of existing expertise at VUMC: acute lung injury and host defense, asthma and airway disease, interstitial lung disease, pulmonary hypertension, or perinatal lung disease over the course of 2-3 years of training. A customized mentoring team is formed for each trainee, consisting of a mentor with nationally recognized expertise in the area and a Research Advisory Committee to provide additional guidance, mentoring, and feedback. The trainee's experience is enhanced by interactions with other investigators and trainees in existing lung disease-focused research programs in the Division of APCCM, an extensive program of seminars and conferences, and coursework tailored to meet the needs of each trainee. As a result, each trainee attains the skills necessary to become a future leader in the field of lung research.

NIH Research Projects · FY 2025 · 2007-04

This postdoctoral research training program in pulmonary and critical care medicine, open to MDs and PhDs in health sciences, is in its fourteenth year. It is designed to provide 2-3 years of support for training in clinical and translational research and offers optional participation in the Vanderbilt Master of Science in Clinical Investigation (MSCI) and Master of Public Health (MPH) programs. Since its inception, 27 trainees have joined the program, 18 MDs, 3 MD/PhDs, and 5 PhDs. Ten of 27 trainees have participated in the MSCI program, and two in the MPH Program. The vast majority of our graduates have gone on to primary research or research-related careers in academic medicine. In addition, 27 junior faculty have participated in our innovative mentor-in-training program. Given the success of the first 14 years, we are requesting renewal of funding support. Remarkable advances in the prevention, treatment, and management of acute and chronic disease have occurred in past decades. However, there is growing national concern that expert clinical investigators who can translate new research findings to practice are decreasing in numbers. It has never been more important to create and maintain a cadre of well-trained translational and clinical scientists, given the unprecedented developments at the cellular and molecular level, including knowledge of the human genome and the advent of big data science. Vanderbilt has a very successful history in developing well trained researchers who have the vision and the skills with which to embark on successful careers in academic research, both basic and clinical. This innovative training program, "Clinical and Translational Research Training Program in Pulmonary Medicine" focuses on mentoring researchers in all aspects of clinical and translational research necessary to prepare them for the unique challenges associated with advancing science in Pulmonary and Critical Care Medicine. The program accepts 2-3 new trainees per year (maximum 5 participants/yr) selecting applicants who show exceptional aptitude for successfully pursuing an academic research career. The program offers trainees opportunities to explore hypotheses anywhere on the continuum of translational research in four core areas: Airway Disease, Pulmonary Vascular Disease, Parenchymal Lung Disease and Critical Care Research; all of these are areas of international recognition and research presence for Vanderbilt. The Program Directors lead a team of expert mentors in these areas who are engaged in successful academic research careers, who play significant roles in supporting trainees in developing research skills; applying those skills; identifying and resolving research-related process problems; and understanding and applying the principles of responsible conduct of research. The overarching goal is to prepare trainees to utilize the skills they acquire in the pursuit of future academic research careers.

NIH Research Projects · FY 2026 · 2007-04

Project Summary/Abstract The specific goals for the proposed T35 Pre-Doctoral Research Traineeship Program at Vanderbilt University Medical Center are to recruit high-quality students as T35 research trainees, provide a productive and meaningful traineeship, nurture the foundation that transforms a clinical to research mindset, and facilitate progression towards a career as an independently NIH-funded clinician-scientist. This program supports the goal of the NIH to build a strong clinician-scientist workforce to meet biomedical, behavioral, and clinical research needs. The proposed T35 traineeship program is specifically for graduate students in training for a clinical doctorate in audiology (AuD). Scientists with a clinical background, such as audiology, are well positioned to identify key clinically driven questions that will ultimately impact patient care and outcomes. Despite the importance of engaging clinicians in research careers, the low number of individuals with clinical training in audiology who are obtaining research expertise and credentials via a PhD in hearing science remains a concern. Short-term support for three months of full-time research training is requested for five pre- doctoral AuD students for each of the five years of the grant. Trainees will select from among eleven preceptors in ten laboratories with active research programs in the Department of Hearing and Speech Sciences at Vanderbilt University Medical Center. Each trainee will conduct hands-on research involving all phases of a specific project in a laboratory under the guidance of their preceptor, complete formal training in responsible conduct in research and research reproducibility, complete a T35 research course taught by the T35 preceptors, participate in journal club discussions, and experience activities typical of a research career. The Vanderbilt preceptors’ research areas span basic and translational research in animal and human models and address a wide range of topics including cochlear and neural physiology, development, aging, hereditary hearing loss, speech perception, multisensory cortical function, directional hearing and amplification, pediatric audiology, cochlear implants and bimodal hearing, listening effort, and auditory fatigue. Trainees will learn about the aspects of developing, designing, collecting, analyzing, and interpreting data, and reporting the results of a research study. All trainees will present their research at a national scientific meeting and develop a manuscript, in collaboration with their preceptor, publishable in a peer-reviewed journal. Strengths of the proposed traineeship program include the standing of the Vanderbilt AuD program in the academic community, the excellent research environment with state-of-the-art laboratories, numerous collaborations among the preceptors, and strong institutional support. Independent researchers with clinical backgrounds are well suited to identify and solve public health problems. The proposed program will provide research training with the goal of developing a scientific mindset that leads the trainee to a research career. This will benefit society by ensuring a strong future for evidence-based research related to hearing health and patient care.

NIH Research Projects · FY 2026 · 2007-02

PROJECT SUMMARY/ABSTRACT The HIV pandemic is one of the greatest ongoing threats to health and development, over 35 years past its recognition. The NIAID-funded Clinical Trials Networks have played critical roles in the coordinated response to key research questions in the HIV/AIDS field, which will contribute to ultimately ending the HIV epidemic. The Vanderbilt HIV Clinical Trials Unit (CTU) will continue the established partnership between Vanderbilt University Medical Center in Nashville, Tennessee, and Washington University in St. Louis, Missouri, which are located in a region of the United States with high incidence and prevalence of HIV. This CTU comprises three highly productive Clinical Research Sites (CRSs) that contribute to three Networks - the therapeutics mission of the AIDS Clinical Trials Group (ACTG), the vaccine mission of the HIV Vaccine Trials Network (HVTN), and the non- vaccine prevention mission of the HIV Prevention Trials Network (HPTN). The Vanderbilt Vaccine CRS and Washington University Therapeutics CRS have been members of the HVTN and ACTG since the inception of these Networks in 1987-1988. The Vanderbilt Therapeutics CRS joined the ACTG in 2000. To contribute more broadly to the Networks, Washington University has provided protocol-specific enrollment to the HPTN since 2016, and proposes to become a full member site of the HPTN, as the Washington University Prevention & Therapeutics CRS. Leaders of this CTU have made high-impact scientific and programmatic contributions to the Networks in areas that include human genomics, contemporary HIV-associated comorbidities, neurological aspects of HIV disease, immunology of vaccine response, and beyond. During the proposed funding period, the Vanderbilt CTU will continue to make substantial contributions to the ACTG, HVTN and HPTN's scientific priorities. ACTG sites at both Vanderbilt and Washington University will focus on strategies to improve the health of people living with HIV/AIDS, tuberculosis, and viral hepatitis. The Vanderbilt HVTN site will contribute both study participants and cutting-edge immunologic technologies to further the major scientific priority of developing and testing a safe and effective vaccine for HIV. The Washington University site will additionally contribute to HPTN's emphasis on long-acting agents for pre-exposure prophylaxis, developing multipurpose technologies such as combining HIV prevention with contraception, and strategies integrating biomedical, behavioral and structural interventions for prevention. All CRSs of this CTU have an established record of success in enrolling participants to clinical trials and conducting studies with utmost fidelity to ensure participant safety and quality data advancing the science of HIV treatment and prevention.

NIH Research Projects · FY 2025 · 2005-03

Integrins are transmembrane receptors composed of α and β subunits that mediate interactions between cells and extracellular matrix. There are 18 α and 8 β subunits, which form dimers with different ligand binding properties. Integrins are classified into collagen, laminin and RGD binding receptors and regulate many cellular functions including adhesion, migration, proliferation, differentiation, and polarization. We previously showed the laminin binding integrins α3β1, α6β1 and α6β4 only play a minor role in kidney collecting system development. By contrast we now demonstrate that deleting the integrin α3 subunit in the developing kidney metanephric mesenchyme causes fatal renal abnormalities within a week of birth. When we introduced the same point mutations as those described in infants who died from renal dysgenesis into the extracellular domain of the α3 integrin subunit, the mice died with dysgenic kidneys, however the phenotypes were not as severe as the integrin α3-null mice. All three mice displayed severe kidney tubule and major glomerular abnormalities. As the mechanism whereby integrin α3β1-laminin interactions regulate organogenesis is unclear, we developed mice with a point mutation in the integrin binding site of the highly conserved γ1 laminin chain, which abrogates laminin- integrin binding to most laminins, without altering the structural integrity of the laminin trimer. When this mutation was introduced into the metanephric mesenchyme, the mice also developed dysplastic kidneys. Mechanistically we have preliminary evidence that in addition to the classic integrin functions of cell adhesion and migration, deleting Integrin α3β1 in polarized kidney epithelial cells causes severe proliferation defects with the cells unable to progress normally through the cell cycle. We have previously shown that Integrin α3β1 regulates Akt activation, a key requirement for cell proliferation. Taken together these new data suggest a critical role for laminin-binding integrins in nephron development and maturation, which contrasts with the mild phenotypes we found in the developing ureteric bud. Therefore, in this grant we will test the novel hypothesis that integrin α3β1 binding to laminin is critical for metanephric mesenchyme development and mutations that affect this interaction results in fatal renal dysgenesis in the following aims: 1) Define the role of integrin-laminin interactions in metanephric mesenchyme development. 2) Define the molecular mechanism whereby integrin α3β1-laminin interactions promote proliferation in metanephric mesenchyme development.

NIH Research Projects · FY 2025 · 2005-02

Abstract (Project Summary) We propose to parse the clinical heterogeneity of psychotic disorders by studying the evolution of hippocampal dysfunction in the early stage of psychosis (ESOP). Smaller hippocampal volume is one of the most significant brain abnormalities in chronic schizophrenia, but is less pronounced in prodromal and early stages of psychosis. In contrast, hyperactivity of the anterior hippocampus has been observed in both early and chronic stages of psychosis. Clinical and preclinical studies have identified excitation/inhibition imbalance as a plausible mechanism for hippocampal hyperactivity in psychosis. Clarifying the timing and mechanism of hippocampal dysfunction will improve our ability to intervene and prevent the progression from early psychosis to schizophrenia. We propose to study 2 ESOP cohorts. ESOP-1 will be a new cohort of acutely ill psychotic patients who meet DSM-5 criteria A for schizophrenia for at least one month, but not more than 2 years (i.e., schizophreniform disorder or early schizophrenia). We expect that, at the end of the study, 2/3 of the ESOP-1 cohort will have progressed to schizophrenia, while the remaining 1/3 will be diagnosed with schizophreniform disorder. ESOP- 2 is a well-characterized sample of schizophrenia patients, who have participated in repeated assessments during the first two years of their illness. From ESOP-1 we will recruit 30 patients and 30 healthy control subjects for the restoration of hippocampal excitation/inhibition balance. We predict that the hippocampus is hyperactive in the ESOP-1 cohort, resulting in perturbations of relational, hippocampal-based memory. We expect to find structural changes of the anterior hippocampus only in those ESOP persons who will progress to schizophrenia. In the ESOP-2 cohort, we predict progressive hippocampal volume loss, advancing from the anterior to the posterior region, resulting in more significant memory deficits. We predict that restoring normal excitation/inhibition balance will improve hippocampal function in ESOP persons. To test our hypotheses, we will collect high-density, multi-dimensional assessments of psychosis. We will use high-resolution parcellation protocols of the hippocampus and functional imaging of resting-state and task-based activation. We will use single dose administration of levetiracetam, an anti-epileptic drug, to modulate excitation/inhibition balance. The proposed combination of longitudinal and pharmacological imaging will allow us to study the timing and mechanism of hippocampal dysfunction in psychotic disorders. The integration of these approaches aims to establish a staging model of psychotic disorders, with the ultimate goal to aid early detection, prevention and treatment.

NIH Research Projects · FY 2025 · 2004-09

SUMMARY This application requests continuing support for post-doctoral training in surgical oncology research for four fellows. The Vanderbilt Department of Surgery has had a continuing commitment to mentored research for both resident research fellows and surgical oncology fellows. Given the rapid pace and complexity of both basic and clinical research, it is imperative to provide trainees with the requisite armamentarium of investigative skills during post-doctoral training. This goal is especially important to keep surgeons involved in all aspects of the range of cancer-related research. The establishment of both research proficiency and a pattern of mentored training are critical for the promotion of successful academic career pathways. Importantly, we have configured a multidisciplinary training program to allow development of investigators along basic, translational patient-oriented, or clinical research tracks. All three of these research paradigms are considered crucial to the success of broad-based cancer-related investigation. The objective of this program is to prepare general surgery and neurosurgery residents and surgical oncology fellows in Urology for investigative careers in research fields related to surgical oncology. Fellows commit at least two years to intensive training in basic, translational or clinical research through a mentored training environment necessary for the development of experience and proficiency in investigative techniques and reasoning. For those interested in basic science research training, opportunities for mentored investigation are available in the laboratories of scientists with broad interests in cancer biology. In addition to bench research training, fellows in the basic research track will participate in didactic course work as determined by the individual advisory committees. Pursuit of a basic science PhD program is available. Fellows interested in patient-oriented research training may pursue a Masters of Science in Clinical Investigation (MSCI). The MSCI program combines broad didactic coursework with a mentored research experience focused on patient related material or therapeutic intervention. Those interested in epidemiological or outcomes research may pursue a Masters of Public Health (MPH). The MPH program combines didactic coursework in clinical epidemiology with a mentored clinical research project. These three training tracks allow fellows to pursue the pathways best suited to their career objectives.

NIH Research Projects · FY 2025 · 2003-09

Summary / Abstract This is an application for renewal of a highly successful, competitive and comprehensive institutional postdoctoral training program in magnetic resonance imaging (MRI) and spectroscopy (MRS) that has been in place at Vanderbilt University since 2003. The 30 preceptor faculty comprise an experienced and expert group of research scientists engaged in the development and application of MR methods in several different important research areas and across different scales. MR methods serve not only as the single most important modality in diagnostic imaging but also provide crucial insights into biological processes and structure to address fundamental questions in biomedical research. There are continuing advances in MR technology, but there is a shortage and a critical need for appropriately trained scientists capable of fully exploiting the potential of MR techniques. We have developed a comprehensive training program in biomedical MRI and MRS designed for outstanding postdoctoral scientists from different backgrounds. Some have been exposed to imaging and MR methods before, but others have had little previous significant experience in biomedical MRI and MRS. Postdoctoral trainees from physics, chemistry, biology, engineering or medicine may receive thorough and exemplary instruction in all of the cognate areas relevant to biomedical NMR in a coherent and comprehensive program. In addition, trainees pursue research in MR methods and applications (mainly) in neuroscience, radiology, cancer and metabolic disorders and are co-mentored by collaborators from relevant clinical departments. Our program continues to evolve and in this renewal several notable enhancements are described. The formal training includes an educational program, consisting of courses, seminars, and journal clubs; a practical program, consisting of faculty-led tutorials and practical training; and a research program, in which trainees are integrated into an active research program. These programs illustrate most major aspects of the applications of MR methods in humans and animals. Trainees have access to outstanding facilities including three research-dedicated human MR systems (2 at 3T and one 7T); animal MR systems at 4.7T, 7T, 9.4T and 15.2T; and other imaging modalities. Trainees are also mentored in the ethics and methods of biomedical research, in rigor and reproducibility, as well as in grant writing and other important career skills. Our previous trainees have been very successful in their careers after leaving our program. Of 50 trainees to date, 20 are now faculty at major research universities, 12 continue as research fellows or research scientists in medical centers, 3 work in MR-related industries, 5 are engaged in biomedical administration or government positions, 2 are physicians, 6 are still in training, one died and and one is no longer able to work. The programs, personnel, and facilities at Vanderbilt provide outstanding opportunities for training in biomedical NMR of the highest caliber, and will ensure the remarkable insights into biology and disease made possible with MRI and MRS will be realized.