Vanderbilt University

NIH Research Projects · FY 2025 · 2002-07

Vanderbilt University proposes a 5-year renewal of its Training Program in Biomedical Informatics and Data Science. Established in 2001, the Vanderbilt program offers MS and PhD degrees in biomedical informatics, nondegree postdoctoral training, and short-term training experiences. The program attracts excellent applicants from a variety of backgrounds, both clinical and scientific, and has strong program outcomes in terms of scientific productivity and successful careers in research. Vanderbilt's commitment to biomedical informatics and data science has produced a uniquely rich and diverse research and training environment. Department of Biomedical Informatics (DBMI) faculty include leaders in clinical informatics and translational bioinformatics, as well as other subdomains of informatics including clinical research informatics, public health informatics, consumer health informatics, biomedical data science, and people and organizational systems. Faculty are well-funded with external grants, and many also hold part-time operational roles in Vanderbilt University Medical Center that allow them to conduct both foundational and applied informatics research. The MS and PhD degree programs include a core curriculum of courses in biomedical informatics structured around core competencies in computer and information science, biomedicine, social sciences, and research methodology. Degree-seeking students establish competency in these core areas and also pursue specialized study in one of several application domains: clinical informatics, translational bioinformatics, or biomedical data science. A new specialization in HIV informatics is being developed, in collaboration with the Tennessee Center for AIDS Research and NIAID-funded researchers at DBMI. In addition, the program offers research- intensive nondegree postdoctoral fellowships and a summer research experience. For the period 2023-2027, Vanderbilt requests 11 full-time training positions. The full-time training positions include 7 NLM-funded predoctoral positions for candidates pursuing the PhD and 3 postdoctoral positions with a training endpoint of the research-oriented MS. In addition, these full-time positions will include 1 NIAID-supported position in HIV informatics. We will continue to recruit through outreach to national and regional institutions, professional societies, and training programs. . The Vanderbilt Training Program in Biomedical Informatics and Data Science has a robust history of meeting the NLM's objectives for biomedical informatics research training, and will continue to do so. Our graduates have excelled in pursuing research to advance informatics as a scientific discipline and apply it to solve problems in health and health care.

NIH Research Projects · FY 2025 · 2001-05

The human lens must maintain transparency over many decades and, to do so without a blood supply, the lens maintains a fluid microcirculation system (MCS) to deliver nutrients throughout the tissue. Although the influx of water, ions, and nutrients occurs at the anterior and posterior poles via the lens sutures and fluid outflow occurs toward the equatorial efflux zone, the molecular details of how the MCS is established and maintained with age are not well understood. It is, however, agreed that spatial differences in the expression and functionality of channels and transporters are critical to the generation of ion and fluid circulation. In this application we focus on lens aquaporins (AQPs) that we hypothesize play important roles in generating the lens MCS by establishing differences in water permeability in influx, outflow, and efflux zones. Aquaporin-0 (AQP0), the most abundant lens membrane protein, has reported roles in lens fiber cell adhesion, in basal water permeability, and in fiber cell organization and, as such, is vital for the development and maintenance of lens transparency. A second aquaporin, AQP5, is also present in lens fiber cells and can act as a regulated water channel since mechanical tension can alter AQP5 subcellular localization in fiber cells of the anterior pole and equator to presumably dynamically regulate water permeability. The long-term goal of our research is to understand how lens protein modifications that occur during development, aging, and cataractogenesis help establish or alter the MCS thereby leading to lens transparency or opacification. In the context of the microcirculation system, we hypothesize that AQP posttranslational modifications and AQP-lipid interactions are important molecular mechanisms used to modulate AQP functionality in the influx, outflow, and efflux zones. To test our hypotheses, we will employ advanced quantitative proteomics, native mass spectrometry, multi-modal imaging methods, and water permeability assays to obtain a molecular level understanding of how the structures and functions of lens AQPs change in influx, outflow, and efflux zones. Further, we will examine changes in AQP modifications and subcellular localization in organ cultured lenses exposed to stimuli that either dynamically regulate lens water transport or compromise the ability of the MCS to maintain lens transparency. This suite of methods will be applied to lens to test three hypotheses: 1) that water influx into the lens is increased by AQP5 membrane trafficking in the anterior suture region of the lens, 2) that AQPs direct intracellular water flow toward the lens equator in the outflow zone, and 3) that AQP5 trafficking to the membrane in the efflux zone dynamically regulates the MCS in response to mechanical tension, and oxidative or osmotic stress; stresses that mimic age related nuclear and diabetic cataract, respectively. We expect to provide a new mechanistic understanding of the roles of AQPs and their modifications in maintaining lens transparency. With this in-depth understanding, strategies for the development of novel therapies to delay the onset and progression of lens cataract can be envisioned.

NIH Research Projects · FY 2025 · 2001-02

PROJECT SUMMARY We and others have shown that stimulation or potentiation of metabotropic glutamate receptor 5 (mGlu5) reverses cognitive deficits in rodent models relevant for schizophrenia and other neurological disorders. We have also made the discovery that co-activation of another mGlu receptor subtype, termed mGlu3, dramatically potentiates mGlu5 signaling in the hippocampus as well as in in vitro culture systems. We demonstrate here that co-activation of mGlu3 and mGlu5 induces hippocampal long-term potentiation (LTP) and potentiates induction of LTP by afferent stimulation. Furthermore, mGlu3 activation enhances hippocampal-dependent learning in an mGlu5-dependent manner. Using mice in which mGlu3 or mGlu5 can be deleted in a cell-type specific pattern, we have also found that loss of either receptor from hippocampal pyramidal cells eliminates the ability of mGlu3 agonists to enhance long-term potentiation or improve performance in a hippocampal-dependent cognitive task. These findings provide a mechanistic bridge to genome-wide association studies (GWAS) and other human genetic studies showing associations between polymorphisms in the GRM3 gene and impaired cognitive function in schizophrenia patients. Additional co-expression studies suggest that this specific mGlu3/mGlu5 cross-talk may also occur in other brain regions that are critical for cognitive deficits in schizophrenia, such as the prefrontal cortex (PFC). For example, mGlu5 also regulates PFC-dependent cognitive function and our preliminary data suggest that activation of mGlu5 induces a novel form of LTP at excitatory synapses from the amygdala projections onto a specific population of inhibitory interneurons that express somatostatin (SST-INs). Mechanistically, these may reverse reductions in PFC inhibitory transmission that are associated with cognitive and negative symptoms of schizophrenia. Both mGlu3 and mGlu5 are expressed in SST-INs, and both have been implicated in forms of memory that depend on activation of SST-INs. We have also found evidence for specific signaling interactions between mGlu3 and mGlu5 in SST-INs. Based on these results, we postulate that mGlu3 and mGlu5 interact to induce LTP in PFC SST-INs. Furthermore, we hypothesize that either mGlu5 PAMs or mGlu3 agonists will enhance forms of cognition that require activation of SST-INs in the PFC, and that this response will be increased upon co-activation of these receptors. Using mGlu3 and mGlu5 subtype-selective modulators, mice lacking each receptor in a cell-type specific pattern, as well as chemogenetic, optogenetic, and a Drugs Acutely Restricted by Tethering (DART) approach to modulate activity of specific neuronal populations, we will test the hypothesis that mGlu3 activation enhances multiple other forms of cognitive function that are regulated by mGlu5 potentiation. Finally, we will determine if this mGlu3/5 interaction is intact after juvenile exposure of rodents to phencyclidine, which induces cognitive deficits that may be relevant for schizophrenia.

NIH Research Projects · FY 2025 · 1998-07

This proposal requests continued support for the Molecular Endocrinology Training Program (METP) at Vanderbilt University. Progress towards understanding and curing obesity, diabetes and many other diseases requires the training of the next generation of scientists with expertise in molecular endocrinology, the goal of this program. The METP comprises 29 faculty members from 5 science departments. The METP preceptors constitute an unusually talented group of individuals whose work covers the spectrum of molecular endocrinology. These preceptors conduct research in the general areas of: 1) signal transduction 2) metabolic regulation and 3) pancreatic islet cell development and function. The request for funding of a steady state level of 8 predoctoral and 4 postdoctoral trainees is justified on the basis of the number, size and quality of the research programs directed by the preceptors and the Institutional commitment to continue the same level of trainee recruitment despite the tough economic climate. All METP trainees are appointed upon the advice of a Steering Committee after being nominated by a preceptor. Postdoctoral trainees have a Ph.D. degree. Rigorous in-depth research training is the focus of both the pre- and postdoctoral training programs. However, the METP also ensures that all trainees receive a broad didactic education. Predoctoral training in the METP usually follows that received in the Interdisciplinary Graduate Program (IGP). The IGP recruits almost all predoctoral trainees in the biomedical sciences at Vanderbilt, provides a first year core curriculum, safety training and formal evaluation and career counseling programs. This centralized recruitment has considerably increased the number and quality of predoctoral students that enter Vanderbilt. After four laboratory rotations predoctoral students choose a preceptor for their thesis project and compete for METP support. The IGP and METP have been very successful in providing training in the Responsible Conduct of Research and Rigor. All METP trainees attend an annual METP Day retreat, trainee-run data clubs and the Vanderbilt Diabetes Center (VDC) seminar series where they meet with visiting scientists. The METP has already successfully trained 173 individuals of whom 128 have gone onto careers involving science with another 45 individuals still in training.

NIH Research Projects · FY 2025 · 1997-08

PROJECT SUMMARY This application seeks continuing support for the Microenvironmental Influences in Cancer Training Program (MICTP) at Vanderbilt University. Over the past 35 years, we have successfully recruited and trained excellent students and postdoctoral fellows, including many from groups underrepresented in science. Based on the strength of our training faculty, in the next five years, we will focus on training our students and postdoctoral fellows in emerging areas of the tumor microenvironment, including quantitative analysis of large datasets, tumor immunology, influences of bone and bone marrow cells, hypoxia and blood vessel normalization, spatial analyses of tumor interactions with the microenvironment, and extracellular vesicles. Overall, the MICTP training program encompasses a group of 30 faculty members from the Vanderbilt University School of Medicine who are experts on the tumor microenvironment. The training program is conducted within a vibrant academic environment and is supported by close interactions with the Vanderbilt-Ingram Comprehensive Cancer Center. In addition to preceptor-specific laboratory instruction, each trainee receives program- specific training in the form of (1) Topical workshops, which introduce trainees to emerging fields of the tumor microenvironment; (2) Individualized training coursework that may include “Cancer Precision Medicine” with individualized clinical experience, (3) a monthly T-32 Scientific Forum with trainee works-in-progress talks and faculty presentations covering science and careers, (4) an annual MICTP mini-retreat, and (5) a five-session grant workshop (6) Training in Diversity and inclusion in collaboration with the Diversity office in the School of Medicine. Faculty preceptors also receive mentorship training including “Culturally Aware Mentoring”. Furthermore, predoctoral students are supported by an Interdisciplinary Graduate Program and the Program in Cancer Biology. Postdoctoral trainees are supported by an institutional Office of Postdoctoral Affairs, which provides both financial and academic support as well as career development advice and career development opportunities. Vanderbilt University and the VICC have committed a significant ongoing investment in training programs, core facilities, state-of- the-art laboratories, and equipment that help create a rich training environment for our trainees. Our program uniquely intersects with VU and VICC to provide training in a novel and critical area to create an essential workforce to understand the complexities of the microenvironmental influence on cancer development and progression, and to translate this information into more effective and less toxic approaches to the treatment and prevention of cancer.

NIH Research Projects · FY 2026 · 1997-04

Project Summary We propose to elucidate fine molecular mechanism of arrestin-1 interaction with rhodopsin, focusing on the aspects of this mechanism that ensure remarkable selectivity of arrestin-1 for light-activated phosphorylated rhodopsin and much lower binding to all other functional forms of rhodopsin (inactive phosphorylated, light-activated unphosphorylated, inactive unphosphorylated, opsin, and phosphorylated opsin). We propose to design “enhanced” arrestin-1 mutants with high binding to unphosphorylated light- activated rhodopsin. We expect these mutants to compensate for defects in rhodopsin phosphorylation in vivo. Mutants of this kind have therapeutic potential in human visual disorders caused by absent or insufficient rhodopsin phosphorylation. Based on the discoveries of non-rhodopsin binding partners of arrestin-1 we propose to use in vivo proximity labeling to identify novel arrestin-1 interaction partners in rod photoreceptors. These partners will be biotinylated by AirID fused to arrestin-1 (we validated both functions of the two fusions we propose to use), purified via biotin binding to avidin, digested into peptides, which will be identified by mass spectrometry (LC-MS/MS).

NIH Research Projects · FY 2025 · 1993-12

PROJECT SUMMARY/ABSTRACT The Vanderbilt Vision Research Center (WRC) request continued support for predoctoral and postdoctoral training. Vision and eye researchers at Vanderbilt maintain an exceptionally strong training record with excellent research progress. Aggressive faculty recruiting has increased the number and quality of mentors and the number of NEI-funded research grants. The program of research and training extends from traditional psychophysics with structural and functional brain imaging and visual neuroscience to cellular and molecular eye research. Individuals trained during previous grant periods have obtained competitive postdoctoral or faculty positions and developed productive, independent careers in vision research. Training will continue in psychophysics, visual neuroscience and molecular mechanisms of transduction, retinal processing and retinal disease. Specific program requirements for predoctoral trainees include (1) The Visual System course team-taught by program faculty, (2) additional courses specified by the trainee's graduate program selected from an extensive curriculum covering molecular biology, neuroscience, perception and engineering, (3) participation in the local Vision Training Seminar series, the invited speaker Vision Research Seminar series, and Eye & Vision Research Colloquia as well as related seminars on campus, (4) participation in international scientific meetings such as Association for Research in Vision & Ophthalmology, Vision Science Society and Society for Neuroscience, (5) participation in a Responsible Conduct of Research program, and (6) most importantly, research supervised by one or more mentors. Postdoctoral trainees are required to fulfill the same requirements except (2) while they prepare an independent NRSA proposal. This training program develops independent, academic vision and eye researchers through interdisciplinary training in vision and eye research fostered by the number and cohesiveness of vision and eye researchers at Vanderbilt.

NIH Research Projects · FY 2025 · 1993-08

Emerging, preclinical, clinical, and human genetic studies raise the exciting possibility that selective activators of the mGlu1 subtype of metabotropic glutamate (mGlu) receptor have potential utility as a novel approach for treatment for schizophrenia. However, until recently, tools were not available to allow studies of the functional roles of mGlu1 in specific brain circuits. We have now developed highly selective mGlu1 positive allosteric modulators (PAMs), along with genetic mouse lines that allow selective deletion of mGlu1 in specific neuronal populations. This provides an unprecedented opportunity to establish the roles of mGlu1 in specific brain circuits that are disrupted in schizophrenia patients. Interestingly, we recently found that highly selective mGlu1 PAMs reduce striatal dopamine (DA) release and have robust efficacy in rodent models of antipsychotic activity, such as reversal of amphetamine-induced hyper-locomotor activity and disruption of sensory motor gating. Based on recent studies and our preliminary data, we postulate that activation of mGlu1 in a specific population of spinal projection neurons that also express the D1-DA receptor (D1-SPNs) is responsible for the ability of mGlu1 PAMs to inhibit DA release and to reverse behavioral effects of amphetamine that are relevant for potential antipsychotic activity. However, it is possible that activation of mGlu1 in DA terminals or other neuronal populations could be responsible for these effects on DA release and for the behavioral effects of mGlu1 PAMs. Thus, we will perform a series of studies in specific aim 1 to rigorously evaluate the importance of mGlu1 in D1-SPNs and other neuronal populations in the effects of mGlu1 PAMs on DA release and associated behaviors. In addition to dysregulation of striatal DA release, multiple clinical and preclinical studies suggest that loss of GABAergic inhibitory transmission in the prefrontal cortex (PFC) and other forebrain regions may play a critical role in the pathophysiological changes underlying cognitive deficits in schizophrenia patients. Additionally, disinhibition is observed in humans and rodents in response to NMDA receptor blockade. We now present exciting new preliminary data suggesting that activation of mGlu1 can increase activity of somatostatin-expressing inhibitory interneurons (SST-INs) and parvalbumin (PV)-expressing interneurons (PV- INs) in the PFC, with an especially robust increase in excitability of SST-INs. In addition, our preliminary data suggest that SST-INs in the PFC are critical for working memory, and led us to postulate that activation of mGlu1 on SST-INs may improve working memory and reverse working memory deficits in rodent models. In specific aim 2 we confirm our preliminary electrophysiology findings and rigorously test the hypothesis that mGlu1 activation increases inhibitory transmission in the PFC by actions on SSN-INs. In specific aim 3, we will test the hypothesis that activation of mGlu1 in SST-INs can reverse deficits in working memory and other behavioral deficits observed in an NMDAR hypofunction model of cortical disinhibition. These studies could provide new mechanistic insights into the therapeutic potential of mGlu1 PAMs for treatment of schizophrenia.

NIH Research Projects · FY 2024 · 1992-02

Abstract: Environmental exposures to aflatoxin B1 (AFB1), a mycotoxin isolated from Aspergillus flavus, are linked to the etiology of hepatocellular cancer (HCC). We propose three aims. The first examines the role of base excision repair (BER) by the hNEIL1 glycosylase, and "cancer- prone" variants of hNEIL1 in regions of exposure to AFB1, in excising AFB1 damage from DNA. Deficiencies in repair of AFB1 DNA damage may be associated with early onset HCC, common in areas of China with high AFB1 exposures, and contribute to the mutagenic signature associated with AFB1 exposures. We will employ genetically edited mouse embryonic fibroblasts (MEFs) to determine how hNEIL1 variants modulate the mutagenic signature. We will employ crystallography to understand mechanism for repair of AFB1 damage in DNA by hNEIL1 and variants. Structural and dynamic changes associated with variants may reveal genetic risk factors for HCC. Our second aim focuses on the mechanism of error-prone DNA replication of AFB1 damage. The polymerase ζ specializes in extension beyond DNA damage and factors in the genesis of A to T transversions characteristic of AFB1 exposures. We will employ cryo-EM to determine structures of pol ζ complexed with AFB1-damaged DNA, accompanied by functional assays. Crystallography will be employed to probe the mechanism of nucleotide insertion opposite AFB1 lesions by DNA polymerase pol η. Our third aim focuses on the respective roles of sequence-specific lesion bypass and formation of AFB1-Fapy-dG lesions in the etiology of “Signature 24”, a sequence-specific pattern of G to T transversions characteristic of exposures to AFB1. Fidelity and efficiency of bypass will be tested using sequence-specific substrates including modeling replication forks. We will examine how the AFB1 mutagenic signature is altered in Pol ζ-deficient MEFs. Sequence-specific rates of adduct formation will be probed by competition assays under conditions in which AFB1-epoxide is the limiting reagent. We will determine if re-arrangement of AFB1-N7-dG to (a) less mutagenic AP sites, or (b) mutagenic AFB1-Fapy-dG, depends upon DNA sequence. We will examine cytosine methylation to probe epigenetic contributions to the AFB1 mutagenic signature. We will employ NMR to monitor complex sequence-specific conformational and configurational equilibria associated with AFB1- Fapy-dG lesions in dsDNAs, in situ. We will also use NMR to measure sequence-specific kinetics of DNA base pair opening, which may control rates of base-flipping during repair. AFB1 is an important environmental genotoxin; our work should provide new understanding of environmental determinants of HCC.

NIH Research Projects · FY 2024 · 1989-07

PROJECT SUMMARY This application is for a 5-year renewal of the T32 Training Program in the Development of Psychopathology: From Brain and Behavior to Intervention. Because mental and substance abuse disorders are more likely to arise early in life, early identification of risk processes and early intervention are crucial (Insel, 2014). As the field has been shifting from a behavioral to a neurodevelopmental focus, this training program also has evolved to reflect important advances in human brain development. The major thrust of this interdisciplinary program is to produce scientists who will (1) contribute to the state of knowledge about neurobiological and psychosocial mechanisms underlying the development and maintenance of psychopathology, and (2) translate findings from basic research to the construction of empirically-based interventions for the prevention and amelioration of psychopathology and for the promotion of mental health. This training program provides individual mentoring in multidisciplinary science complemented by didactic activities. A personalized training plan is developed for each fellow and re-evaluated each semester. In the last five years, we have continued to increase training on multidisciplinary research on neurobiological, psychophysiological, genetic, and psychosocial mechanisms underlying psychiatric illness. To this end, we have made some changes to our core, training faculty. All 24 faculty are currently funded, with 75% as PIs on at least one grant, and the others serving as co-PIs or investigators. Two-thirds of our current training faculty are actively involved in neuroscience research. Another 54% of our faculty conduct intervention studies aimed at reducing or preventing psychiatric problems including depression, anxiety, and substance use. In the last decade, all of our 26 pre- and 10 post-doctoral trainees have continued to contribute to the field through scholarly research, teaching, and administration. Three predocs remain in training on this T32; 2 former trainees are working on their dissertations; 4 are doing their required clinical internship. All 17 remaining former predoc trainees have completed their PhDs; 4 are engaged in research intensive faculty positions in academic departments of psychology or medicine; 3 are doing research intensive postdoctoral fellowships. The remaining 10 former predoc trainees are doing some research related work including teaching, supervision, or administration. Of the 10 postdoctoral fellows, 2 are still in training; 6 of the 8 (75%) former postdocs are actively involved in research intensive faculty positions and all have received some kind of external funding (e.g., K’s; R01, Foundations). In the past 10 years, 22% of all trainees were from under- represented ethnic minority or economically disadvantaged groups; 83% are female. This renewal application proposes to again support 4 predoctoral and 2 postdoctoral trainees annually. Goals for the next 5 years are to continue to train independent research scientists who can discover and translate basic knowledge from clinical neuroscience into interventions for reducing psychopathology.

NIH Research Projects · FY 2025 · 1987-06

Project Abstract This renewal application seeks support for the training of predoctoral students and postdoctoral fellows in biochemical, chemical, biological and structural approaches for cancer research. The training program integrates contemporary cancer biology (e.g., oncogenes and tumor suppressors, signal transduction, oncogenic transcription factors, DNA modifications, cell cycle control, genomic surveillance) with the allied fields of chemical biology, chemical-genetics, and structural biology. Over the past 35 years, this Training Program has an outstanding training record and seeks to continue this multidisciplinary training program that is composed of 29 preceptors from nine academic departments and programs representing the Vanderbilt University School of Medicine, School of Engineering, the College of Arts and Sciences and the Vanderbilt University Medical Center. The training program is conducted within a vibrant academic environment and is supported by close interactions with the Vanderbilt-Ingram NCI-designated Comprehensive Cancer Center, the Vanderbilt Institute of Chemical Biology, and the Vanderbilt Center for Structural Biology, all of which offer resources for trainees and preceptors. In addition to departmental and preceptor-specific laboratory instruction, each trainee receives cancer- related training in the form of three courses focused on cancer biology and experimental cancer research. An Interdisciplinary Graduate Program (IGP), the Chemical and Physical Biology Program (CPB), and an independent graduate program in Chemistry all academically support predoctoral trainees. This renewal applications continues several recent enhancements to our training program including a Precision Cancer Medicine course that provides an immersive clinical experience. In the COVID era, we have also lauched 15 bioinformics micro-training courses for large datasets. We have an active mentoring program that includes former student trainees, postdoctoral mentors, and faculty mentors, which ensures the continued development of academic skills for cancer research and career development. Significant institutional investment in training programs, core facilities, state-of-the-art laboratories and equipment that provide technology resources applicable to cancer biology and molecular structures also enhance trainee development. The institution has also made additional investiments to provide an inclusing training environment that his free of any form of harassment or discrimination while emphasizing rigor, reproducibility and transparency. This integrated training in biochemistry, chemistry, structural biology, and cancer biology is critical to the molecular understanding of cancer and the development of new approaches to molecularly targeted therapeutics.

NIH Research Projects · FY 2025 · 1978-06

Project Summary/Abstract The proposed studies will clarify the mechanisms by which glucose metabolism is dysregulated following consumption of a diet high in fat and fructose (HFHF; i.e. “Western diet”). Studies will be carried out in normal and diet-induced glucose intolerant dogs. The canine model is unique in that it allows infusion into the hepatic portal vein (e.g., insulin, glucagon, glucose, amino acids, etc.), as happens with feeding, something that is not possible in the human or rodent. In the transition from feeding to fasting the liver switches from glucose production to uptake (HGP→HGU), a process critical to the maintenance of normal glucose tolerance. Hepatic glucose metabolism is regulated by three principal signals: insulin, glucose, and neural input (portal glucose signal [PGS]). The latter occurs when the glucose concentration in the hepatic portal vein is greater than in arterial blood, as occurs when glucose is absorbed from the gut. Consuming a HFHF diet severely impairs HGU. Although this is due, in part, to liver insulin resistance, we recently found that hepatic glucose resistance plays an even greater role. In this proposal we: 1) explore the impact of the route of insulin delivery on the compromised liver. Patients with diabetes are normally treated with subcutaneous insulin injection, which results in a very different distribution in the body (enriching the liver with insulin) than when insulin is secreted by the pancreas. We will determine the metabolic consequences of peripheral insulin delivery on liver glucose metabolism in the HFHF dog. This will shed light on the need for ways to insulinize the liver preferentially. 2) We will determine how the signals that regulate mealtime HGU interact with each other in HFHF fed animals and the relative importance of the loss of insulin action and the loss of the PGS in the regulation of HGU. 3) Like with the PGS, there are sensors in the hepatoportal region that detect when protein (amino acids) has been consumed. The body responds to amino acids and glucose by producing insulin and glucagon, hormones that regulate the liver's response to nutrients. While the HFHF diet causes severe hepatic glucose dysfunction, less is known about how it affects the liver's handling of amino acids and protein metabolism. Likewise, the interaction between liver glucose and protein metabolism in the HFHF fed liver will be examined. 4) Glucagon has a complex role in metabolism. It counters the hypoglycemic effects of insulin (its levels increase as glucose levels fall). On the other hand, glucagon also increases when protein is consumed. While this might be expected to negatively impact the glucose lowering effects of insulin, recent evidence suggests that high levels of glucagon might somehow work together with insulin to clear ingested amino acids from the blood and to reduce glucose levels. We will determine if this is the case under more physiological circumstances. We believe that the knowledge gained from the proposed experiments will assist in the development of new therapeutic approaches in the treatment of metabolic disorders.

NIH Research Projects · FY 2025 · 1975-07

PROJECT SUMMARY/ABSTRACT The Training Program in Environmental Toxicology is a long-standing research training program that emphasizes molecular toxicology. The long-term objectives of the program are to provide rigorous training in molecular toxicology through didactic approaches, while concurrently providing resources and support to permit full and vibrant development of trainees’ research skills and careers. We will support a total of eight predoctoral and four postdoctoral fellows annually. Our Specific Aims are to 1) Identify and recruit a diverse group of faculty that allows trainees maximal choice in research topics, approaches, and mentoring styles; 2) Identify and recruit strong trainees interested in pursuing a career in toxicology-related research and support their development during critical periods of their predoctoral and postdoctoral fellowships; 3) Provide clear instruction in the principles of molecular toxicology and ensure that this education addresses fundamental principles of toxicology and also reflects developing themes in research in toxicology and environmental health in general. These aims are realized through the clear program plan, the strong faculty of preceptors, and the robust training environment and resources at Vanderbilt. Our preceptor list includes 25 faculty with diverse research interests and strong extramural support, with research programs having current year direct costs for NIH and VA funded research totaling over $17 million. Faculty preceptors are identified whose research bears a strong relevance to the NIEHS mission of understanding environmental drivers of human health and disease, and preceptors are required to have attended formal mentoring training programs. In addition to the highly experienced and successful mentors, inclusion of more junior faculty ensures continuation of our strong tradition in investing in our trainees and their faculty to maximize potential. Predoctoral trainees are nominated to the program at the end of their first year in graduate school following entry via one of the Vanderbilt ‘umbrella’ (interdisciplinary) programs. A series of three or four rotations during labs within the first year allows trainees to select mentors and laboratories that are the best fit for them intellectually and according to topic and allows mentors to identify students with a passion for toxicology-relevant research. In addition to hands-on lab-based training and personalized mentorship, trainees receive comprehensive training in molecular toxicology through one semester of didactic teaching (offered annually) and continued educational opportunities and career development seminars in monthly meetings. In the present application the training approach has been updated to reflect best practices in teaching and trainee feedback. Novel aspects in this project period include introduction of new preceptors and a new multi-PI model. We have also refined our training program to including a stronger focus on multiple aspects of career development suitable for those continuing to academia, administrative, and industry positions.

Other NSERC · FY 2024

Soft Robotics, Continuum Robotics, Surgical Devices, Sensory Systems, Control Systems, Mechatronics, Image Guided Surgery

Other NSERC · FY 2024

medical imaging, spinal cord, MRI sequence development, magnetic resonance imaging, software development, 3D motion correction, CEST MRI, multi-slice acquisition