This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The objective of this application is to further establish an NMR metabolomics core for the Redox Biology Center (RBC). The central goal of the proposed research is to continue our on-going support for multiple RBC research projects that benefit from the inclusion of NMR metabolomics studies, to provide preliminary data to enhance RBC grant proposal submissions, to educate RBC faculty about the value of NMR-based metabolomics experiments, and to further develop NMR-based metabolomics technology to benefit the RBC community. Specifically, the proposed project will continue to provide systems biology and NMR metabolomics support for the following RBC projects: a. Raul Barletta and Ofelia Chacon: Essentiality of M. tuberculosis (Mtb) D-alanine racemase (Alr) and murC (UDP-N-acetylmuramate-alanine ligase MurC) gene. b. Donald Becker: Modulation of proline metabolism during stress. c. Jay Reddy: Identification of metabolites in the pathogenesis and treatment of experimental autoimmune encephalomyelitis. d. Greg Somerville: Citric acid cycle regulation of exopolysaccharide synthesis in staphylococci. These projects cover a diverse range of important human health issues that include: antibiotic resistance, cancer, multiple sclerosis, tuberculosis, and staphylococcal infections. NMR metabolomics provides a systems biology approach to monitor global changes or perturbations in the metabolome caused by disease or environmental stimuli (drugs). Our differential NMR metabolomics technology and metabolomics tree diagrams enable the comparative analysis between different cell states which will permit us to address the following questions: (i) are Alr and murC essential functions of Mtb and is Alr the target of the prototype antimicrobial D-cycloserine?, (ii) how does proline metabolism regulate intracellular redox status and cellular homeostasis (relationship to cancer therapy)?, (iii) can potential metabolite biomarkers in the murine MS model be used to assess MS response to treatments?, and (iv) are external signals transduced into internal metabolic signals by the TCA cycle to control PIA and capsule synthesis in Staphylococcal infections? Furthermore, we will use NMR to identify and quantify metabolites with concentration changes resulting from different disease and/or cell states. This will facilitate the construction of metabolite networks to further understand the systems global response to the disease, drug or cellular process. The proposed work is naturally collaborative and has already led to a number of successful projects, published papers, funded and submitted grants. Importantly, the proposed work will enable the continued support of existing and new RBC research projects and grant applications. It also supports the NIH Roadmap for Medical Research: Metabolomics Technology Development.
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