? DESCRIPTION (provided by applicant): This application responds to FOA PA-14-046, Mentored Clinical Scientist Research Career Development Award (Parent K08), which provides support and protected time to individuals with a clinical doctoral degree for an intensive, supervised research career development experience in the fields of biomedical and behavioral research, including translational research. The metabolic syndrome (MetS) is a cluster of co-existing conditions including obesity and diabetes, important risk factors for chroni kidney disease and cardiovascular morbidity. Coexisting MetS and renal artery stenosis (MetS+RAS) intensify inflammation and lead to chronic kidney disease, underscoring the need for effective interventions to attenuate inflammation in the post-stenotic kidney. Our preliminary data suggest that treatment with mitochondria-targeted peptides decreases tissue damage and improves renal function in the swine stenotic-kidney, but whether mitoprotection rescues kidney function in a pre-clinical large animal model of MetS+RAS remains unknown. The hypothesis underlying this proposal is that superimposed MetS induces mitochondrial injury and exacerbates it in the stenotic RAS kidney. Hence, mitoprotection would attenuate renal structural and functional impairment that MetS magnifies in the stenotic-kidney, such as apoptosis, fibrosis, oxidative stress, and vascular loss. To test this hypothesis we will take advantage of a novel swine model of MetS with and without RAS that we recently developed that specifically mimics the disease. We will also take advantage of unique physiological imaging techniques to study single-kidney function and structure in-vivo and ex-vivo. Three specific aims will be pursued: Specific Aim 1 will test the hypothesis that MetS induces progressive renal mitochondrial damage and dysfunction. Specific Aim 2 will test the hypothesis that MetS exacerbates renal mitochondrial dysfunction in RAS. Specific Aim 3 will test the hypothesis that mitoprotection preserves renal structure and function in MetS+RAS. The proposed studies could allow rational development of adequate treatment strategies to ameliorate renal dysfunction in patients with MetS+RAS. This proposal is well aligned with the applicant's career goals and will provide him with unique skills from theoretical and experimental knowledge to technical proficiency required for his future independent career.
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