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A potential role for mitoprotection in preserving the kidney in metabolic syndrome and renal artery stenosis

有丝分裂保护在代谢综合征和肾动脉狭窄中保护肾脏的潜在作用

基本信息

批准号：
9115146
负责人：
Alfonso Eirin
金额：
$ 16.15万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9115146
关键词：
Address Animal Model Apoptosis Attenuated Behavioral Research Biomedical Research Blood Vessels Cardiolipins Cardiovascular system Cell Respiration Cell physiology Cells Child Chronic Chronic Kidney Failure Clinical Data Development Diabetes Mellitus Diet Disease Doctor&apos s Degree Family suidae Fibrosis Functional disorder Future Generations Goals Health Imaging Techniques Incidence Individual Inflammation Infusion procedures Injury Inner mitochondrial membrane Insulin Resistance K-Series Research Career Programs Kidney Kidney Diseases Knowledge Lead Magnetic Resonance Imaging Measures Mentors Metabolic syndrome Mitochondria Modeling Morbidity - disease rate Obesity Organ Organelles Oxidative Stress Parents Pathogenesis Patients Peptides Physiological Production Reactive Oxygen Species Recovery Renal Artery Stenosis Renal function Research Risk Factors Role Scientist Secondary Hypertension Structure Subcutaneous Injections Techniques Testing Time Tissues Translational Research Tubular formation Work X-Ray Computed Tomography blood oxygen level dependent career career development detector effective intervention experience functional disability functional outcomes improved in vivo kidney vascular structure mitochondrial dysfunction mortality novel peroxidation pre-clinical prevent skills treatment strategy

项目摘要

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.