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

• 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
• 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' 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

 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.

 描述（由申请人提供）：本申请响应FOA PA-14-046，“指导临床科学家研究职业发展奖（父K 08）”，该奖项为具有临床博士学位的个人提供支持和“受保护的时间”，以便在生物医学和行为研究领域（包括转化研究）获得密集，监督的研究职业发展经验。代谢综合征（MetS）是一组包括肥胖和糖尿病的共存疾病，是慢性肾脏疾病和心血管疾病的重要危险因素。共存的MetS和肾动脉狭窄（MetS+RAS）加剧炎症并导致慢性肾脏疾病，强调需要有效的干预措施来减轻狭窄后肾脏的炎症。我们的初步数据表明，用靶向肽治疗可减少组织损伤并改善猪STEPS-肾的肾功能，但在MetS+RAS的临床前大型动物模型中，线粒体保护是否能挽救肾功能仍是未知数。该提议的假设是叠加的MetS诱导线粒体损伤并加剧狭窄RAS肾中的线粒体损伤。因此，mitoprotection将减轻肾脏结构和功能的损害，MetS放大在stetra-kidney，如细胞凋亡，纤维化，氧化应激和血管损失。为了验证这一假设，我们将利用我们最近开发的一种新的具有和不具有RAS的MetS猪模型，该模型专门模拟该疾病。我们还将利用独特的生理成像技术来研究体内和体外的单肾功能和结构。将追求三个具体目标：具体目标1将检验MetS诱导进行性肾线粒体损伤和功能障碍的假设。具体目标2将检验MetS加重RAS中肾线粒体功能障碍的假设。具体目标3将检验线粒体保护在MetS+RAS中保留肾结构和功能的假设。拟议的研究可以合理制定适当的治疗策略，以改善MetS+RAS患者的肾功能不全。该提案与申请人的职业目标非常一致，并将为他提供从理论和实验知识到未来独立职业所需的技术熟练程度的独特技能。