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Mitochondrial biogenesis in kidney disease

肾脏疾病中的线粒体生物发生

基本信息

批准号：
8554360
负责人：
Samir M Parikh
金额：
$ 36.52万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-27 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8554360
关键词：
Accounting Acute Renal Failure with Renal Papillary Necrosis Address Affect Agonist Animal Experiments Antioxidants Back Behavior Biochemical Biogenesis Biology Blood Vessels Cell Death Cells Chronic Kidney Failure Clinical Complication Critical Illness Data Dependency Disease Disease Progression Dose Drops Electron Transport Enzymes Experimental Designs Experimental Models Failure Figs - dietary Filtration Functional disorder Genes Genetic Genetic Transcription Health Hospitalization Human Incidence Inflammation Inflammation Mediators Inflammatory Injury Ischemia Kidney Kidney Diseases Knock-out Knockout Mice Knowledge Life Metabolism MicroRNAs Mitochondria Modeling Molecular Morbidity - disease rate NF-kappa B Natural regeneration Oxygen Consumption PPAR gamma Pathogenesis Pathway interactions Patients Pharmacologic Substance Predisposition Process Proteins Publishing Recovery Renal function Renal tubule structure Reperfusion Injury Reporting Research Risk Risk Factors Role Sepsis Signal Transduction Structural Protein TNF gene Technology Testing Therapeutic Time Translating Tubular formation adenylate kinase cost design falls gain of function imaging modality novel novel therapeutics receptor renal ischemia research study response restoration septic small molecule stressor tool

项目摘要

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is a major complication for hospitalized patients, and renal ischemia is a predominant risk factor. Intensive research into mechanisms underlying renal dysfunction following ischemia have not translated to new therapies, in part because different forms of ischemia may involve non- overlapping molecular pathways. RATIONALE: PGC-1a, a regulator of mitochondrial biogenesis, is heavily expressed in the proximal tubule, becomes suppressed early during sepsis and ischemia-reperfusion injury, and in both situations, exacerbates renal function when genetically deleted from the proximal tubule. Human proximal tubular cells respond to inflammatory mediators by suppressing downstream effectors of PGC-1a and diminishing oxygen consumption, changes reversed by forced expression of PGC-1a. HYPOTHESIS: This proposal will test the hypothesis that suppression of PGC-1a may be a shared mechanism that exacerbates renal function in two forms of ischemic AKI, sepsis and ischemia-reperfusion injury (IRI). AIMS: The first aim will investigate mechanisms that enable inflammatory mediators to suppress PGC-1a expression in primary human proximal tubular cells. The second aim will use models of sepsis and IRI in proximal tubular PGC-1a knockout mice to elucidate critical downstream effectors of PGC-1a that may be unique or shared in these two forms of AKI. The third aim will ask whether proximal tubular induction of PGC- 1a can ameliorate these forms of AKI by applying pharmaceutical inducers in wildtype, global and tubule- specific knockout mice. RESEARCH DESIGN: The design offers loss- and gain-of-function experiments to examine upstream regulators and downstream effectors of PGC-1a. The experimental design will integrate findings across cellular and live animal experiments, imaging modalities and biochemical studies, using stringent genetic tools to address the core hypothesis.

描述（由申请人提供）：急性肾损伤（AKI）是住院患者的主要并发症，肾缺血是主要危险因素。对缺血后肾功能障碍机制的深入研究尚未转化为新的治疗方法，部分原因是不同形式的缺血可能涉及不重叠的分子途径。理由：PGC-1a是线粒体生物发生的调节因子，在近端小管中大量表达，在败血症和缺血再灌注损伤的早期被抑制，在这两种情况下，从近端小管中基因缺失会加剧肾功能。人近端小管细胞通过抑制PGC-1a的下游效应物和减少氧气消耗来响应炎症介质，这种变化被PGC-1a的强制表达逆转。假设：本提案将验证PGC-1a抑制可能是两种缺血性AKI（败血症和缺血再灌注损伤（IRI））中肾功能恶化的共同机制。目的：第一个目的是研究炎症介质抑制人近端小管细胞中PGC-1a表达的机制。第二个目标将使用近端管PGC-1a敲除小鼠的脓毒症和IRI模型来阐明PGC-1a的关键下游效应，这些效应可能在这两种形式的AKI中是独特的或共有的。第三个目标将探讨PGC- 1a近端小管诱导是否可以通过在野生型、全局型和小管特异性敲除小鼠中应用药物诱导剂来改善这些形式的AKI。研究设计：该设计提供功能损失和功能获得实验，以检查PGC-1a的上游调节因子和下游效应因子。实验设计将整合细胞和活体动物实验、成像模式和生化研究的发现，使用严格的遗传工具来解决核心假设。