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：
8730635
负责人：
Samir M Parikh
金额：
$ 37.85万
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/8730635
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）：急性肾脏损伤（AKI）是住院患者的主要并发症，肾脏缺血是主要的危险因素。对缺血后肾功能障碍的基础机制的深入研究尚未转化为新疗法，部分原因是不同形式的缺血可能涉及非重叠的分子途径。理由：PGC-1A是线粒体生物发生的调节剂，在近端小管中大量表达，在脓毒症和缺血 - 再灌注损伤的早期被抑制，并且在这两种情况下，当从近端小管近端遗传上删除肾功能时会加剧肾功能。人近端管状细胞通过抑制PGC-1A的下游效应子和减少氧气消耗，对炎症介质的反应，随着PGC-1A的强迫表达而逆转的变化。假设：该建议将检验以下假设：PGC-1A的抑制可能是一种共同的机制，可以加剧肾功能，以两种形式的缺血性AKI，败血症和缺血 - 重新灌注损伤（IRI）。目的：第一个目的将调查能够抑制原代人近端管细胞中PGC-1A表达的机制。第二个目标将使用败血症和IRI模型在近端管状PGC-1A基因敲除小鼠中阐明PGC-1A的关键下游效应子，这些效应可能是在这两种AKI形式中唯一或共享的。第三个目标将询问PGC-1A的近端管状诱导是否可以通过在野生型，全球和小管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：该设计提供了功能障碍和功效实验，以检查PGC-1A的上游调节器和下游效应器。实验设计将使用严格的遗传工具来解决核心假设的细胞和活动物实验，成像方式和生化研究的发现。