Mitochondrial biogenesis in kidney disease

肾脏疾病中的线粒体生物发生

• 批准号: 8437404
• 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
• 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/8437404
• 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

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. PUBLIC HEALTH RELEVANCE: Sepsis and ischemia-reperfusion injury are major contributors to ischemic renal injury suffered by hospitalized patients. The effect of PGC-1a in experimental models of both suggests that this molecule may participate in a general mechanism of ischemic renal injury. Understanding how PGC- 1a becomes suppressed in these settings and what effectors of PGC-1a are most critical has potential not only to advance our fundamental understanding of renal biology, but also to translate into novel therapeutic possibilities for this common and morbid disease. PUBLIC HEALTH RELEVANCE: Acute kidney Injury (AKI) is a costly and morbid complication that affects 2-7% of all hospitalized patients. No effective therapies exist to combat this problem We have found that mitochondria-the energy-producing factories of the cell-within the kidney become injured as AKI develops and that a unique molecular pathway governed by a gene called PGC-1alpha helps the kidney rebuild its mitochondria as it attempts to recover from AKI. In this application, we will ask whether this new insight has potential to translate into a first-i-class therapy for people afflicted by this disorder.

描述(申请人提供)：急性肾损伤(AKI)是住院患者的主要并发症，而肾脏缺血是主要的危险因素。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通路。原理：PGC-1a是一种线粒体生物发生的调节因子，在近端小管大量表达，在脓毒症和缺血再灌注损伤时早期受到抑制，在这两种情况下，当基因从近端小管上删除时，会加剧肾功能。人近端肾小管上皮细胞通过抑制PGC-1a下游效应因子和减少氧气消耗来对炎症介质作出反应，而PGC-1a的强制表达逆转了这种变化。假设：这项提议将验证这样的假设，即抑制PGC-1a可能是两种形式的缺血性AKI-脓毒症和缺血再灌注损伤(IRI)加重肾功能的共同机制。目的：第一个目标是研究炎症介质抑制原代人近端肾小管上皮细胞PGC-1a表达的机制。第二个目标将使用近端肾小管PGC-1a基因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中是独特的或相同的。第三个目标将询问近端小管诱导PGC-1a是否可以通过在野生型、全局和小管特异性基因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增益实验，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结果，使用严格的遗传工具来解决核心假设。公共卫生相关性：脓毒症和缺血-再灌注损伤是住院患者遭受缺血性肾损伤的主要原因。PGC-1a在两者的实验模型中的作用表明，该分子可能参与了缺血性肾损伤的一般机制。了解PGC-1a是如何在这些环境中被抑制的，以及PGC-1a的哪些效应是最关键的，不仅有可能促进我们对肾脏生物学的基本理解，而且还可能转化为这种常见和病态疾病的新的治疗可能性。 公共卫生相关性：急性肾损伤(AKI)是一种代价高昂且病态的并发症，影响所有住院患者的2-7%。目前还没有有效的治疗方法来解决这个问题。我们已经发现，随着AKI的发展，肾脏内的线粒体--细胞的能量产生工厂--会受到损害，而且一种由名为PGC-1α的基因控制的独特分子途径有助于肾脏在试图从AKI中恢复时重建其线粒体。在这一应用中，我们将询问这种新的洞察力是否有可能转化为对患有这种疾病的人进行一流的治疗。