Mitochondrial Biogenesis in Kidney Disease

肾脏疾病中的线粒体生物发生

• 批准号: 10062945
• 负责人: Samir M Parikh
• 金额: $ 46.61万
• 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 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062945
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Anabolism; Animals; Area; Attenuated; Award; Biogenesis; Biology; Biosensor; Blood flow; CRISPR/Cas technology; Cell Death; Cell Respiration; Cell model; Cell physiology; Cells; Chronic Kidney Failure; Clinical; Communities; Complex; Consumption; Disease model; Dose; Energy Metabolism; Enzymes; Exhibits; Funding; Genes; Genetic Models; Health; Homeostasis; Human; Impairment; Individual; Injury; Injury to Kidney; Ischemia; Kidney; Kidney Diseases; Knockout Mice; Laboratories; Mendelian disorder; Metabolic; Metabolic Pathway; Metabolism; Minor; Mitochondria; Modeling; Natural History; Niacinamide; Nicotinamide adenine dinucleotide; Organ; Outcome; Output; PPAR gamma; Pathway interactions; Positioning Attribute; Public Health; Recovery; Recovery of Function; Renal tubule structure; Reperfusion Therapy; Research; Resistance; Risk Factors; Role; Sepsis; Speed; Stress; Syndrome; Testing; Therapeutic; Transgenic Mice; Tubular formation; Work; base; falls; fortification; frontier; in vivo; innovation; kidney cell; lipidomics; loss of function; metabolic abnormality assessment; metabolomics; mimetics; novel; prevent; public health relevance; renal ischemia; response; septic; solute; stressor; systemic inflammatory response; therapeutic target; tool; transcription factor; transcriptome sequencing

PROJECT SUMMARY Acute kidney injury (AKI) is a growing public health burden. The syndrome itself is occurring in more diverse contexts and the long-term sequelae of AKI include chronic kidney disease (CKD). More than ever then, AKI research must identify candidate pathways that can be assessed and targeted in humans. In the first four years of this award, the applicant's laboratory has found that the mitochondrial biogenesis regulator, PGC1α (PPARγ-coactivator-1α), confers robust resistance to simple, common acute stressors that culminate in AKI such as acute systemic inflammation and renal ischemia. Moreover, we have observed that renal PGC1α expression is markedly suppressed in human AKI. Finally, we have implicated a novel downstream effector pathway for PGC1α—biosynthesis of the energy carrier nicotinamide adenine dinucleotide (NAD+). Based upon these results, we hypothesize that the PGC1α-NAD+ pathway may be a critical determinant of metabolic defense against diverse renal tubular insults. To test this concept in ways that advance both our fundamental understanding of this emerging candidate and that catalyze translational efforts, we propose three parallel aims: (1) identify when in the CKD-AKI spectrum tubular PGC1α induction is most beneficial; (2) critically evaluate the role of NAD+ biosynthetic pathways in experimental AKI downstream of PGC1α; and (3) dissect the relative contributions of mitochondrial biogenesis versus NAD+ biosynthesis in the metabolic protection conferred by PGC1α. To accomplish this, our team is composed of individuals possessing complementary expertise with a proven track record of collaborating to investigate metabolism in AKI. We have developed a suite of tools ranging from metabolomics and lipidomics applications to gene-edited cells to function- ultrastructure analysis of mitochondria. The output from the proposed aims will advance our understanding of how renal tubular metabolism bridges CKD and AKI; identify specific contexts in which PGC1α-NAD+ should be pursued clinically; and deepen our fundamental understanding of PGC1α and NAD+ in renal health. In concert with a growing number of outstanding groups investigating renal metabolism, it is our hope that the proposed studies help expand this new frontier in renal biology.

项目概要 急性肾损伤（AKI）是日益严重的公共卫生负担。该综合征本身发生在更加多样化的人群中 AKI 的背景和长期后遗症包括慢性肾脏病 (CKD)。 AKI 比以往任何时候都更 研究必须确定可以在人类中评估和靶向的候选途径。在最初的四年里 在该奖项中，申请人的实验室发现线粒体生物合成调节因子PGC1α (PPARγ-coactivator-1α)，对最终导致 AKI 的简单、常见急性应激源具有强大的抵抗力 如急性全身炎症、肾缺血等。此外，我们观察到肾PGC1α 在人类 AKI 中表达明显受到抑制。最后，我们暗示了一种新颖的下游效应器 PGC1α 途径——能量载体烟酰胺腺嘌呤二核苷酸 (NAD+) 的生物合成。基于 根据这些结果，我们假设 PGC1α-NAD+ 途径可能是代谢的关键决定因素 防御多种肾小管损伤。以推进我们的基本原则的方式测试这一概念 为了理解这一新兴候选者并促进转化努力，我们提出了三个并行的方案 目的：(1) 确定在 CKD-AKI 谱中何时诱导肾小管 PGC1α 最有益； (2) 批判性地 评估 NAD+ 生物合成途径在 PGC1α 下游实验性 AKI 中的作用； (3) 解剖 线粒体生物发生与 NAD+ 生物合成在代谢保护中的相对贡献 由 PGC1α 赋予。为了实现这一目标，我们的团队由具有互补性的个人组成 拥有丰富的专业知识，在合作研究 AKI 代谢方面拥有良好的记录。我们开发了一个 一套工具，范围从代谢组学和脂质组学应用到基因编辑细胞再到功能- 线粒体超微结构分析。拟议目标的产出将增进我们对 肾小管代谢如何连接 CKD 和 AKI；确定 PGC1α-NAD+ 应该使用的特定环境 进行临床研究；加深我们对 PGC1α 和 NAD+ 在肾脏健康中的基本了解。在 与越来越多研究肾脏代谢的杰出团体合作，我们希望 拟议的研究有助于扩大肾脏生物学的这一新领域。