Mitochondrial Biogenesis Promotes Recovery from Oxidant Injury

线粒体生物发生促进氧化损伤的恢复

• 批准号: 9090165
• 负责人: Rick G Schnellmann
• 金额: $ 1.23万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9090165
• 关键词: ATP Synthesis Pathway; Acceleration; Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Adrenergic Agonists; Animals; Asthma; Bilateral; Biogenesis; Brain Injuries; Cell Death; Cells; Chemicals; Clinical; Creatinine; Development; Dose; Drug usage; Electron Transport; Event; FDA approved; Failure; Functional disorder; Goals; Health; Heart Injuries; Injury; Ischemia; Kidney; Kidney Failure; Lead; Mitochondria; Modeling; Morbidity - disease rate; Mus; Operative Surgical Procedures; Organ; Organ failure; Oxidants; Pharmaceutical Preparations; Proteins; Rattus; Recovery; Renal function; Reperfusion Therapy; Research; Rhabdomyolysis; Rodent; Serum; Signal Pathway; Therapeutic; Therapeutic Agents; Time; Trauma; Tubular formation; cell injury; drug discovery; formoterol; in vivo; liver injury; mitochondrial dysfunction; programs; renal ischemia; repaired; research study; toxicant

DESCRIPTION (provided by applicant): The goal of this project is to identify therapeutics that accelerate the recovery from acute organ failure. Cell injury and death induced by ischemia/reperfusion (I/R), drugs, toxicants, and trauma lead to failure of many organs, including the kidney. Mitochondrial dysfunction is a common consequence of these insults and a major mechanism of cell injury and death. The majority of research in the field of acute kidney injury (AKI) has focused on the events that initiate renal dysfunction, but therapeutic agents are lacking. This suggests that more successful therapies require the examination of new targets and a focus on accelerating recovery from AKI. We recently determined that mice subjected to bilateral renal I/R induced AKI and rats subjected to myoglobinuric AKI had elevated serum creatinine 24 h after injury which partially recovered over six days post- injury. Mitochondrial electron transport chain and ATP synthesis proteins were depleted 24 h after injury and did not recover over six days, revealing persistent disruption of mitochondrial function after AKI. Consequently, we propose that therapeutics that increase mitochondrial biogenesis (MB) will promote recovery from AKI. As part of our drug discovery program to identify drugs that induce MB we identified formoterol, a specific long- acting b2-adrenergic receptor agonist (b2-AR), was a potent and efficacious inducer of MB in renal proximal tubular cells (RPTC). Formoterol is a FDA-approved drug used to treat asthma. Additional studies revealed that formoterol induced MB in the kidneys of mice at a low dose. However, the signaling pathway(s) responsible for formoterol-induced MB has not been elucidated. Finally, preliminary studies demonstrated that mice treated with formoterol 24 h after I/R, when renal dysfunction is established, accelerated recovery of [mitochondrial and] renal function. We hypothesize that formoterol induces MB through the b2-AR and that formoterol accelerates recovery of [mitochondrial and] renal function following I/R in mice. To address this hypothesis we propose the following Specific Aims: 1) Elucidate the signaling pathway(s) of formoterol- induced MB in RPTC [and following oxidant injury in RPTC], 2) Determine efficacy, potency and mechanism of formoterol-induced MB in mice, and 3) Elucidate the effects of formoterol on the recovery of mitochondrial and renal function following renal I/R-induced AKI in vivo. Successful completion of these experiments will advance the field by 1) identifying the precise signaling pathway that induces MB through b2-AR, 2) demonstrating that stimulating the recovery of mitochondrial function results in the acceleration of recovery of renal function, and 3) providing a rapidly clinically translatable treatment for AKI.

描述（由申请人提供）：该项目的目的是确定可以加速急性器官衰竭恢复的治疗剂。缺血/再灌注（I/R）引起的细胞损伤和死亡，药物，毒物和创伤导致包括肾脏在内的许多器官失败。线粒体功能障碍是这些侮辱的普遍结果，也是细胞损伤和死亡的主要机制。急性肾脏损伤领域（AKI）领域的大多数研究都集中在启动肾功能障碍的事件上，但缺乏治疗剂。这表明更成功的疗法需要检查新目标，并专注于加速从AKI中恢复。我们最近确定受到双侧肾脏I/R诱发的小鼠诱发了AKI和受到肌球蛋白AKI的大鼠，损伤后24小时升高血清肌酐升高，在受伤后六天内部分恢复。线粒体电子传输链和ATP合成蛋白在受伤后24小时耗尽，并且在六天内没有恢复，揭示了AKI后线粒体功能的持续破坏。因此，我们建议增加线粒体生物发生（MB）的治疗剂将促进从AKI中恢复。作为我们识别诱导MB的药物的药物发现计划的一部分，我们鉴定出formoterol是一种特定的长作用B2-肾上腺素能受体激动剂（B2-AR），是MB在肾脏近端管状细胞（RPTC）中的有效且有效的诱导剂。 Formoterol是一种用于治疗哮喘的FDA批准药物。进一步的研究表明，福莫特罗在低剂量的小鼠肾脏中诱导MB。然而，尚未阐明负责福兰特罗诱导的MB的信号通路。最后，初步研究表明，I/R后24小时用福洛托赛处理的小鼠在建立肾功能障碍时，加速了[线粒体和]肾功能的恢复。我们假设Formoterol通过B2-AR诱导MB，并且在小鼠I/R之后，formoterol加速了[线粒体和]肾功能的恢复。为了解决这一假设，我们提出以下具体目的：1）阐明rPTC中福利赛诱导的MB的信号传导途径[s）[RPTC中的氧化剂损伤]，2）确定formoterol诱导的MB的功效，效力和机制aki in Vivo。这些实验的成功完成将通过1）确定诱导MB通过B2-AR的精确信号传导途径，2）证明刺激线粒体功能的恢复会导致肾功能恢复的加速，而3）为AKI提供快速临床可转换的治疗。