Stimulation of Mitochondrial Biogenesis with 5-HT Receptor Agonists

用 5-HT 受体激动剂刺激线粒体生物发生

• 批准号: 8061465
• 负责人: Jennifer Harmon
• 金额: $ 3.67万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8061465
• 关键词: Acute; Acute Disease; Acute Renal Failure with Renal Papillary Necrosis; Affect; Agonist; Animal Model; Biogenesis; Cell model; Cell physiology; Cells; Cellular Structures; Cessation of life; Comorbidity; Data; Development; Disease; Drug Exposure; Enzymes; Exhibits; Functional disorder; Goals; Heavy Metals; Hospitals; Human; In Vitro; Injury; Intervention; Ischemia; Kidney; Knowledge; Laboratories; Measures; Metal exposure; Methods; Mitochondria; Modeling; Monitor; Morbidity - disease rate; Mus; Nephrotoxic; Onset of illness; Organ; Organ failure; Oxidants; Oxidative Stress; PPAR gamma; Pathogenesis; Patients; Peroxisome Proliferators; Process; Proximal Kidney Tubules; Receptor Activation; Receptor Signaling; Recovery; Renal function; Reperfusion Injury; Reperfusion Therapy; Respiration; Role; Serotonin; Signal Pathway; Signal Transduction Pathway; Small Interfering RNA; Survival Rate; Testing; Tissues; Toxicant exposure; Tubular formation; Work; cell injury; in vivo; inhibitor/antagonist; knock-down; mitochondrial dysfunction; mortality; novel; novel therapeutics; prevent; receptor; renal ischemia; restoration; serotonin receptor; therapeutic development; toxicant; treatment strategy

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is a rapid-onset disease with significant morbidity and mortality that affects up to 5% of long-term hospital patients. Most cases of AKI result from renal ischemia/reperfusion (I/R) or acute drug or toxicant exposure. The development of therapeutic strategies to treat AKI in humans has been largely unsuccessful and the mortality resulting from AKI has remained unchanged for several decades. Therefore, the development of more successful therapies necessitates the examination of novel targets. It has been demonstrated that renal proximal tubule cells exposed to acute oxidant injury, such as that found in acute I/R or toxicant exposure, exhibit serious mitochondrial dysfunction. It has been further demonstrated that the recovery of mitochondrial function in these cells is temporally related to recovery of cellular function, and that the recovery of mitochondrial function is temporally related to the expression of peroxisome-proliferator- receptor-3-coactivator-11 (PGC-11), the "master regulator" of mitochondrial biogenesis. Our lab has recently demonstrated that 5-HT2 receptor agonists stimulate mitochondrial biogenesis in vitro by increasing the expression of PGC-11. We first seek to examine the signaling pathway between 5-HT2 receptor activation and PGC-11 expression and to verify our in vitro data in an animal model. We then intend to test our hypothesis that 5-HT2 receptor agonists will induce mitochondrial biogenesis and promote recovery of kidney function after in an animal model of acute I/R injury. Specific Aims: 1) Elucidate the 5-HT2 signaling pathway of mitochondrial biogenesis. 2) Determine the 5-HT2 signaling pathway of renal mitochondrial biogenesis in mice. 3) Determine the effect of 5-HT2 agonists on the recovery of renal function following I/R injury. Methods: The first aim will be accomplished by using pharmacological inhibitors to signaling pathway enzymes proposed to be involved in the stimulation of mitochondrial biogenesis by 5-HT2 receptor agonists. The second aim will be accomplished by "knocking down" components of the elucidated signaling pathway in mice using siRNA and measuring mitochondrial biogenesis as a result of 5-HT2 receptor agonist treatment. The third aim will be performed by subjecting mice to a model of I/R acute kidney injury and treating them with 5-HT2 receptor agonists. These mice will be monitored for improvements in kidney function in the presence and absence of these agonists. Goal: To further understand the role and signaling pathway of 5-HT2 receptor agonists in stimulating mitochondrial biogenesis and to probe their usefulness as novel therapeutics to treat acute kidney injury. Relevance to agency: Toxicant exposure is a significant culprit in the pathogenesis of acute kidney injury; these toxicants may be intentionally administered, such as nephrotoxic chemotherapeutics, or unintentionally introduced, such as in the case of environmental heavy metal exposure. This work seeks to examine the usefulness of 5-HT2 receptor agonists in the treatment of this acute disease state. PUBLIC HEALTH RELEVANCE: Acute kidney injury is a serious disease state affecting up to 5% of all long-term hospital patients. The development of therapeutic strategies to treat AKI in humans has been largely unsuccessful and the number of deaths resulting from AKI has remained unchanged for several decades. This project seeks to examine the mechanism and usefulness of serotonin receptor activation in the treatment of AKI, with the hope that agents that activate serotonin receptors will offer new and better treatment options for patients with this serious disease.

描述（由申请人提供）：急性肾损伤（AKI）是一种具有显著发病率和死亡率的快速发病疾病，影响高达5%的长期住院患者。大多数AKI病例是由于肾缺血/再灌注（I/R）或急性药物或毒物暴露所致。治疗人类AKI的治疗策略的发展在很大程度上是不成功的，并且由AKI引起的死亡率几十年来一直保持不变。因此，开发更成功的治疗方法需要检查新的靶点。已经证明，肾近端小管细胞暴露于急性氧化损伤，如急性I/R或毒物暴露，表现出严重的线粒体功能障碍。研究进一步证明，这些细胞线粒体功能的恢复与细胞功能的恢复存在时间性关系，线粒体功能的恢复与线粒体生物发生的“主调控因子”过氧化物酶体-增殖体-受体-3-共激活因子-11 （PGC-11）的表达存在时间性关系。我们的实验室最近证明，5-HT2受体激动剂通过增加PGC-11的表达来刺激线粒体的体外生物发生。我们首先试图检查5-HT2受体激活和PGC-11表达之间的信号通路，并在动物模型中验证我们的体外数据。然后，我们打算在急性I/R损伤动物模型中验证我们的假设，即5-HT2受体激动剂会诱导线粒体生物发生并促进肾功能恢复。具体目的：1)阐明线粒体生物发生的5-HT2信号通路。2)确定小鼠肾线粒体生物发生的5-HT2信号通路。3)确定5-HT2激动剂对I/R损伤后肾功能恢复的影响。方法：第一个目的将通过对信号通路酶的药理抑制剂来实现，这些酶被认为参与了5-HT2受体激动剂对线粒体生物发生的刺激。第二个目标将通过在小鼠中使用siRNA“敲除”已阐明的信号通路的成分并测量5-HT2受体激动剂治疗后的线粒体生物发生来实现。第三个目标将通过将小鼠置于I/R急性肾损伤模型中并用5-HT2受体激动剂治疗它们来实现。这些小鼠将在存在和不存在这些激动剂的情况下监测肾功能的改善。目的：进一步了解5-HT2受体激动剂在刺激线粒体生物发生中的作用和信号通路，探讨其作为治疗急性肾损伤的新药物的价值。与机构的相关性：毒物暴露是急性肾损伤发病的重要原因；这些毒物可能是有意给药的，如肾毒性化疗药物，也可能是无意引入的，如环境重金属暴露。这项工作旨在检查5-HT2受体激动剂在治疗这种急性疾病状态中的有效性。