Novel mitochondrial protective properties of annexin A1

膜联蛋白 A1 的新型线粒体保护特性

• 批准号: 10661073
• 负责人: Jamie R Privratsky
• 金额: $ 32.2万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661073
• 关键词: Acetylation; Acute Renal Failure with Renal Papillary Necrosis; Agonist; Annexin A1; Anti-Inflammatory Agents; Applications Grants; Behavior; Binding; Blood Vessels; Blood flow; Cell Death; Cells; Complication; Data; Deacetylase; Deacetylation; Death Rate; Development; Exposure to; FPR2 gene; Family; G-Protein-Coupled Receptors; Genetic; Goals; Health; Human; Injury to Kidney; Interruption; Ischemia; Kidney; Kidney Transplantation; Knowledge; Life; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolic stress; Metabolism; Mission; Mitochondria; Mitochondrial Proteins; Morbidity - disease rate; Mus; Nature; Necrosis; Operative Surgical Procedures; Organ; Organism; Oxidative Phosphorylation; PPAR gamma; Parents; Pathogenesis; Pathway interactions; Patients; Peptide Fragments; Perioperative; Permeability; Persons; Postoperative Period; Predisposition; Production; Property; Public Health; Quality of life; Renal function; Renal tubule structure; Reperfusion Therapy; Research; Role; Signal Pathway; Sirtuins; Specificity; Stress; Therapeutic; Transgenic Mice; Translating; Transplantation; Transplantation Surgery; Tubular formation; United States National Institutes of Health; Up-Regulation; antagonist; cyclophilin D; design; disability; drug development; efficacy evaluation; fMet-Leu-Phe receptor; improved outcome; kidney cell; kidney epithelial cell; member; mimetics; mitochondrial dysfunction; mitochondrial metabolism; mortality; nephrogenesis; novel; novel therapeutics; operation; organ injury; peptidomimetics; post-transplant; prevent; renal ischemia; septic; translational study; tubular necrosis

ABSTRACT Acute kidney injury (AKI) is one of the most common forms of perioperative organ injury occurring in up to 30% of post-surgical patients, and it significantly increases morbidity and mortality. A number of vascular and transplant surgeries require interruption of blood flow to the kidney, rendering the kidney ischemic and causing significant metabolic stress. The timing of this kidney insult is known; thus, the possibility exists to intervene to protect the kidney. However, no treatment options exist to prevent or treat post-surgical AKI. The development of kidney protective therapeutics has the potential to greatly improve outcomes in the millions of people who undergo surgical operations and kidney transplants each year. Our long-term goal is to develop kidney protective therapeutics to limit post-operative and post- transplant AKI. One such therapy could be to limit mitochondrial stress as the kidney is particularly susceptible to mitochondrial stress due to its high metabolic demands. As such, the development of mitochondrial protectants that could limit post-surgical and transplant AKI holds considerable promise. Along these lines, our group has developed a novel peptide mimetic of the parent annexin A1 molecule that in our preliminary data shows that it can ameliorate ischemic kidney injury in mice by limiting kidney tubular cell death and upregulating sirtuin-3 (SIRT3) to augment mitochondrial function. Despite the promise of our therapeutic to limit ischemic kidney injury, the novel mechanism by which it protects the kidney is not known. Thus, the objectives of this proposal are to determine the mechanism through which our annexin A1 mimetic augments mitochondrial function and metabolism and limits kidney tubular necrosis to ameliorate AKI. In this proposal, we will determine the cellular signaling pathway through which our compound upregulates SIRT3 and augments mitochondrial ATP production. We will also determine the mechanism through which it limits mitochondrial-mediated necrosis in the kidney. We will treat transgenic mice with our therapeutic and subject to both ischemia-reperfusion kidney injury and kidney cross transplantation. We will measure kidney injury and perform a variety of measures of cellular metabolism and mitochondrial function to assess efficacy and establish the mechanism of our therapeutic. Once completed, we will have defined the mechanism through which our novel therapeutic can augment mitochondrial energy production and limit mitochondria-mediated necrosis to limit post-surgical AKI. After study completion, we will be primed to pursue translational studies and further drug development. The development of our new therapeutic would not only limit postoperative and transplant AKI but also have broad implications for protection of other organs following surgery and transplantation. 1

摘要 急性肾损伤（阿基）是围手术期最常见的器官损伤之一 在高达30%的手术后患者中，它显著增加了发病率和死亡率。一些 血管和移植手术需要中断流向肾脏的血流， 局部缺血并引起显著的代谢应激。这种肾脏损伤的时间是已知的;因此， 存在干预以保护肾脏的可能性。然而，没有治疗方案可以预防或治疗 术后阿基。肾脏保护疗法的发展有可能大大改善 每年有数百万人接受外科手术和肾脏移植。 我们的长期目标是开发肾脏保护疗法，以限制术后和术后 移植阿基。一种这样的治疗方法可能是限制线粒体应激，因为肾脏特别 由于其高代谢需求，易受线粒体应激的影响。因此，发展 可以限制手术后和移植阿基的线粒体保护剂具有相当大的前景。 沿着这些路线，我们的小组已经开发了一种新的亲膜联蛋白A1分子的肽模拟物 在我们的初步数据显示，它可以改善缺血性肾损伤小鼠通过限制肾脏 肾小管细胞死亡和上调sirtuin-3（SIRT 3）以增强线粒体功能。尽管 我们的治疗方法有希望限制缺血性肾损伤，它保护肾脏的新机制， 肾脏未知。因此，本提案的目的是确定一种机制， 我们的膜联蛋白A1模拟物增强线粒体功能和代谢， 坏死以改善阿基。 在这项提案中，我们将确定我们的化合物通过细胞信号通路， 上调SIRT 3并增加线粒体ATP的产生。我们还将确定机制 从而限制肾脏中由尿道介导的坏死。我们将用 我们的治疗和受缺血再灌注肾损伤和肾交叉移植。 我们将测量肾损伤，并对细胞代谢和线粒体进行各种测量。 评估疗效和建立我们的治疗机制的功能。 一旦完成，我们将确定我们的新疗法可以通过的机制。 增加线粒体能量产生并限制线粒体介导的坏死， 阿基研究完成后，我们将准备进行转化研究和进一步的药物治疗。 发展我们新疗法的发展不仅限制了术后和移植 阿基还对手术和移植后其他器官的保护具有广泛的意义。 1