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: 10343330
• 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/10343330
• 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; 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; Perioperative; Permeability; Postoperative Period; 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; cyclophilin D; design; disability; drug development; 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

抽象的 急性肾脏损伤（AKI）是围手术器官损伤的最常见形式之一 在多达30％的手术后患者中，它大大增加了发病率和死亡率。许多 血管和移植手术需要中断流向肾脏的血液流动，使肾脏呈现 缺血并引起明显的代谢应激。这种肾脏侮辱的时机是众所周知的。因此， 存在干预以保护肾脏的可能性。但是，没有治疗方案可以预防或治疗 手术后的Aki。肾脏保护疗法的发展有可能大大改善 每年接受手术手术和肾脏移植的数百万人的结果。 我们的长期目标是开发肾脏保护性治疗剂，以限制术后和术后 移植Aki。一种这样的疗法可能是限制线粒体压力，因为肾脏尤其是 由于其高代谢需求，因此容易受到线粒体压力的影响。因此，发展 可能限制外科和移植AKI的线粒体保护剂具有相当大的希望。 沿着这些线路，我们的小组开发了一种新型的肽模拟于父伴附属物A1分子 在我们的初步数据中，它可以通过限制肾脏来改善小鼠的缺血性肾脏损伤 管状细胞死亡和上调Sirtuin-3（SIRT3）以增强线粒体功能。尽管有 我们的治疗性有望限制缺血性肾脏损伤，这是一种新的机制 肾脏不知道。因此，该提案的目标是确定 我们的膜联蛋白A1模拟增强线粒体功能和代谢，并限制肾小管 坏死以改善AKI。 在此提案中，我们将确定我们的化合物的细胞信号通路 上调SIRT3并增强线粒体ATP生产。我们还将确定机制 通过它限制了线粒体介导的肾脏坏死。我们将用 我们的治疗性并受到缺血 - 重新灌注肾脏损伤和肾脏交叉移植的约束。 我们将测量肾脏损伤，并执行各种细胞代谢和线粒体的测量 功能评估功效并确定我们治疗的机制。 完成后，我们将定义我们的新型治疗方法的机制 增强线粒体能量产生并限制线粒体介导的坏死以限制手术后的 aki。研究完成后，我们将准备进行翻译研究和进一步的药物 发展。我们的新治疗性的发展不仅会限制术后和移植 AKI，但也对保护手术和移植后的其他器官具有广泛的影响。 1