Mitochondrial Therapy for Kidney Injury

肾损伤的线粒体治疗

基本信息

批准号：
9789257
负责人：
Amandeep Bajwa
金额：
$ 34.88万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-22 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9789257
关键词：
Acute Renal Failure with Renal Papillary Necrosis Aftercare Allogenic Animals Anti-inflammatory Attenuated Autologous Biochemical Bioenergetics Biogenesis Blood Pressure Blood flow Boston Cell Death Cell Line Cell physiology Cells Chronic Kidney Failure Clinical Data Collaborations Creatinine Critical Illness Data Development Disease Disease Progression Dose Energy-Generating Resources Family suidae Fibrosis Flow Cytometry Fluorochrome Gene Expression Gene Proteins Genes Genetic Genus Hippocampus Goals Health Histologic Histology Immune Immune system In Situ Nick-End Labeling In Vitro Infiltration Inflammation Inflammatory Inflammatory Response Injections Injury Ischemia Kidney Knockout Mice Label Liver Lung Measures Mediating Mitochondria Mitochondrial Swelling Modeling Morbidity - disease rate Mus Muscle Oxygen Consumption PPAR gamma Pathogenesis Patients Pediatric Hospitals Pharmacology Plasma Predisposition Prevention Production Public Health Reactive Oxygen Species Recovery Renal function Reperfusion Therapy Respiratory physiology Reverse Transcriptase Polymerase Chain Reaction Risk Factors Role Sepsis Signal Transduction Source Speed Spleen Supportive care Techniques Testing Therapeutic Therapeutic Intervention Therapeutic Uses Time Tissues Toxic effect cytokine effective therapy efficacy evaluation hospitalization rates improved in vivo inhibitor/antagonist intravenous injection kidney preservation loss of function mitochondrial metabolism mortality novel therapeutics prevent public health relevance renal ischemia repaired response response to injury side effect therapeutic evaluation treatment strategy uptake

项目摘要

Project Summary or Abstract Prevention and treatment of acute kidney injury (AKI) continues to remain a significant health problem. Considerable data suggest that the immune system mediates AKI, and development of anti-inflammatory treatments can significantly attenuate tissue injury and loss of function. However, the side effects of common anti-inflammatory therapies combined with the lack of clinical data, supporting the involvement of the immune system in AKI pathogenesis, have hindered the development of anti-inflammatory options. Mitochondria, critical players in AKI, have dual roles as a primary source of energy (ATP) and as key regulators of cell death. Renal ischemia followed by reperfusion (IRI) induces mitochondrial fragmentation in 30-40% of proximal tubule (PT) cells along with reduced expression of the mitochondrial biogenesis regulator, PGC1 (PPARγ- coactivator 1). Systemic intravenous injection of fluorochrome labeled isolated healthy mitochondria signal is found in various tissue including spleen, kidneys, liver and lungs as early as 15 mins after injection. In kidneys the isolated labeled mitochondria are predominantly taken up by PT. Our preliminary studies demonstrate a potential therapeutic role for healthy mitochondria isolated from a healthy source (muscle or liver) to alter immune and kidney resident cellular responses to prevent injury (pretreatment) and induce recovery (post- treatment) that may involve activation of recipient mitochondria biogenesis through induction of PGC1α. The transferred mitochondria 1) enhance ATP production and oxygen consumption rate of recipient cell, 2) localize to the kidneys, 3) reduce inflammatory responses (cell death, cytokines, inflammatory cell infiltration), and 4) induce recipient cell PGC1, a pivotal determinant of renal responses, to protect kidneys from AKI. Therefore, direct mitochondrial transfer as a therapeutic intervention to repair, reprogram and replace mitochondria, improve mitochondrial health and restore respiratory function is beneficial for prevention and/or treatment of disease. Accordingly, we hypothesize that treatment with healthy mitochondria enhances recipient cell energy production to help replace damaged mitochondria by inducing PGC1α and rescues cellular functions. We will test our hypothesis with the following three aims: Aim 1: To test the hypothesis that treatment with isolated healthy mitochondria helps maintain cellular functions to block (pretreatment) AKI and prevent (post-treatment) progression of disease in two models (IRI and LPS-induced sepsis) of AKI in mice. Aim 2: To test the hypothesis that uptake of healthy mitochondria induces the mitochondrial metabolism gene (PGC1α) to increase mitochondrial numbers and intracellular ATP to protect from AKI. Aim 3: To test the hypothesis that treatment with isolated mitochondria helps maintain cellular functions in larger animals (swine) to protect kidneys from IRI.

项目概要或摘要急性肾损伤（AKI）的预防和治疗仍然是一个重大的健康问题。大量数据表明免疫系统介导 AKI 以及抗炎药物的发展治疗可以显着减轻组织损伤和功能丧失，但副作用也很常见。抗炎治疗加上缺乏临床数据，支持免疫系统的参与 AKI 发病机制中的系统，阻碍了抗炎选择的发展。 AKI 中的关键参与者，具有作为主要能量来源 (ATP) 和细胞死亡关键调节者的双重作用。肾缺血再灌注 (IRI) 会导致近端肾小管 30-40% 发生线粒体断裂 (PT) 细胞以及线粒体生物合成调节因子 PGC1α (PPARγ- 全身静脉注射荧光染料标记的分离的健康线粒体信号是注射后 15 分钟即可在各种组织中发现，包括脾、肾、肝和肺。分离的标记线粒体主要被 PT 吸收。从健康来源（肌肉或肝脏）分离的健康线粒体具有潜在的治疗作用，可以改变免疫和肾脏驻留细胞反应，以防止损伤（治疗前）并诱导恢复（治疗后）治疗），可能涉及通过诱导 PGC1α 激活受体线粒体生物发生。转移线粒体 1) 增强受体细胞的 ATP 产生和耗氧率，2) 定位对肾脏，3) 减少炎症反应（细胞死亡、细胞因子、炎症细胞浸润），以及 4) 诱导受体细胞 PGC1（肾脏反应的关键决定因素）以保护肾脏免受 AKI 侵害。因此，直接线粒体转移作为修复、重编程和替换的治疗干预线粒体，改善线粒体健康并恢复呼吸功能有利于预防和/或因此，我们认为用健康的线粒体进行治疗可以增强疾病的治疗效果。受体细胞产生能量，通过诱导 PGC1α 来帮助替换受损的线粒体并进行救援我们将通过以下三个目标来检验我们的假设：目标 1：检验以下假设：使用分离的健康线粒体进行治疗有助于维持细胞功能，以阻止（治疗前）AKI 和在小鼠 AKI 的两种模型（IRI 和 LPS 诱导的脓毒症）中预防（治疗后）疾病进展。目标 2：检验健康线粒体的摄取诱导线粒体代谢基因的假设 (PGC1α) 增加线粒体数量和细胞内 ATP 以预防 AKI 目标 3：测试假设用分离的线粒体治疗有助于维持大型动物（猪）的细胞功能保护肾脏免受 IRI 侵害。