Mitochondrial Therapy for Kidney Injury

肾损伤的线粒体治疗

• 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
• 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

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.

项目摘要或摘要 急性肾脏损伤（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，免疫系统介导了AKI和抗炎的发展 治疗可显着减弱组织损伤和功能丧失。但是，共同的副作用 抗炎疗法结合缺乏临床数据，支持免疫参与 AKI发病机理中的系统阻碍了抗炎选择的发展。线粒体， AKI的关键参与者具有双重作用，是主要能源（ATP）和细胞死亡的关键调节剂。 肾脏缺血随后再灌注（IRI）在30-40％的近端小管中诱导线粒体碎片 （PT）细胞以及线粒体生物发生调节剂PGC1的表达降低（PPARγ- 共激活器1）。全身静脉注射荧光素标记为孤立的健康线粒体信号为 在注射后15分钟后，在包括脾脏，儿童，肝脏和肺在内的各种组织中发现。在孩子们 孤立的标记线粒体主要用Pt占据。我们的初步研究表明 从健康来源（肌肉或肝脏）分离的健康线粒体的潜在治疗作用以改变 免疫和肾脏居民细胞反应以防止受伤（预处理）并诱导恢复（ 治疗）可能涉及通过诱导PGC1α激活线粒体生物发生。 转移的线粒体1）增强受体细胞的ATP产生和氧消耗率，2）本地化 肾脏3）减少炎症反应（细胞死亡，细胞因子，炎症细胞浸润），4） 诱导受体细胞PGC1，这是肾脏反应的关键确定剂，以保护肾脏免受AKI的侵害。 因此，直接线粒体转移作为治疗干预措施，以修复，重新编程和更换 线粒体，改善线粒体健康和恢复呼吸功能对预防和/或 疾病的治疗。彼此之间，我们假设使用健康的线粒体治疗增强 接受者细胞能量生产可帮助替代受损的线粒体，并诱导PGC1α并营救 细胞功能。我们将以以下三个目标检验我们的假设：目标1：检验以下假设。 用孤立的健康线粒体治疗有助于维持细胞功能以阻止（预处理）AKI和 在小鼠的两个模型（IRI和LPS诱导的败血症）中，预防（治疗后）疾病进展。 目的2：检验摄取健康线粒体诱导线粒体代谢基因的假设 （PGC1α）增加线粒体数和细胞内ATP以保护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的细胞功能（猪） 保护肾脏免受IRI的侵害。