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Mitochondrial Therapy for Kidney Injury

肾损伤的线粒体治疗

基本信息

批准号：
10188518
负责人：
Amandeep Bajwa
金额：
$ 34.65万
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 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10188518
关键词：
Acute Renal Failure with Renal Papillary Necrosis Aftercare Allogenic Animals Anti-Inflammatory Agents 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 Injury to Kidney 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 therapeutic intervention prevent public health relevance renal ischemia repaired response response to injury side effect therapeutic evaluation tissue injury 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.

项目摘要或摘要