Mitochondrial Therapy for Kidney Injury

肾损伤的线粒体治疗

• 批准号: 10431830
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-22 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10431830
• 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; 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

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 预防和治疗急性肾损伤（阿基）仍然是一个重要的健康问题。 相当多的数据表明，免疫系统介导阿基，并且抗炎性免疫应答的发展是由免疫系统介导的。 治疗可以显著减轻组织损伤和功能丧失。然而，常见的副作用 抗炎治疗与缺乏临床数据相结合，支持免疫系统的参与。 系统在阿基发病机制中的作用，阻碍了抗炎选择的发展。线粒体， 阿基中的关键参与者具有作为主要能量来源（ATP）和作为细胞死亡的关键调节剂的双重作用。 肾缺血再灌注（IRI）诱导近端小管30-40%的线粒体断裂 (PT)细胞沿着线粒体生物合成调节因子PGC 1 β（过氧化物酶体增殖物激活受体γ- 共活化剂1 μ g）。全身静脉注射荧光染料标记的分离的健康线粒体信号是 早在注射后15分钟就在包括脾、肾、肝和肺的各种组织中发现。肾脏 分离的标记的线粒体主要被PT摄取。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， 免疫和肾脏驻留细胞反应，以防止损伤（治疗前）和诱导恢复（治疗后）。 可能涉及通过诱导PGC 1 α激活受体线粒体生物合成。的 转移的线粒体1）增强受体细胞的ATP产生和耗氧速率，2）定位 3）减少炎症反应（细胞死亡、细胞因子、炎性细胞浸润），和4） 诱导受体细胞PGC 1 β，肾反应的关键决定因素，以保护肾脏免受阿基。 因此，直接线粒体转移作为一种治疗干预，以修复，重编程和替换 线粒体、改善线粒体健康和恢复呼吸功能有益于预防和/或 疾病的治疗。因此，我们假设用健康的线粒体治疗可以增强 受体细胞产生能量，通过诱导PGC 1 α和拯救来帮助替换受损的线粒体 细胞功能。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 用分离的健康线粒体治疗有助于维持细胞功能以阻断（预处理）阿基， 在小鼠阿基的两种模型（IRI和LPS诱导的脓毒症）中预防（治疗后）疾病进展。 目的2：验证健康线粒体摄取诱导线粒体代谢基因的假说 (PGC1α）增加线粒体数量和细胞内ATP，以防止阿基。目标3：测试 用分离的线粒体治疗有助于维持较大动物（猪）的细胞功能的假说 保护肾脏免受IRI的侵害。

项目成果

A Review of Defatting Strategies for Non-Alcoholic Fatty Liver Disease.

• DOI: 10.3390/ijms231911805
• 发表时间: 2022-10-05
• 期刊: International journal of molecular sciences
• 影响因子: 5.6

Exogenous mitochondrial transfer increases energy expenditure and attenuates adiposity gains in mice with diet-induced obesity.

外源性线粒体转移会增加饮食引起的肥胖小鼠的能量消耗并减弱肥胖的增加。

• DOI: 10.1101/2023.12.23.573206
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Namwanje,Maria;Mazumdar,Soumi;Stayton,Amanda;Patel,PrishaS;Watkins,Christine;White,Catrina;Brown,Chester;Eason,JamesD;Mozhui,Khyobeni;Kuscu,Cem;Pabla,Navjot;Stephenson,ErinJ;Bajwa,Amandeep
• 通讯作者: Bajwa,Amandeep

Piceatannol induces regulatory T cells and modulates the inflammatory response and adipogenesis.

• DOI: 10.1016/j.biopha.2023.114514
• 发表时间: 2023-05
• 期刊: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

Role of Mitochondrial Therapy for Ischemic-Reperfusion Injury and Acute Kidney Injury.

• DOI: 10.1159/000520698
• 发表时间: 2022
• 期刊: NEPHRON
• 影响因子: 2.5
• 作者: Pabla, Navjot;Bajwa, Amandeep
• 通讯作者: Bajwa, Amandeep