Platelet-mitochondria transplantation to treat mitochondrial dysfunction in acute kidney injury

血小板线粒体移植治疗急性肾损伤中的线粒体功能障碍

• 批准号: 10629759
• 负责人: Rihab Bouchareb
• 金额: $ 33.8万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-14 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629759
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Area; Azotemia; Blood Platelets; Cardiovascular system; Cell Proliferation; Cell physiology; Cells; Chronic Kidney Failure; Cisplatin; Collaborations; Critical Care; Cytoplasm; Deterioration; Diabetes Mellitus; Dialysis procedure; Disease; Drug toxicity; Electrical Resistance; Electrolyte Disorder; Encapsulated; End stage renal failure; Endocytosis; Epithelial Cells; Etiology; Event; Excretory function; Faculty; Fluorescence; Glucose; Growth; Health; Heart; Heart Valve Diseases; Heart failure; Hepatocyte; Hospitalization; Human body; Hypoxia; In Vitro; Incidence; Injury; Injury to Kidney; Interstitial Nephritis; Ions; Kidney; Kidney Diseases; Lead; Measures; Medicine; Mitochondria; Morbidity - disease rate; Myocardial Ischemia; Nanotubes; Nephrology; Nutrient; Organ; Oxygen Consumption; Patients; Pharmaceutical Preparations; Positioning Attribute; Prevention strategy; Process; Production; Prognosis; Protein Synthesis Inhibition; Reactive Oxygen Species; Recovery; Renal Replacement Therapy; Renal function; Source; Structure; Testing; Therapeutic; Therapeutic Intervention; Tight Junctions; Tissues; Transmission Electron Microscopy; Transplantation; Tubular formation; Uremia; Vesicle; Visualization; absorption; cell dedifferentiation; cytochrome c oxidase; fatty acid oxidation; fluorescence imaging; in vivo; innovation; insight; ischemic injury; kidney cell; malignant breast neoplasm; member; microvesicles; mitochondrial dysfunction; mitochondrial permeability transition pore; mortality; novel strategies; novel therapeutic intervention; oxidant stress; pharmacologic; prevent; renal ischemia; response to injury; sensor; therapeutically effective; tool; ultra high resolution; uptake

(PLEASE KEEP IN WORD, DO NOT PDF) This project responds directly to PAR-21-038; the PI changes direction from valvular heart disease to study acute kidney injury (AKI). Indeed, the PI is a new faculty member in the Division of Nephrology, Department of Medicine. The PI will apply her previous expertise in platelet structure to examine a new therapeutic approach to deliver mitochondria to injured kidneys and therefore stop the progression of AKI to end-stage renal disease. The PI is working closely with Dr. Daehn, an expert in kidney disease and mitochondrial function. In addition, she will be collaborating with Dr. Brestoff, an expert in mitochondria transplantation, to validate the proposed experimental approach. AKI is a critical health condition characterized by a sudden decline in kidney function. It occurs in approximately 20%-30% of hospitalized patients. In the US, AKI is leading to high morbidity and mortality. Although AKI encompasses various etiologies, tubular injury is an early and decisive step in AKI. During hypoxia, proximal tubular epithelial cells (PTECs) undergo oxidant stress, mitochondrial damage, protein synthesis inhibition, and growth arrest. Non-treated AKI can progress to chronic kidney disease (CKD) and end-stage renal disease. Renal replacement therapy is necessary for patients with a survival of only 10%. Currently, there are no pharmacological or preventive strategies available to reverse or reduce the occurrence of severe AKI or to stop its progression to chronic kidney disease and end-stage kidney, emphasizing the need for new therapeutic strategies in this area. The central hypothesis in this application will test an innovative approach to treating kidneys using mitochondria transplants to prevent AKI. This hypothesis will be tested in one Specific Aim; To examine a new delivery approach of competent mitochondria to isolated proximal tubular epithelial cells using naked mitochondria or encapsulated mitochondria.

（请保持文字，不要PDF） 该项目直接响应PAR-21-038; PI将方向从心脏瓣膜病改为研究急性肾损伤（阿基）。事实上，PI是医学系肾脏科的新教员。PI将运用她之前在血小板结构方面的专业知识，研究一种新的治疗方法，将线粒体输送到受损的肾脏，从而阻止阿基进展为终末期肾病。PI正在与肾脏疾病和线粒体功能专家Daehn博士密切合作。此外，她将与线粒体移植专家Brestoff博士合作，以验证所提出的实验方法。阿基是一种严重的健康状况，其特征是肾功能突然下降。它发生在大约20%-30%的住院患者中。在美国，阿基导致高发病率和死亡率。虽然阿基包括各种病因，但肾小管损伤是阿基的早期决定性步骤。在缺氧期间，近端肾小管上皮细胞（PTECs）经历氧化应激、线粒体损伤、蛋白质合成抑制和生长停滞。未经治疗的阿基可进展为慢性肾病（CKD）和终末期肾病。对于生存率仅为10%的患者，肾脏替代治疗是必要的。目前，没有药理学或预防策略可逆转或减少重度阿基的发生或阻止其进展为慢性肾病和终末期肾病，强调需要在该领域制定新的治疗策略。本申请的中心假设将测试使用线粒体移植治疗肾脏以预防阿基的创新方法。该假设将在一个特定目的中进行测试;使用裸线粒体或包封线粒体检查感受态线粒体向分离的近端肾小管上皮细胞的新递送方法。