Unanticipated roles of C5aR1 Signaling Leading from Acute to Chronic Kidney Disease

C5aR1 信号转导从急性肾病到慢性肾病的意外作用

• 批准号: 10591053
• 负责人: Mon-Wei Yu
• 金额: $ 16.57万
• 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: 2023-07-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591053
• 关键词: 3-Dimensional; Acceleration; Actins; Acute; Acute Renal Failure with Renal Papillary Necrosis; Adenosine Triphosphate; Adult; Affect; Animals; Apoptosis; Area; Aristolochic Acids; Autoimmune Diseases; Awareness; Big Data; Biology; C5a anaphylatoxin receptor; Cell Aging; Cell Cycle Arrest; Cell Survival; Cells; Chronic Kidney Failure; Clinical; Complement; Complement 5a; Complement Activation; Complement component C5; Data; Data Analyses; Development; Disease Progression; End stage renal failure; Environment; Epithelial Cells; Faculty; Fibrosis; Foundations; Future; Genetic; Glycolysis; Grant; Hallmark Cell; Health; Histologic; Homeostasis; Hospitals; Human; Immune; Immunologics; Immunology; In Vitro; Infection; Infiltration; Inflammasome; Inflammation; Inflammatory; Injury; Injury to Kidney; K-Series Research Career Programs; Kidney; Kidney Diseases; Kidney Transplantation; Knowledge; Lead; Length of Stay; Macrophage; Manuscripts; Mediating; Metabolic; Modeling; Molecular; Morbidity - disease rate; Mus; Myeloid Cell Activation; Myeloid Cells; Nephrology; Organoids; Outcome; Oxygen; Pathogenesis; Patients; Phagocytes; Phagocytosis; Phase; Phenotype; Population; Preparation; Prevalence; Production; Reactive Oxygen Species; Recovery; Role; Scientist; Signal Transduction; Smooth Muscle; Solid; Techniques; Testing; Therapeutic; Tissues; Training; Training Activity; Tubular formation; antagonist; career; career development; cell injury; design; experience; experimental study; in vivo; innovation; kidney fibrosis; medical schools; mitochondrial dysfunction; mortality; mouse model; novel; novel marker; prevent; profibrotic cytokine; receptor; recruit; senescence; single cell analysis; skills; tool

Project Summary: Chronic kidney disease (CKD) continues to be a significant factor in global morbidity and mortality. Patients experiencing repetitive acute kidney injury (AKI) are predisposed to CKD. Despite discoveries of novel biomarkers and increasing awareness of kidney health, the prevalence of CKD and end- stage kidney disease (ESKD) continues to rise. To date, the lack of therapeutic options halting progression from AKI to CKD still represents an unmet need. Our preliminary data suggest while activation of complement component 5 receptor 1 (C5aR1) promotes renal tubular epithelial cell (RTEC) damage, C5aR1 signaling on myeloid cells may confer renoprotective effects ameliorating AKI. This project will determine the roles of C5a- C5aR1 axis activation in 1) RTEC cellular senescence and kidney fibrosis (Aim 1), and in 2) myeloid cells responsible for AKI pathogenesis (Aim 2). These aims will test our central hypothesis that C5aR1 activation in kidney resident macrophage (KRM) mitigates the acute phase of AKI, whereas C5a-C5aR1 signaling in RTEC mediates their cellular senescence with subsequent CKD progression and fibrosis. Our findings will lay the fundamental knowledge of the potential clinical use of complement-regulating therapies for kidney diseases. Candidate and Training: The primary objective of this application is to support Dr. Mon-Wei (Sam) Yu's career development into an independent basic scientist in the fields of complement biology and kidney diseases by using novel murine models and immunological approaches. Dr. Yu's proposed training activities are in four areas: 1) Establish innovative scientific questions and design appropriate experiments to answer those questions; 2) Attain the necessary techniques, especially in the immunology field, to perform experiments; 3) Gain training and experiences for big data analysis, and 4) Refine the skills for grantsmanship and manuscript preparation. Environment: Division of Nephrology at Mount Sinai Hospital and the Icahn School of Medicine at Mount Sinai (ISMMS) are fully committed to junior faculty career and scientific development. Dr. Paolo Cravedi and Dr. John Cijiang He (Division Chief) are renowned experts in complement and tubular biology with a strong K Award trainees track record.

项目摘要：慢性肾脏病（CKD）仍然是全球发病率的重要因素， mortality.反复急性肾损伤（阿基）患者易患CKD。尽管 发现新的生物标志物，提高对肾脏健康、CKD患病率和终末期肾病的认识， 阶段性肾病（ESKD）继续上升。到目前为止，缺乏治疗选择阻止了进展， 从阿基到CKD仍然代表未满足的需求。我们的初步数据表明，当补体激活时， 组分5受体1（C5 aR 1）促进肾小管上皮细胞（RTEC）损伤，C5 aR 1信号转导在肾小管上皮细胞（RTEC）中起作用。 骨髓细胞可以赋予改善阿基的肾保护作用。该项目将确定C5 a的作用- 1）RTEC细胞衰老和肾纤维化（Aim 1）和2）髓样细胞中的C5 aR 1轴激活 负责阿基发病机制（目的2）。这些目标将检验我们的中心假设，即C5 aR 1的激活在 肾驻留巨噬细胞（KRM）减轻阿基的急性期，而RTEC中的C5 a-C5 aR 1信号传导 介导其细胞衰老以及随后的CKD进展和纤维化。我们的发现将奠定 补体调节疗法在肾脏疾病中潜在临床应用的基础知识 疾病候选人和培训：本申请的主要目的是支持孟伟博士（山姆） Yu的职业发展成为补体生物学和肾脏领域的独立基础科学家 通过使用新的小鼠模型和免疫学方法来治疗疾病。于博士建议的培训活动 有四个方面：1）建立创新的科学问题，并设计适当的实验来回答 2）获得必要的技术，特别是在免疫学领域，以执行 实验; 3）获得大数据分析的培训和经验，以及4）完善granitarian的技能 和手稿准备。环境：西奈山医院肾脏科和伊坎 西奈山医学院（ISMMS）完全致力于初级教师的职业生涯和科学 发展Paolo Cravedi博士和John Cijiang He博士（部门负责人）是著名的补充专家 和管状生物学有着优秀的K奖学员记录