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

项目摘要：慢性肾脏疾病(CKD)仍然是全球发病率和 死亡率。反复急性肾损伤(AKI)患者易患CKD。尽管 新生物标志物的发现和人们对肾脏健康、慢性肾脏病和终末期肾病的认识不断提高。 阶段性肾病(ESKD)继续上升。到目前为止，缺乏治疗选择阻碍了进展 从AKI到CKD仍代表着一种未得到满足的需求。我们的初步数据表明，当补体激活时 组分5受体1(C5aR1)促进肾小管上皮细胞(RTEC)损伤，C5aR1信号转导 髓系细胞可能具有肾脏保护作用，改善AKI。本项目将确定C5a的角色- C5aR1轴在1)RTEC细胞衰老和肾脏纤维化(AIM 1)和2)髓系细胞中的激活 负责AKI的发病机制(目标2)。这些目标将检验我们的中心假设，即C5aR1在 肾脏驻留巨噬细胞(KRM)减轻急性肾损伤急性期，而C5a-C5aR1信号在RTEC中的作用 通过随后的CKD进展和纤维化来调节它们的细胞衰老。我们的发现将为 补体调节疗法在肾脏潜在临床应用的基础知识 疾病。候选人和培训：此应用程序的主要目标是支持孟伟博士(Sam) 俞敏洪的职业发展成为补充生物学和肾脏领域的独立基础科学家 利用新的小鼠模型和免疫学方法研究疾病。余博士建议的培训活动 在四个方面：1)建立创新的科学问题，并设计适当的实验来回答 这些问题；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；4)完善技能 和手稿准备。环境：西奈山医院和伊坎医院的肾脏科 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。保罗·克拉维迪博士和何慈江博士(科长)是补体领域的知名专家 和肾小管生物学有着很强的K奖学员的记录。

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.