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.

项目总结：慢性肾脏疾病（CKD）仍然是全球发病率和死亡率的重要因素