Unanticipated roles of C5aR1 Signaling Leading from Acute to Chronic Kidney Disease
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Principal Investigator: Mon-Wei Yu Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI Fiscal Year: 2024 Award: $75,600 Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases 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. Terms: <21+ years old><3-D><3-Dimensional><3D><Acceleration><Actins><Active Oxygen><Acute><Acute Renal Failure with Renal Papillary Necrosis><Adenosine Triphosphate><Adenylpyrophosphate><Adult><Adult Human><Affect><Anaplastic T-Lymphocyte with Horseshoe-Shaped Nucleus><Anaplastic T-Lymphocyte with Kidney-Shaped Nucleus><Animals><Apoptosis><Apoptosis Pathway><Area><Aristolochic Acids><Autoimmune Diseases><Autoregulation><Awareness><Big Data><BigData><Biology><Body Tissues><C5 a><C5a><C5a Receptors><C5a anaphylatoxin receptor><CD88 Antigens><Career Development Awards><Career Development Awards and Programs><Career Development Programs K-Series><Cell Aging><Cell Body><Cell Communication and Signaling><Cell Cycle Arrest><Cell Senescence><Cell Signaling><Cell Survival><Cell Viability><Cells><Cellular Aging><Cellular Senescence><Cellular injury><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><Clinical><Complement><Complement 5><Complement 5a><Complement 5a Receptor><Complement Activation><Complement C5><Complement C5a><Complement Component 5><Complement Proteins><Complement component C5><Data><Data Analyses><Data Analysis><Development><Disease Progression><ESRD><End stage renal failure><End-Stage Kidney Disease><End-Stage Renal Disease><Environment><Epithelial Cells><Faculty><Fibrosis><Foundations><Future><Genetic><Glycolysis><Grant><Hallmark Cell><Health><Histologic><Histologically><Homeostasis><Hospitals><Human><Immune><Immunes><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Immunology><In Vitro><Infection><Infiltration><Inflammasome><Inflammation><Inflammatory><Injury><Injury to Kidney><Intracellular Communication and Signaling><Involuntary Muscle><K-Awards><K-Series Research Career Programs><Kidney><Kidney Diseases><Kidney Grafting><Kidney Transplantation><Kidney Transplants><Kidney Urinary System><Knowledge><Lead><Length of Stay><Macrophage><Manuscripts><Mediating><Metabolic><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Morbidity><Morbidity - disease rate><Murine><Mus><Myeloid Cell Activation><Myeloid Cells><Mφ><Nephrology><Nephropathy><Number of Days in Hospital><O element><O2 element><Organoids><Outcome><Oxygen><Oxygen Radicals><Pathogenesis><Patients><Pb element><Phagocytes><Phagocytic Cell><Phagocytosis><Phase><Physiological Homeostasis><Population><Preparation><Prevalence><Pro-Oxidants><Production><Programmed Cell Death><Reactive Oxygen Species><Receptor Protein><Recombinant C5a><Recovery><Renal Disease><Renal Grafting><Renal Transplantation><Renal Transplants><Replicative Senescence><Research Career Program><Role><Scientist><Signal Transduction><Signal Transduction Systems><Signaling><Smooth Muscle><Solid><Techniques><Testing><Therapeutic><Tissues><Training><Training Activity><Tubular><Tubular formation><acute kidney injury><adulthood><amebocyte><antagonism><antagonist><autoimmune condition><autoimmune disorder><autoimmunity disease><biological signal transduction><career><career development><cell damage><cell injury><cellular damage><chronic kidney disease><complement pathway regulation><complementation><damage to cells><data interpretation><design><designing><developmental><experience><experiment><experimental research><experimental study><experiments><heavy metal Pb><heavy metal lead><hospital days><hospital length of stay><hospital stay><in vivo><injuries><injury to cells><innovate><innovation><innovative><kidney disorder><kidney fibrosis><kidney injury><kidney tx><medical college><medical schools><mitochondrial dysfunction><mortality><mouse model><murine model><new marker><novel><novel biomarker><novel marker><preparations><prevent><preventing><profibrotic cytokine><receptor><recruit><renal><renal disorder><renal fibrosis><renal injury><school of medicine><senescence associated secretome><senescence associated secretory phenotype><single cell analysis><skills><social role><three dimensional><tool><training module>