Delineation of pathogenic mechanisms of NOS1AP and TRIM8 mutations in monogenic SRNS/FSGS.

描述单基因 SRNS/FSGS 中 NOS1AP 和 TRIM8 突变的致病机制。

• 批准号: 10214843
• 负责人: Amar J Majmundar
• 金额: $ 16.94万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10214843
• 关键词: Actins; Adaptor Signaling Protein; Advisory Committees; Albuminuria; Antibodies; Biological; Blood; Boston; CDC42 gene; Cell physiology; Cells; Child; Childhood; Chronic; Chronic Kidney Failure; Co-Immunoprecipitations; Coupled; Creatinine; Critical Pathways; Data; Defect; Development Plans; Diffuse; Disease; Disease model; Edema; Electron Microscopy; End stage renal failure; Ensure; Environment; Epilepsy; Exhibits; Family; Focal Segmental Glomerulosclerosis; Foot Process; Functional disorder; Funding; Genes; Genetic; Grant; Growth; Guanine Nucleotide Exchange Factors; Hand; Human; Hypoalbuminemia; Immunofluorescence Immunologic; Immunoprecipitation; Impairment; Kidney; Kidney Failure; Kidney Glomerulus; Knock-in; Label; Laboratories; Life; Mediating; Medicine; Mentors; Methodology; Microscopy; Modeling; Mus; Mutate; Mutation; Nephrology; Nephrotic Syndrome; Nitric Oxide Synthase Type I; Nuclear; Nucleoplasm; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pediatric Hospitals; Program Development; Proteins; Proteinuria; Proteomics; Publications; Research; Research Proposals; Research Support; Resistance; Role; Science; Serum; Serum Albumin; Services; Steroid therapy; Steroid-resistant idiopathic nephrotic syndrome; Structure; Training; Ubiquitin; Urine; Vocational Guidance; Western Blotting; base; career; career development; glomerulosclerosis; innovation; kidney biopsy; light microscopy; liquid chromatography mass spectrometry; medical schools; meetings; migration; mouse model; mutant; novel; overexpression; podocyte; research and development; success; symposium; ubiquitin-protein ligase

PROJECT SUMMARY Title:Delineation of pathogenic mechanisms of NOS1AP and TRIM8 mutations in monogenic SRNS/FSGS Steroid resistant nephrotic syndrome (SRNS) is a leading cause of childhood chronic kidney disease1, marked by proteinuria and edema. Renal biopsy typically reveals focal segmental glomerulosclerosis (FSGS). 59% of children with SRNS are unresponsive to standard therapy1,2. A majority of them progress to end-stage renal disease with loss of the kidney glomerular filtering cells, podocytes1,2. Mendelian genetic causes of SRNS/FSGS have been detected in ~11-30% of pediatric cases3–6. SRNS/FSGS disease genes encode critical pathway components in podocyte biology2,7–10. Human mutations impair these SRNS/FSGS pathways, causing podocytopathies2,7–10. The proposed research will explore the pathogenic mechanisms underlying two novel monogenic causes of SRNS/FSGS in human NOS1AP and TRIM8 mutations, which were discovered by the applicant. The applicant’s preliminary data generated the hypothesis that human NOS1AP and TRIM8 mutations cause SRNS/FSGS through dysregulation of the CDC42 pathway and TRIM8 E3 ligase functions, respectively. The applicant, thus, proposes the following specific aims (SAs) using innovative cell biological, proteomics, and mouse models approaches: (SA1) Define the mechanism of CDC42 dysregulation caused by NOS1AP SRNS mutations; (SA2) Dissect the pathogenesis of TRIM8 SRNS/FSGS mutations in podocytes; (SA3) Delineate the pathogenesis of NOS1AP and TRIM8 mutations in SRNS in mice. The applicant has created a comprehensive career development plan supported by his mentor to (1) ensure his progress and success in carrying out this research proposal and (2) to facilitate his transition to an independent research career focused on disease modeling of nephrotic syndrome. This plan begins with regular meetings with his mentor and advisory committee—national and global academic leaders in medicine and science—to provide research and career guidance. The plan additionally includes (i) research and career development seminars, (ii) proteomics and microscopy methodology courses and (iii) activities for career growth including conference presentations and publications, mentoring of junior trainees, and application for independent research funding. The applicant and mentor have, also, agreed upon a transition plan to distinguish himself from the mentor’s laboratory. His training will be carried out in an unparalleled academic environment at Boston Children’s Hospital and Harvard Medical School, which provides dedicated career development programs and all necessary research support and supplies through his mentor and institutional core services. Collectively, this research and career development proposal is a product of the applicant’s ambition and capacity to transition to an independent research career in nephrology.

项目总结