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.

项目摘要 标题：单基因SRNS/FSG中NOS1AP和TRIM8突变的致病机理的描述 抗类固醇肾病综合征（SRN）是儿童慢性肾脏病的主要原因1，标记为 由蛋白尿和水肿。肾脏活检通常揭示局灶性节段性肾小球硬化症（FSGS）。 59％ SRN的儿童对标准疗法没有反应1,2。他们中的大多数发展到终端肾脏 肾脏肾小球滤波细胞丧失的疾病，足细胞1,2。 Mendelian遗传原因SRNS/FSGS 在约11-30％的小儿病例中检测到3-6。 SRNS/FSGS疾病基因编码关键途径 足细胞生物学中的成分2,7-10。人类突变会损害这些SRN/FSGS途径，导致 足细胞病2,7-10。 拟议的研究将探索两个新的单基因原因的致病机制 申请人发现的人NOS1AP和TRIM8突变中的SRN/FSG。申请人的 初步数据产生了以下假设：人NOS1AP和TRIM8突变引起SRNS/FSGS 通过CDC42途径和TRIM8 E3连接酶功能的失调。申请人， 因此，建议使用创新细胞生物学，蛋白质组学和小鼠的以下特定目标（SAS） 模型方法：（ SA1）定义由NOS1AP SRN引起的Cdc42失调的机理 突变； （SA2）剖析足细胞中TRIM8 SRNS/FSGS突变的发病机理； （SA3）描述 小鼠SRN中NOS1AP和TRIM8突变的发病机理。 申请人制定了一项全面的职业发展计划，由他的心理支持（1） 确保他在执行这项研究建议方面的进步和成功，（2）促进他的过渡 独立研究职业专注于肾病综合征的疾病建模。这个计划开始了 与他的心理和咨询委员会定期会议 - 本地和全球学术领袖 医学和科学 - 提供研究和职业指导。该计划还包括（i）研究和 职业发展半货人，（ii）蛋白质组学和显微镜方法学课程以及（iii）职业活动 增长包括会议演讲和出版物，初级学员的心理以及申请 独立研究资金。申请人和精神上也同意了一个过渡计划，以区分 他自己来自精神实验室。他的培训将在无与伦比的学术环境中进行 波士顿儿童医院和哈佛医学院，提供专门的职业发展 计划以及所有必要的研究通过其心理和机构核心服务提供支持和供应。 总的来说，这项研究和职业发展建议是申请人的野心和 过渡到肾脏病独立研究职业的能力。