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：描述单基因SRNS/FSGS中NOS 1AP和TRIM 8突变的致病机制 激素抵抗性肾病综合征（SRNS）是儿童慢性肾病的主要原因1， 蛋白尿和水肿肾活检通常显示局灶节段性肾小球硬化症（FSGS）。59%的 SRNS患儿对标准治疗无反应1，2.其中大多数进展到终末期肾 肾小球滤过细胞（足细胞）丧失的疾病1，2。SRNS/FSGS的孟德尔遗传原因 在约11-30%的儿科病例中检测到3 -6。SRNS/FSGS疾病基因编码关键途径 成分在足细胞生物学2，7-10。人类突变会损害这些SRNS/FSGS途径， podocytopathies2，7-10. 这项研究将探索两种新的单基因病因的致病机制， 人NOS 1AP和TRIM 8突变中的SRNS/FSGS，其由申请人发现。申请人的 初步数据产生了一个假设，即人类NOS 1AP和TRIM 8突变导致SRNS/FSGS 分别通过CDC 42通路和TRIM 8 E3连接酶功能的失调。申请人， 因此，提出了以下具体目标（SA），使用创新的细胞生物学，蛋白质组学和小鼠 模型方法：（SA 1）确定NOS 1AP SRNS引起的CDC 42失调的机制 （SA 2）剖析足细胞中TRIM 8 SRNS/FSGS突变的发病机制;（SA 3）描述足细胞中TRIM 8 SRNS/FSGS突变的发病机制;（SA 4）描述足细胞中TRIM 8 SRNS/FSGS突变的发病机制;（SA 5）描述足细胞中TRIM 8 SRNS/FSGS突变的发病机制。 小鼠SRNS中NOS 1AP和TRIM 8突变的发病机制。 申请人已经制定了一个全面的职业发展计划，并得到了导师的支持，以（1） 确保他在实施这项研究计划方面取得进展和成功，以及（2）促进他的过渡 到一个独立的研究生涯，专注于肾病综合征的疾病建模。这个计划开始于 定期与他的导师和咨询委员会-国家和全球学术领袖， 医学和科学-提供研究和职业指导。该计划还包括（一）研究和 职业发展研讨会，（ii）蛋白质组学和显微镜方法学课程和（iii）职业活动 增长，包括会议演讲和出版物，初级学员的辅导，以及申请 独立研究经费。申请人和导师还商定了一个过渡计划， 从导师的实验室里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 计划和所有必要的研究支持和用品通过他的导师和机构的核心服务。 总的来说，这个研究和职业发展计划是申请人的雄心壮志的产物， 有能力过渡到肾脏病学的独立研究生涯。