Friday, April 19, 2024
4/19/2024
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
