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Understanding the mechanisms of TRPC6 mediated FSGS

了解 TRPC6 介导的 FSGS 机制

基本信息

批准号：
10063516
负责人：
JOHANNES S SCHLONDORFF
金额：
$ 39.38万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-06 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063516
关键词：
Actins Address Affect Age Agonist Angiotensins Animal Model Animals Apoptosis Behavior Biochemical Biological Biological Assay Biology CRISPR screen CRISPR/Cas technology Calcineurin Cations Cause of Death Cell Death Cell Line Cell model Cell physiology Cell surface Cells Chronic Kidney Failure Clustered Regularly Interspaced Short Palindromic Repeats Cytoskeleton Data Development Disease Disease model Dominant-Negative Mutation Electrophysiology (science)End stage renal failure Focal Segmental Glomerulosclerosis Gene Mutation Genes Genetic Genetic Diseases Genetic Screening Genotype Goals Histologic Human Human Genetics In Vitro Infusion procedures Injury Ion Channel Kidney Kidney Diseases Knock-in Mouse Lead Mediating Methodology Modeling Molecular Molecular Target Mus Mutate Mutation Nephritis Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Pharmacology Phenotype Predisposition Prevention Property Proteinuria Regulation Renal glomerular disease Reporting Research Role Serum Signal Pathway Signal Transduction Small Interfering RNA Stress Therapeutic Agents base cell immortalization cytotoxicity effective therapy gain of function gain of function mutation glomerular function in vivo inhibitor/antagonist insight knock-down knockin animal loss of function mutation mouse model mutant nephrotoxicity novel novel strategies novel therapeutic intervention overexpression podocyte response response to injury stressor therapeutic target

项目摘要

PROJECT SUMMARY Focal segmental glomerulosclerosis (FSGS) is a significant cause of chronic kidney disease, has few effective treatment options, and usually progresses to end-stage renal disease (ESRD). FSGS has a substantive genetic component. Study of gene mutations that cause FSGS has provided invaluable insight into normal glomerular function and the disease pathogenesis of FSGS. Mutations in TRPC6 are a known cause of FSGS. In addition, TRPC6 levels are often increased in more common forms of kidney disease, implying that TRPC6 activity may impact both acquired and genetic forms of FSGS. TRPC6 is an ion channel found on the surface of cells, making it an attractive pharmacologic target. However, two key questions about TRPC6 and the development of FSGS remain unanswered. Is it simply that excess TRPC6 activity is detrimental to glomerular function, or is TRPC6 like Goldilocks, with either too much or too little detrimental? Which of the multiple signaling pathways intersecting with TRPC6 are relevant to the development of glomerular pathology? We have created novel animal models - mice with the equivalent of a human FSGS mutation in Trpc6 and others with a dominant negative (DN) Trpc6 mutation - to be able to address these questions. Our experimental plan has three Specific Aims with the goal of providing answers to the above questions: (1) To ascertain whether mice with FSGS- or DN-mutations in Trpc6 develop FSGS with age or require a “second hit” to manifest disease. (2) To characterize the effect of TRPC6 mutations on podocyte behaviors known to be affected in FSGS, focusing on regulation of their actin cytoskeleton, calcineurin-NFAT signaling, and cell death. (3) To determine the genes necessary for mutant TRPC6-induced cell death. Our proposed studies have the potential to significantly enhance our understanding of FSGS. They will help us understand how increased and decreased TRPC6 activity alters glomerular response to stress, and will clarify which of the known signaling pathways activated by TRPC6 mediate pathology. The research has the potential to uncover novel molecular mechanisms involved in regulating TRPC6 and promoting FSGS. Ultimately, the results will help determine whether blocking TRPC6 activity might be a potential, and much needed, new therapeutic approach for the treatment of FSGS.

项目总结

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Trpc6 gain-of-function disease mutation enhances phosphatidylserine exposure in murine platelets.

DOI：
10.1371/journal.pone.0270431
发表时间：
2022
期刊：
PLOS ONE
影响因子：
3.7
作者：
Boekell, Kimber L.;Brown, Brittney J.;Talbot, Brianna E.;Schlondorff, Johannes S.
通讯作者：
Schlondorff, Johannes S.

My, oh, MYO9A! Just how complex can regulation of the podocyte actin cytoskeleton get?

我的，哦，MYO9A！