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Biological Mechanism of INF2-mediated FSGS

INF2介导的FSGS的生物学机制

基本信息

批准号：
10551239
负责人：
HENRY N HIGGS
金额：
$ 43.94万
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：
2010
资助国家：
美国
起止时间：
2010-07-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10551239
关键词：
Acceleration Acetylation Actins Behavior Binding Binding Proteins Biochemical Biological Biology C-terminal Calcium Cells Charcot-Marie-Tooth Disease Complement Complex Defect Disease Disinhibition Endoplasmic Reticulum Event Exhibits Family member Focal and Segmental Glomerulosclerosis Functional disorder Genes Genetically Engineered Mouse Goals Golgi Apparatus Grant Human Inherited Kidney Kidney Diseases Knockout Mice Lead Mediating Mitochondria Molecular Monomeric GTP-Binding Proteins Mus Mutation N-terminal Organelles Persons Phenotype Play Point Mutation Polymers Protein Isoforms Protein Region Proteins RNA Splicing Regulation Role Site Testing Therapeutic Time Variant constriction depolymerization disease-causing mutation formin-2 gain of function genetic regulatory protein human disease in vivo loss of function mouse model mutant podocyte polymerization protein complex segregation stressor

项目摘要

SUMMARY The goal of project is to understand the molecular mechanisms by which mutations in INF2 cause focal segmental glomerulosclerosis (FSGS) in humans. More than 45 different FSGS-associated mutations have been identified. A subset of people with FSGS-causing INF2 mutations also exhibit Charcot Marie Tooth disease. INF2 is unique for a formin family member in that it accelerates both actin polymerization and depolymerization. Formins can autoinhibit their own activity by an intramolecular interaction between two domains, the N-terminal DID (diaphanous inhibitory domain) and the C-terminal DAD (diaphanous autoregulatory domain). INF2 has two major splice variants, one of which is associated with the endoplasmic reticulum, INF2-CAAX, and a second isoform, INF2-nonCAAX, that helps maintain Golgi integrity. INF2-CAAX is the major podocyte isoform. During the last period of this grant, we made significant progress in our understanding of both INF2 biology and how INF2 function is altered by mutations. We now understand the role INF2 plays in organelle function, and have a clearer understand of its role in regulating mitochondrial fission. We have identified a major mechanism of inhibition of INF2 activity, an interaction with an endogenous protein complex (cyclase-associated protein bound to actin that is post-translationally acetylated). We have also found that the INF2 protein undergoes cleavage at a site between the N-terminal DID region and the C-terminus, containing the FH2 and DAD regions, which may be important in regulating INF2 function and perhaps disinhibiting the functions of both regions of the protein. We have found that INF2 undergoes a cleavage event that may be important in regulating INF2 function The fact that in contrast to essentially all other actin regulatory proteins, INF2-DID mutations are a relatively common form of inherited FSGS, suggests that INF2-DID possesses unique and non-redundant functions in the podocyte. Our long-term goal is to understand these functions and, ultimately, exploit them for therapeutic benefit. We have four major goals: (1) Define the specific biochemical effects of FSGS-causing mutants. We will test the effects of multiple FSGS mutants on the interaction of INF2 with the endogenous inhibitory complex and examine INF2 mutant interactions with its binding partners; (2) Define INF2 function and mutation-mediated dysfunction in cells. This includes examination of how INF2 mutations alter its regulation of mitochondrial function; (3) Define the function of INF2 cleavage; (4) Use genetically engineered mice to better understand INF2 function and mutation mediated dysfunction in vivo.