权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Role of the novel gene fam4b in phosphatidylserine synthesis in podocytes and mai

新基因fam4b在足细胞和麦磷脂酰丝氨酸合成中的作用

基本信息

批准号：
8302056
负责人：
HUA A LU
金额：
$ 25.74万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-17 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8302056
关键词：
Acute Glomerulonephritis Affect Animal Model Animals Apoptosis Binding Biochemical Biological Assay Biological Models Biology Cell membrane Cells Co-Immunoprecipitations Complex Data Diacylglycerol Kinase Disease Down-Regulation Dynamin Embryo Endothelium Filtration Fluorescence Fluorescence Recovery After Photobleaching Focal Segmental Glomerulosclerosis Foot Process Functional disorder Genes Guanosine Triphosphate Phosphohydrolases Human Imaging technology Kidney Kidney Diseases Kidney Failure Lipids Maintenance Mediating Membrane Microdomains Membrane Proteins Metabolism Modeling Morphology Mus NPHS2 protein Organ Patients Phosphatidylserine Synthase Phosphatidylserines Phospholipid Metabolism Phospholipids Plasma Play Process Protein Kinase Protein Kinase C Proteins Proteinuria Renal function Renal glomerular disease Reporter Role Sampling Signal Pathway Signal Transduction Signaling Molecule Specialized Epithelial Cell Structure System Testing Ultrafiltration Vesicle Water Yeasts Zebrafish blood filter glomerular basement membrane glomerular filtration in vitro Model in vivo knock-down migration mouse model nephrin new therapeutic target novel overexpression podocyte protein transport salt balance slit diaphragm spine bone structure trafficking wasting yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): The central function of mammalian kidney is ultrafiltration of plasma through the complex glomerular filtration barrier that is composed of a fenestrated endothelium, a glomerular basement membrane (GBM) and specialized epithelial cells called podocytes. The foot processes of each podocyte interconnect on the top of the GBM and protein bridges between neighboring cells from the slit diaphragm. Disruption of the slit diaphragm (SD) causes leakiness of the glomerulus, manifested as proteinuria, a typical presentation in many renal diseases. Therefore, maintaining the integrity of the glomerular filtration barrier is critical for normal kidney function. Several podocyte gene products have been found to contribute to the structure and function of the SD, such as Nephrin, CD2AP and Podocin. From a search for other factors contributing to SD function, we discovered a novel gene, fam49b, that is highly expressed in developing and mature podocytes in both zebrafish and mouse kidneys. Knocking down fam49b in zebrafish embryos led to podocyte foot process effacement, altered podocyte morphology, and renal failure. A down regulation of fam49b expression was consistently observed in kidneys from mice with proteinuric glomerular dysfunction and from patients with focal segmental glomerulosclerosis (FSGS). From a yeast two-hybrid screen we identified phosphatidylserine synthase-1 (PSS1) as a Fam49b interacting partner. Overexpression of fam49b in HEK293 cells increases the binding of a phosphatidylserine (PS)-binding reporter (Lactadherin-GFP) and enhances vesicular activity in LLCPK1 cells, suggesting that Fam49b positively regulates PSS1 activity and PS content, and increases vesicular activity in cell. Therefore, we propose that Fam49b, a novel protein, plays a conserved and critical role in maintaining the structural and functional integrity of the glomerula filtration barrier by regulating phospholipids metabolism in podocytes. For this study, we will take advantage of the well-characterized zebrafish model in combination with various in vitro model systems to explore the functional role of Fam49b. In addition, we will explore how phospholipid modulates the podocyte function therefore contribute to the pathophysiology of glomerular diseases. Specifically, we will: 1) investigate the role of Fam49b in podocyte biology and maintenance of the structure and function of slit diaphragm (SD); and 2) explore the mechanism that Fam49b regulates the structure and function of the SD through modulating phospholipids metabolism, lipid raft mediated protein trafficking and cell signaling. Our proposed study will further our understanding of not only the function of this novel gene, fam49b, but also explore the role of phospholipids in the pathophysiology of podocyte, therefore provide potentially new therapeutic targets to treat glomerular disease. PUBLIC HEALTH RELEVANCE: Kidney is a critical organ for filtering blood, removing wastes, and regulating water and salt balance in vertebral animals. We have discovered a new gene, fam49b to be critical for formation and/or function of the kidney filter, slit diaphragm. We proposed to examine the underlying mechanism of this gene and understand its contribution to the pathophysiology of "leaky" kidney diseases.