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Phosphatidylinositol Signaling and Human Disease

磷脂酰肌醇信号传导与人类疾病

基本信息

批准号：
7217272
负责人：
PHILIP W MAJERUS
金额：
$ 68.71万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1979
资助国家：
美国
起止时间：
1979-04-01 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7217272
关键词：
Active Sites Adaptor Signaling Protein Affect Apoptosis Apoptotic Bicarbonates Biological Assay Burkholderia pseudomallei Cell Line Cell-Free System Cells Chloride Channels Clathrin Cloning Collaborations Complex Cysteine Defect Disease Enzymes Family member Fibroblasts Functional disorder Gene Deletion Gene Family Genes Goals Golgi Apparatus Grant Hela Cells Homologous Gene Human Inositol Inositol Metabolism Pathway Inositol Phosphate Metabolism Pathway Inositol Phosphates InsP5 Laboratories Lysosomes Messenger RNA Mus Mutate Mutation Nuclear Nuclear Export Oculocerebrorenal Syndrome Organism Pathogenesis Pathway interactions Phenocopy Phosphatidylinositol Signaling System Pathway Phosphatidylinositols Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiology Phytic Acid Plants Play Process Production Protein Kinase Protein Overexpression Proteins Proximal Kidney Tubules RNA Interference Reaction Recombinant Proteins Recombinants Recruitment Activity Role Signal Pathway Signal Transduction Sorting - Cell Movement Structure Substrate Specificity TNF gene Testing Title Vesicle Virulence Virulence Factors Work Yeasts human disease inositol pentakisphosphate kinase inositol-1,4,5-trisphosphate 5-phosphatase insight mRNA Export metabolic abnormality assessment mutant myo-inositol-1 (or 4)-monophosphatase myotubularin receptor mediated endocytosis research study response stable cell line trafficking

项目摘要

DESCRIPTION (provided by applicant): The major goal of this grant is to define defects in the phosphatidylinositol signaling pathway that result in human diseases. The role of inositol (1,3,4)-P3 5/6-kinase in inhibition of TNF-induced apoptosis will be investigated. Is the effect due to some inositol phosphate product or to phosphorylation of a protein of the apoptotic pathway? Mutant forms of recombinant kinase that lack either inositol or protein kinase activity will be created and tested for their ability to block TNF apoptosis. The enzymes leading to inositol hexaphosphate will be overexpressed in 293 cells or inhibited by RNAi to elucidate functions for the higher inositol phosphates in apoptosis, nuclear export of mRNA, and intracellular vesicle trafficking. The role of the B. pseudomallei protein BobB in virulence of this organism will be studied by determining whether it is an inositol phosphate phosphatase. The substrate specificity of two human homologues of BopB will be determined by cloning cDNA's encoding these proteins and producing recombinant protein in Sf9 cells. Continued studies of the myotubularin gene family (mutations of which cause several different human diseases) will be performed by investigating complexes between myotubularin related proteins 6 and 7 that are enzymatically active with the inactive myotubularin related protein 9. The role of complex formation in the pathogenesis of Lowe syndrome will be studied by determining the function of the inositol polyphosphate 5-phosphatase (OCRL) that is mutated in that disease. The role of OCRL in Golgi vesicle trafficking will be studied and the effect of mutated OCRL on the processing and/or activity of the NBC1 bicarbonate transporter of renal proximal tubules will be investigated. Malfunction of this transporter is suggested by the finding that mutations in NBC1 in humans produce a phenocopy of Lowe syndrome

描述(由申请者提供)：这项资助的主要目标是确定导致人类疾病的磷脂酰肌醇信号通路中的缺陷。肌醇(1，3，4)-P35/6-激酶在抑制肿瘤坏死因子诱导的细胞凋亡中的作用将被研究。这种效应是由于某些肌醇磷酸产物，还是由于细胞凋亡途径中的一种蛋白质的磷酸化？缺乏肌醇或蛋白激酶活性的突变形式的重组激酶将被创造出来，并测试它们阻止肿瘤坏死因子凋亡的能力。导致肌醇六磷酸的酶将在293细胞中过表达或被RNAi抑制，以阐明较高的肌醇磷酸在细胞凋亡、mRNA核输出和细胞内小泡运输中的功能。假鼻疽杆菌蛋白Bobb在这种生物毒力中的作用将通过确定它是否是一种肌醇磷酸酶来研究。两个人BOPB同源物的底物特异性将通过克隆编码这些蛋白的cDNA并在Sf9细胞中产生重组蛋白来确定。对肌管蛋白基因家族(其突变导致几种不同的人类疾病)的继续研究将通过研究肌管蛋白相关蛋白6和7与失活的肌管蛋白相关蛋白9之间具有酶活性的复合体来进行。复合体的形成将通过确定在该疾病中突变的肌醇多聚5-磷酸酶(OCRL)的功能来研究其在Lowe综合征发病机制中的作用。将研究OCRL在高尔基体小泡运输中的作用，并研究突变的OCRL对肾近端小管重碳酸盐转运体Nbc1的加工和/或活性的影响。这一转运蛋白的功能障碍可能是因为人类NBC1基因突变导致了洛威综合征的表型