Perk eIF2a Kinase Integrates Proinsulin Quality Control and Insulin Secretion

Perk eIF2a 激酶整合胰岛素原质量控制和胰岛素分泌

基本信息

批准号：
9274953
负责人：
DOUGLAS R. CAVENER
金额：
$ 32.55万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
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：
2010-09-27 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9274953
关键词：
Adult Beta Cell Blood Circulation Blood Glucose Cell physiology Defect Degradation Pathway Development Diabetes Mellitus Dominant-Negative Mutation Elements Endoplasmic Reticulum Ensure Enzymes Equilibrium Functional disorder GRP78 gene Gene Expression Glucose Golgi Apparatus Guanabenz Health Heterozygote Housekeeping Human Hyperglycemia Insulin Knockout Mice Mediating Metabolic Modeling Molecular Molecular Chaperones Mus Mutagenesis Mutant Strains Mice Mutation Neonatal Non-Insulin-Dependent Diabetes Mellitus Pathologic Pathway interactions Phosphorylation Phosphotransferases Physiological Play Process Production Proinsulin Promoter Regions Protein Dephosphorylation Proteolytic Processing Quality Control Regulation Role Secretory Vesicles Testing Transcription Repressor/Corepressor Transcriptional Regulation Wolcott-Rallison syndrome base cis acting element design endoplasmic reticulum glycoprotein p72 experimental study gene repression inhibitor/antagonist insulin granule insulin secretion islet knock-down loss of function mutant neonatal diabetes mellitus novel overexpression prevent promoter protein degradation protein folding public health relevance response trafficking transcription factor

Adult Beta Cell Blood Circulation Blood Glucose Cell physiology Defect Degradation Pathway Development Diabetes Mellitus Dominant-Negative Mutation Elements Endoplasmic Reticulum Ensure Enzymes Equilibrium Functional disorder GRP78 gene Gene Expression Glucose Golgi Apparatus Guanabenz Health Heterozygote Housekeeping Human Hyperglycemia Insulin Knockout Mice Mediating Metabolic Modeling Molecular Molecular Chaperones Mus Mutagenesis Mutant Strains Mice Mutation Neonatal Non-Insulin-Dependent Diabetes Mellitus Pathologic Pathway interactions Phosphorylation Phosphotransferases Physiological Play Process Production Proinsulin Promoter Regions Protein Dephosphorylation Proteolytic Processing Quality Control Regulation Role Secretory Vesicles Testing Transcription Repressor/Corepressor Transcriptional Regulation Wolcott-Rallison syndrome base cis acting element design endoplasmic reticulum glycoprotein p72 experimental study gene repression inhibitor/antagonist insulin granule insulin secretion islet knock-down loss of function mutant neonatal diabetes mellitus novel overexpression prevent promoter protein degradation protein folding public health relevance response trafficking transcription factor

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项目摘要

DESCRIPTION (provided by applicant): Monogenic forms of permanent neonatal diabetes and type 2 ß-cell decompensation have highlighted the importance and vulnerability of proinsulin processing in the endoplasmic reticulum (ER). Once thought to be housekeeping functions, the processes of proinsulin folding, ER associated protein degradation (ERAD)- mediated quality and quantity controand trafficking of proinsulin from the ER to the Golgi are all highly regulated as a function of the metabolic state and demand for insulin. We have identified the PERK eIF2a kinase, whose loss of function results in permanent neonatal diabetes in the Wolcott Rallison syndrome, as a key regulator of proinsulin processing in the ER. We postulated a novel and controversial model that PERK regulates proinsulin processing by controlling the expression of key ER chaperone and folding proteins including GRP78 and ERp72, which, in turn, control whether proinsulin is degraded by the ERAD pathway or trafficked forward to the Golgi for proteolytic processing and packaging into secretory granules. In this proposal we will further test this model by manipulating the PERK-eIF2a pathway and the expression of key ER chaperones and assessing the fate and processing state of proinsulin. We will also determine how PERK- eIF2a modulates proinsulin processing in response to fluctuating glucose levels in order to provide the appropriate level of insulin production. Based on preliminary results that Guanabenz, an eIF2a dephosphorylation inhibitor, can reverse the severe proinsulin aggregation seen in PERK deficient ß-cells, we proposed to test its ability to prevent or reverse the severe permanent neonatal diabetes associated with the Wolcott Rallison Syndrome and dominant-negative acting insulin mutants (MIDY). This strategy may also be applicable to treatment of ß-cell dysfunctions associated with type 2 diabetes decompensation. The final Aim is designed to identify the molecular mechanisms underlying PERK-dependent regulation of ER chaperones and is essential for understanding the regulatory context in which PERK plays a central role in regulating ß-cell functions.

描述（由适用提供）：永久性新生儿糖尿病的单基因形式和2ß细胞的代偿性代偿化表明，促硫素处理在内质网（ER）中的重要性和脆弱性。一旦被认为是家政功能，促蛋白折叠，与ER相关的蛋白质降解（ERAD）的过程 - 介导的质量和数量对促硫蛋白从ER到高尔基体的贩运和贩运和多高尔基体的运输都受到了高度调节，我们已经确定了perk eif2a激酶的功能丧失，其功能丧失了永久性的透明型含量，该阶段是由含有透明的二聚体构成的，构成了w的构成。 ER中的促硫蛋白加工。我们假设了一个新颖且有争议的模型，该模型通过控制关键ER伴侣和折叠蛋白（包括GRP78和ERP72）的表达来调节Proinsulin的加工，从而控制Proinsulin是由ERAD途径降解的，是由ERAD途径降解还是将GoLGI转移到Golgi中，以使蛋白水解加工和包装蛋白质水解加工和包装。在此提案中，我们将通过操纵PERK-EIF2A途径以及关键ER伴侣的表达并评估促硫素的命运和加工状态来进一步测试该模型。我们还将确定PERK-EIF2A如何根据波动葡萄糖水平调节蛋白质加工，以提供适当的胰岛素产生水平。 Based on preliminary results that Guanabenz, an eIF2a dephosphorylation inhibitor, can reverse the severe proinsulin aggregation seen in PERK deficient ß-cells, we proposed to test its ability to prevent or reverse the severe permanent neonatal diabetes associated with the Wolcott Rallison Syndrome and dominant-negative acting insulin mutants (MIDY).该策略也可能适用于治疗与2型糖尿病相关的ß细胞功能障碍。最终目的旨在确定ER伴侣伴侣依赖PERK依赖性调节的分子机制，对于理解PERK在调节ß细胞功能中起核心作用的调节环境至关重要。