Physiological Regulation of Proinsulin Quality and Quantity Control in the Pancre

胰腺中胰岛素原质量和数量控制的生理调节

• 批准号: 8050218
• 负责人: DOUGLAS R. CAVENER
• 金额: $ 37.35万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-27 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8050218
• 关键词: Physiological; Regulation; Proinsulin; Quality; Quantity

DESCRIPTION (provided by applicant): The focus of this proposal is to investigate the role of the PERK eIF2a kinase (EIF2AK3) in regulating proinsulin trafficking and quality control in the endoplasmic reticulum. PERK is among a small set of genes identified in mice and humans that are so critically important to beta cell functions that loss of function mutations result in permanent neonatal diabetes due to insulin insufficiency. Moreover, mutations in Perk are the most common cause of consanguineous permanent neonatal diabetes in man. Our investigation of global and tissue-specific Perk KO mice led to the discovery that PERK is required for normal beta cell proliferation, proinsulin trafficking, and insulin secretion. However, the severity and magnitude of the beta cell defects seen when PERK expression is entirely absent makes the Perk KO unsuitable as the primary tool to discover the molecular and physiological functions of PERK in beta cells. We have chosen an alternative strategy whereby we will modulate PERK expression from 0.2 to 2-fold of normal levels and then investigate the acute effects on proinsulin trafficking and insulin secretion. A key assumption of this strategy is that more modest changes in expression can alter physiological outcomes. In support of this assumption we have already shown that reducing Perk gene dosage in half results in reduced blood glucose levels and ameliorates the progression of diabetes of the Akita insulin mutant mouse, whereas increasing Perk dosage above normal results in increased blood glucose levels and accelerates the progression of diabetes in Akita mice. We propose that PERK is required to regulate proinsulin quality control and trafficking in the endoplasmic reticulum as a function of the physiological demand for insulin. Hence our overall strategy is to test the this hypothesis by determining how PERK regulates quality control and trafficking of wildtype and Akita proinsulin, determine how PERK regulates ER chaperone and folding proteins underlying these functions, and determine how the regulation of PERK activity responds to normal changes in metabolism to mediate changes in proinsulin trafficking and insulin secretion. PUBLIC HEALTH RELEVANCE: Over the past several decades the number of cases of diabetes mellitus has grown significantly and is now one of our nation's leading causes of death and disability. Insufficient insulin synthesis and secretion contributes to all forms of diabetes mellitus in humans, so understanding how these processes work is critical if we are to continue to help patients manage this disease and eventually find a cure. The aims of this proposal are to characterize how a key gene in regulating functions of the insulin-secreting beta cell controls the synthesis and secretion of insulin.

描述（由申请人提供）：该提案的重点是调查PERK EIF2A激酶（EIF2AK3）在调节内质网中促硫素运输和质量控制中的作用。 PERK是在小鼠和人类中鉴定出的一小部分基因之一，这些基因对β细胞功能至关重要，以至于由于胰岛素不足而导致功能突变的丧失导致永久性新生儿糖尿病。此外，PERK中的突变是人类亲属永久性新生儿糖尿病的最常见原因。我们对全球和组织特异性PERK KO小鼠的研究导致发现，正常β细胞增殖，促硫素运输和胰岛素分泌需要PERK。但是，完全不存在PERK表达时看到的Beta细胞缺陷的严重程度和大小使Perk Ko不适合作为发现Beta细胞中Perk的分子和生理功能的主要工具。我们选择了一种替代策略，从而将PERK表达从0.2倍至2倍正常水平调节，然后研究对促硫素运输和胰岛素分泌的急性影响。该策略的关键假设是表达的更适度变化可以改变生理结果。为了支持这一假设，我们已经表明，将PERK基因剂量降低一半会导致血糖水平降低，并改善Akita胰岛素突变蛋白突变型小鼠的糖尿病的进展，而将PERK剂量提高到正常水平，导致血糖水平增加，并加速糖尿病的进展并加速糖尿病的进展。我们建议，需要PERK来调节内质网中促蛋白质质量控​​制和贩运作为胰岛素生理需求的函数。 Hence our overall strategy is to test the this hypothesis by determining how PERK regulates quality control and trafficking of wildtype and Akita proinsulin, determine how PERK regulates ER chaperone and folding proteins underlying these functions, and determine how the regulation of PERK activity responds to normal changes in metabolism to mediate changes in proinsulin trafficking and insulin secretion. 公共卫生相关性：在过去的几十年中，糖尿病病例的数量已大大增长，现在已成为我们国家的死亡和残疾原因之一。胰岛素合成和分泌不足会导致人类的所有形式的糖尿病，因此，如果我们要继续帮助患者管理这种疾病并最终找到治愈方法，那么了解这些过程的工作方式至关重要。该建议的目的是表征如何调节分泌胰岛素β细胞功能的关键基因控制胰岛素的合成和分泌。