GLUCOKINASE GENE EXPRESSION IN PANCREATIC BETA CELL

胰腺β细胞中的葡萄糖激酶基因表达

• 批准号: 6177284
• 负责人: MARK A MAGNUSON
• 金额: $ 20.72万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-06-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6177284
• 关键词: biological models; blood glucose; enzyme activity; gene expression; gene targeting; genetically modified animals; glucokinase; glucose metabolism; homeostasis; hyperglycemia; immunocytochemistry; laboratory mouse; liver disorder; molecular pathology; noninsulin dependent diabetes mellitus; northern blottings; pancreatic islet function; polymerase chain reaction; radioimmunoassay; western blottings

Glucokinase (GK) plays an essential role in glucose homeostasis. In humans, mutations in this enzyme cause both maturity onset diabetes of youth, type 2 (MODY-2) and persistant hyperinsulinemic hypoglycemia of infancy (PHHI). Although GK gene mutations are one of only a few genetically-defined causes of diabetes, we do not yet fully understood how mutations in this gene actually alter the plasma glucose concentration. This is a proposal to make use of novel lines transgenic and gene- altered mice to learn more about the cell-specific roles of glucokinase (GK) in glucose homeostasis and about adaptive responses that occur in response to acute and chronic alternations in the plasma glucose concentration. Aim 1 will define the tissue-specific functions of GK in glucose homeostasis by selectively removing it from different cell types using a Cre/LoxP strategy. Aim 2 will develop mice with inducible defects in either hepatic glucose utilization and/or beta cell insulin secretion, and characterize the adaptations that occur in response to both an acute loss of either hepatic or islet GK. Together, these studies will provide fundamental new insights into the molecular pathogenesis MODY-2 as well adaptations that occur in response to hyperglycemia. Thus, these studies are also relevant to the pathogenesis and treatment of Type 2 diabetes mellitus.

葡萄糖激酶(GK)在葡萄糖稳态中起着至关重要的作用。在……里面 人类，这种酶的突变会导致成熟发作性糖尿病 青年、2型(MODY-2)和持续性高胰岛素血症 婴儿(PHHI)。尽管GK基因突变是为数不多的 糖尿病的基因定义的原因，我们还没有完全了解 这个基因的突变是如何改变血糖的 集中精神。 这是一项利用转基因和转基因新品系的建议。 改变小鼠以了解更多关于葡萄糖激酶的细胞特异性作用 (Gk)在葡萄糖动态平衡和发生在 对急性和慢性血糖变化的反应 集中精神。目标1将定义GK的组织特异性功能 通过选择性地将其从不同的细胞中移除来维持葡萄糖的稳态 使用CRE/LOXP策略的类型。AIM 2将培育出具有诱导性的小鼠 肝脏葡萄糖利用和/或胰岛细胞胰岛素缺陷 分泌物，并描述了响应于 两者都是肝脏或胰岛GK的急性丢失。加在一起，这些 研究将提供对分子的基本新见解 致病机制MODY-2以及对 高血糖症。因此，这些研究也与 2型糖尿病的发病机制及治疗。