TRANSGENIC MOUSE MODEL FOR FAMILIAL HYPERINSULINISM

家族性高胰岛素血症转基因小鼠模型

• 批准号: 6381037
• 负责人: Joseph Bryan
• 金额: $ 20.37万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2003-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6381037
• 关键词: B lymphocyte; calcium channel; diabetes mellitus genetics; disease /disorder model; drug receptors; electrophysiology; gene mutation; gene targeting; genetic disorder; genetically modified animals; glucagon; glucose metabolism; hyperinsulinism; hypoglycemia; insulin; laboratory mouse; membrane potentials; neurons; noninsulin dependent diabetes mellitus; pancreatic islet function; pancreatic islets; potassium channel; somatostatin; sulfonylurea; tissue /cell culture

The objective of this proposal is to understand how beta-cells couple metabolism to membrane activity using SUR1 null mice. We have reconstituted the beta-cell ATP-sensitive K+ channel, KATP, from the high affinity sulfonylurea receptor (SUR1) and a silent member of the small inward rectifier family (KIR6.2). KATP is the target for the sulfonylureas used to treat non-insulin dependent diabetes mellitus, NIDDM, and for K+ channel openers (KCOs) used to treat hyperinsulinism. SUR1 is a member of the ATP-binding cassette superfamily with multiple transmembrane domains and two nucleotide binding folds (NBFs). KATP channels play a key role in regulating insulin secretion. Glucose metabolism alters the ATP/ADP ratio in beta-cells, particularly MgADP levels that stimulate openings of KATP, which set the beta-cell resting membrane potential. SUR1 senses changes in nucleotide levels and reduces K+ flux through KATP thus depolarizing the beta-cell membrane. Depolarization activates voltage-gated Ca2+ channels; the resulting Ca2+ transients trigger insulin exocytosis. Mutations in SUR1 that inactivate KATP, or affect its regulation by MgADP, cause persistent hyperinsulinemic hypoglycemia of infancy (PHHI), an autosomal recessive disease of newborns characterized by high insulin levels despite severe hypoglycemia. We have made SUR1 null mice in order to characterize the PHHI phenotype and study the functions of KATP channels in insulin secretion. We propose to characterize these animals, specifically, the levels of glucose, insulin, glucagon and somatostatin will be assayed to determine if homozygotic SUR1 null mice are hyperinsulinemic and hypoglycemic and to characterize heterozygotic animals. Pancreatic islets will be cultured and used for electrophysiological characterization of KATP. These mice will provide research material for the study of the most common cause of persistent hypoglycemia in newborns, and will provide insight into the physiology and pathology of insulin secretion. We will correct the pancreatic defect by expressing SUR1 cDNA in the pancreas under control of the rat insulin II promoter. The resulting animals will be used to study extra-pancreatic functions of the SUR/KIR6.2 ATP-sensitive potassium channels, particularly in neurons.

这项提议的目的是了解β细胞是如何偶联的