Regulation of Pancreatic Functions by PERK elF2 Kinase

描述（由申请人提供）： 胰腺的主要分泌蛋白的合成和分泌是间歇性调节的，以满足生物体快速变化的生理和发育需求。钙从内质网（ER）库的动员介导分泌颗粒的胞吐作用。虽然胰腺中刺激偶联分泌的机制已被很好地理解，但对控制胰腺分泌能力和维持分化状态的基因的调节知之甚少。切除PERK eIF 2 α激酶基因的小鼠显示胰腺外分泌缺陷，包括消化酶产生减少、转分化为肝样细胞和胰腺结构变性，伴随着侵入腺泡的成纤维细胞增殖。PERK依赖性内分泌缺陷的特征在于胰岛β细胞的早期新生儿损失，这最终导致胰岛几乎完全消失，并且在出生后第三周失去血糖控制。我们发现Perk-/-小鼠在新生期胰岛的进行性丢失是由于13细胞增殖失败而不是β细胞凋亡增加的结果。PERK功能的丧失也与患有Wolcott-Rallison综合征的人类中的早期婴儿胰腺衰竭相关。我们提出PERK活性的生理调节介导β细胞增殖因子，并调节控制胰腺分泌能力和分化状态的其他基因。该提案的主要重点是确定由PERK控制的调节和代谢途径。使用遗传学方法，我们将确定PERK依赖性β细胞群维持的细胞基础，包括鉴定由PERK调节的潜在13细胞增殖因子的方法。我们还将评估PERK对正常胰腺发育的重要性，并将确定PERK是否调节基因的表达，这些基因的功能是调节内分泌和外分泌胰腺的分泌能力。我们的研究将直接涉及Wolcott-Rallison综合征的病理生理学，特别是糖尿病的早期发病。

DESCRIPTION (provided by applicant): The synthesis and secretion of the major secretory proteins of the pancreas is episodically regulated to meet rapidly changing physiological and developmental needs of the organism. Mobilization of calcium fromendoplasmic reticulum (ER) stores mediates exocytosis from secretory granules. Although the mechanisms of stimulus-coupled secretion in the pancreas are well understood, relatively little is known about the regulation of the genes that control pancreatic secretory capacity and the maintenance of the differentiated state. Mice ablated for the PERK eIF2alpha kinase gene display exocrine pancreatic defects that include reduced digestive enzyme production, transdifferentiation to liver-like cells and degeneration of pancreatic structure that is accompanied by proliferation of fibroblasts that invade the acini. PERK-dependent endocrine defects are characterized by the early neonatal loss of islet beta cells, which ultimately leads to an almost complete disappearance of the islets and loss of glycemic control by the third postnatal week. We show that the progressive loss of the islets during the neonatal period in Perk-/- mice is due to a failure of the 13cells to proliferate and not the result of an increase in beta cell apoptosis. The loss of PERK function is also associated with early infantile pancreatic failure in humans with the Wolcott-Rallison Syndrome. We propose that the physiological regulation of PERK activity mediates beta cell proliferation factors and regulates other genes that control the secretory capacity and differentiated state of the pancreas. The major focus of this proposal is to determine the regulatory and metabolic pathways that are controlled by PERK. Using a genetic approach we will determine the cellular basis for PERK-dependent maintenance of beta cell mass that includes approaches to identify potential 13cell proliferation factors that are regulated by PERK. We will also assess the importance of PERK for the normal pancreatic development and will determine if PERK regulates the expression of genes that function to modulate the secretory capacity of both the endocrine and exocrine pancreas. Our studies will directly bear on the pathophysiology of Wolcott-Rallison syndrome, and in particular the early onset of diabetes mellitus.