Regulation of Pancreatic Functions by PERK elF2 Kinase

描述(由申请人提供)： 胰腺主要分泌蛋白的合成和分泌受到间歇性调节，以满足机体快速变化的生理和发育需要。从内质网(ER)储备物中动员钙可以调节分泌颗粒的胞吐作用。虽然胰腺中刺激偶联分泌的机制已经很清楚，但对控制胰腺分泌能力和维持分化状态的基因的调控知之甚少。去除了perk eIF2α激酶基因的小鼠表现出胰腺外分泌缺陷，包括消化酶产生减少，向肝样细胞的转分化，以及伴随着侵入腺泡的成纤维细胞增殖的胰腺结构退化。依赖PERK的内分泌缺陷的特征是新生儿早期胰岛β细胞的丢失，最终导致胰岛几乎完全消失，并在出生后第三周失去血糖控制。我们证明，PERK-/-小鼠在新生期胰岛的进行性丧失是由于13个细胞无法增殖，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综合征的人类早期婴儿胰腺衰竭有关。我们认为，PERK活性的生理调节介导了β细胞增殖因子，并调节了其他控制胰腺分泌能力和分化状态的基因。这项提议的主要焦点是确定由PERK控制的调节和代谢途径。使用遗传学方法，我们将确定依赖PERK维持β细胞质量的细胞学基础，其中包括识别受PERK调控的潜在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是否调节内分泌和外分泌胰腺分泌能力的基因表达。我们的研究将直接关系到Wolcott-Rallison综合征的病理生理学，特别是早期糖尿病的发病。

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.