CHROMOGRANIN A RELATED PEPTIDES IN THE GUT AND PANCREAS

嗜铬粒蛋白A（CGA）是一种分泌性糖蛋白，在几乎所有的 内分泌神经内分泌细胞。CGA通常与共同驻留的 分泌颗粒中的肽类，其内容物在应答时被释放 外部刺激。虽然确切的生理意义 CGA仍然是一个谜，已经提出了几个想法。有人建议 CGA是一种前体（即激素原）， 缩氨酸例如，胰蛋白酶抑制剂，一种CGA加工的产品， 存在于胰腺和胃肠道的肠内分泌细胞中。 胰抑素是一种有效的胰岛素分泌抑制剂。在内分泌方面- 神经内分泌细胞，CGA转化为胰抑素最有可能 涉及CGA在单个或成对的碱性氨基酸处的裂解， 内切蛋白水解酶。直到最近才有一些内切蛋白酶 (also称为激素原转化酶[PC]）。我们打算 检查两个特定PC（PC-1和PC-2）在 将CGA加工成胰抑素。关于CGA的另一个假设 功能表明它与存储和处理 肽注定为调节分泌途径;因此，我们将 检测CGA及其共存肽的稳态调节。 胃肽胃泌素伴随基因的基因表达 CGA在人卵巢腺癌细胞系中的表达;和 钙调节肽，甲状旁腺相关肽PTHrp）， 由人肝细胞系合成和释放。我们打算 检查CGA及其共存肽是否显示出 调节分泌，如果CGA被加工成胰抑素， 细胞系本研究提案的工作假设包括： 嗜铬粒蛋白A（CGA）是生物活性肽的前体 胃肠道（GI）的肠内分泌细胞， 胰腺;激素原转化酶（PC）参与加工 CG与其产物胰蛋白酶抑制剂的关系; CGA及其 共同驻留肽连接;和，生产和分泌的胃泌素- 胰腺癌、结肠癌和卵巢癌细胞系中的相关肽，和 甲状旁腺素相关肽（PTHrp）在肝细胞系中的表达， 由CGA陪同。这项建议的具体目标是：1） 表征胰腺中的胰抑素样肽， 胃肠道，2）检查激素原的参与 转化酶PC-1和PC-2在胰抑素变体形成中的作用 3）研究CGA及其共存基因的调控 肽（即胰岛素）稳态，以及控制CGA加工， 内分泌胰腺中的胰蛋白酶抑制剂，4）检查假设 CGA与胃泌素肽共同存在于胰腺、结肠和 卵巢癌细胞中的PTHrp和肝细胞中的PTHrp（HEP-G2）;并且， CGA及其共存肽显示出调节分泌的性质。

Chromogranin A (CGA) is a secretory glycoprotein identified in nearly all endocrine-neuroendocrine cells. CGA is stored typically with co-resident peptides in secretory granules whose contents are released in response to external stimulation. Although the exact physiological significance of CGA remains an enigma, several ideas have been put forth. One suggests that CGA is a precursor (ie, prohormone) of smaller, biologically active peptides. For instance, pancreastatin, a product of CGA processing, is found in enteroendocrine cells of the pancreas and GI tract. Pancreastatin is a potent inhibitor of insulin secretion. In endocrine- neuroendocrine cells, the conversion of CGA to pancreastatin most likely involves cleavage of CGA at single or paired basic amino acids by endoproteolytic enzymes. Only recently have some of the endoproteases (also called prohormone convertases [PCs]) been identified. We intend to examine the relevance of two specific PCs, PC-1 and PC-2, in the processing of CGA to pancreastatin. Another hypothesis regarding CGA function suggests that it is linked to the storage and processing of peptides destined for the regulated secretory pathway; therefore, we will examine the regulation of homeostasis of CGA and its co-resident peptide. Gene expression of a stomach peptide, gastrin, accompanies gene expression for CGA in a human ovarian adenocarcinoma cell line; and, a calcium regulatory peptide, parathyroid hormone-related peptide PTHrp), is synthesized and released by a human hepatic cell line. We intend to examine whether CGA and its co-resident peptide show characteristics of regulated secretion, and if CGA is processed to pancreastatin in these cell lines. The working hypotheses for this research proposal include: chromogranin A (CGA) serves as precursor for biologically active peptides in enteroendocrine cells of the gastrointestinal (GI) tract and pancreases; prohormone convertases (PCs) participate in the processing of CG to its product, pancreastatin; cellular homeostasis of CGA and its co-resident peptide are linked; and, production and secretion of gastrin- related peptides in pancreatic, colon and ovarian cancer cell lines, and of parathyroid hormone-related peptide (PTHrp in a hepatic cell line are accompanied by CGA. The Specific Aims of this proposal are: 1) to characterize pancreastatin-like peptides in the pancreas and gastrointestinal tract, 2) to examine the involvement of the prohormone convertases, PC-1 and PC-2, in the formation of pancreastatin variants from CGA, 3) to investigate the regulation of CGA and its co-resident peptide (ie, insulin) homeostasis, and the control of CGA processing to pancreastatin in the endocrine pancreas, 4) to examine the hypothesis that CGA co-resides with gastrin peptides in pancreatic, colon and ovarian cancer cells and with PTHrp in liver cells (HEP-G2); and, that CGA and its co-resident peptide show properties of regulated secretion.