PARATHYROID CHROMOGRANIN A, PANCREASTATIN, PTH RELATION

甲状旁腺嗜铬粒蛋白 A、胰抑素、PTH 关系

• 批准号: 2140346
• 负责人: DAVID V COHN
• 金额: $ 21.06万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-05-01 至 1995-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2140346
• 关键词: amidation /deamidation; diabetes mellitus; glycosylation; homeostasis; hormone regulation /control mechanism; hyperparathyroidism; hypothalamic pituitary axis; insulin inhibitor; laboratory rabbit; pancreatic islet function; parathyroid hormones; phosphorylation; protein biosynthesis; proteolysis; secretion; secretory protein; sulfation

Parathormone, a key factor in Ca2+ homeostasis, was thought until recently to be the only biologically active peptide secreted by the parathyroid. It is now recognized that the gland synthesizes, processes and secretes another major molecule, chromogranin A (CgA, Secretory Protein-I) that may exert significant effects on biological processes. CgA appears to be universally distributed in endocrine, but not exocrine, glands. It is composed of about 450 amino acids and is glycosylated, sulfated and phosphorylated. Highly purified parathyroid CgA has been shown to inhibit insulin secretion at physiological blood concentrations and appears to be the precursor molecule for pancreastatin, a C-terminally amidated 49 amino acid peptide, that is derived from CgA by proteolysis and amidation. Pancreastatin potently inhibits stimulated secretion by the parathyroid, endocrine and exocrine pancreas, gastric parietal cells, and possibly the adrenal and other cells. In addition to acting as a hormone and/or hormone precursor, there is speculation that CgA modifies intracellular processing or traffic of those secretory granules in which it is packaged. The data already available raise the real possibility that CgA and peptide(s\) derived form it are involved in a hitherto unsuspected level of endocrine regulation and interaction. The present research focuses on several aspects of CgA/pancreastatin biology in the parathyroid. Specific Aims include a) determination if and how pancreastatin is formed from CgA; b) evaluation of the biochemical mechanism(s) by which pancreastatin inhibits secretion by the parathyroid (and other cells), including its effect on cytosolic Ca2+, interaction with putative membrane receptors, and possible autoregulation of the parent cell; c) examination of posttranslational modifications of CgA and correlation of these changes to 1) the biological activity of the molecule and 2) to the "age" of the evaluation of action of CgA on bone and on cells and tissues; and f) screening other peptides that comprise non-pancreastatin regions of the Cga core amino acid chain for biological activity. The information obtained int his investigation could provide new insights into normal endocrine regulation and into metabolic disorders associated with endocrine diseases including primary and secondary hyperparathyroidism, diabetes and multiple endocrinopathies.

甲状旁腺素是 Ca2+ 稳态的关键因素，直到最近才被认为 是甲状旁腺分泌的唯一具有生物活性的肽。它 现在人们认识到腺体合成、加工和分泌 另一种主要分子嗜铬粒蛋白 A（CgA，分泌蛋白-I）可能 对生物过程产生重大影响。 CgA 似乎是 普遍分布于内分泌腺，但不分布于外分泌腺。 这是 由约450个氨基酸组成，被糖基化、硫酸化和 磷酸化。 高度纯化的甲状旁腺 CgA 已被证明可以抑制 胰岛素在生理血液浓度下的分泌似乎是 胰酶前体分子，C 端酰胺化的 49 个氨基 酸性肽，是由CgA经蛋白水解和酰胺化而衍生的。 胰酶有效抑制甲状旁腺刺激的分泌， 内分泌和外分泌胰腺、胃壁细胞以及可能的 肾上腺和其他细胞。 除了充当激素和/或激素 前体，有人推测 CgA 会改变细胞内加工 或包装它的那些分泌颗粒的运输。 数据 已经可用的提高了 CgA 和肽（s\）的真正可能性 它的衍生形式涉及迄今为止未被怀疑的内分泌水平 调节和相互作用。 目前的研究主要集中在几个方面 甲状旁腺中 CgA/胰酶生物学的各个方面。 具体目标 包括 a) 确定胰蛋白酶是否以及如何由 CgA 形成； b) 评估胰酶抑制的生化机制 甲状旁腺（和其他细胞）的分泌，包括其对 胞质 Ca2+，与假定的膜受体的相互作用，以及可能的 亲本细胞的自动调节； c) 翻译后检查 CgA 的修饰以及这些变化与 1) 生物学的相关性 分子的活性和2）对分子作用评价的“年龄” 骨骼、细胞和组织上的 CgA； f) 筛选其他肽 包含 Cga 核心氨基酸链的非胰腺素区域 生物活性。 他在调查中获得的信息可以 为正常内分泌调节和代谢提供新见解 与内分泌疾病相关的疾病，包括原发性和 继发性甲状旁腺功能亢进症、糖尿病和多种内分泌疾病。