Novel catecholamine release-inhibitory peptide

新型儿茶酚胺释放抑制肽

• 批准号: 7122640
• 负责人: DANIEL T O'CONNOR
• 金额: $ 29.25万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7122640
• 关键词: biological signal transduction; cardiovascular disorder risk; catecholamines; chromogranins; genetic polymorphism; human subject; hypertension; immunoprecipitation; matrix assisted laser desorption ionization; molecular genetics; neurophysiology; neurotransmitter antagonist; neurotransmitter biosynthesis; neurotransmitter transport; nicotinic receptors; physiologic stressor; protein structure function; radioimmunoassay; scintillation spectrometry; single nucleotide polymorphism; sympathetic nervous system

Sympathoadrenal catecholamine secretion is exocytotic (all-or-none), releasing not just catecholamines but also the acidic proteins with which catecholamines are stored: chromogranins/secretogranins, quantitatively major components being chromogranin A (CHGA) and chromogranin B (CHGB). Both CHGA and CHGB seem to be necessary factors (?on/off switches?) in the biogenesis of catecholamine secretory vesicles. CHGA is cleaved to biologically active fragments, including the endogenously formed ?catestatin? that inhibits catecholamine and vesicular co-transmitter release; its specific inhibitory mechanism seems to be nicotinic cholinergic antagonism. Data collected in the initial stages of HL58120 include discovery of substantial and functional human genetic diversity (polymorphism) at the CHGA and CHGB loci, including 3 novel variants of catestatin with differential potency as nicotinic antagonists, and 8 common CHGA proximal promoter SNPs, giving rise to common CHGA promoter haplotypes with different transcriptional activities in chromaffin cells. Common CHGA promoter polymorphisms (especially G-988T) predicted plasma CHGA concentration. Common 3?-UTR polymorphisms in both CHGA (C+87T) and CHGB (C+85A) predicted heritable variation in stress blood pressure responses in human twins. CHGB expression cosegregated (LOD=5.84) with a novel locus on chromosome 11q24-q25, suggesting the presence of a previously uncharacterized major gene regulating human sympathetic outflow. We will therefore emphasize effects of common human genetic variation (polymorphism) at the CHGA and CHGB loci on their biosynthesis, release, cellular targets, and autonomic consequences. We will characterize the inhibitory effects of catestatin variants on nicotinic cholinergic receptors and their signal transduction, as well as vesicular co-transmitter release. We will explore whether polymorphisms at CHGA/catestatin and CHGB influence catecholamine release and autonomic physiology in vivo or in vitro. To explore the significance of such polymorphisms, we propose a series of 5 specific aims, in which questions give rise to testable hypotheses that can be confirmed or refuted by crucial experiments. The studies are designed to shed light upon heritable regulation of nicotinic receptor-mediated release of catecholamines, and their consequences for autonomic control of the circulation and hence genetic risk of hypertension.

交感肾上腺儿茶酚胺分泌是胞吐的（全或无），不仅释放儿茶酚胺，而且释放储存儿茶酚胺的酸性蛋白质：嗜铬粒蛋白/分泌粒蛋白，定量上主要组分是嗜铬粒蛋白A（CHGA）和嗜铬粒蛋白B（CHGB）。CHGA和CHGB似乎都是必要的因素（？开关（On/Off Switch）在儿茶酚胺分泌囊泡的生物发生中。CHGA被切割成生物活性片段，包括内源性形成的？catestatin？抑制儿茶酚胺和囊泡共递质释放;其特定的抑制机制似乎是烟碱胆碱能拮抗作用。在HL 58120的初始阶段收集的数据包括在CHGA和CHGB基因座发现了大量和功能性人类遗传多样性（多态性），包括作为烟碱拮抗剂具有不同效力的3种新型catestatin变体，以及8种常见的CHGA近端启动子SNP，从而产生了在嗜铬细胞中具有不同转录活性的常见CHGA启动子单倍型。常见的CHGA启动子多态性（尤其是G-988 T）可预测血浆CHGA浓度。 普通3？- CHGA（C+87 T）和CHGB（C+85 A）的UTR多态性预测了遗传性 人类双胞胎压力血压反应的变化。CHGB表达共分离 (LOD=5.84）与染色体11 q24-q25上的一个新位点，表明存在以前未表征的调节人类交感神经流出的主基因。因此，我们将强调在CHGA常见的人类遗传变异（多态性）的影响 和CHGB基因座对它们的生物合成、释放、细胞靶点和自主后果的影响。我们将表征catestatin变体对烟碱胆碱能受体及其信号转导的抑制作用，以及囊泡共递质释放。我们将探讨在CHGA/catestatin和CHGB的多态性是否影响体内或体外的儿茶酚胺释放和自主生理。为了探索这种多态性的意义，我们提出了一系列的5个具体目标，在这些目标中，问题会产生可验证的假设，这些假设可以通过关键实验来证实或反驳。这些研究旨在阐明烟碱受体介导的儿茶酚胺释放的遗传调节及其对循环自主控制的后果，从而揭示高血压的遗传风险。