Novel catecholamine release-inhibitory peptide

新型儿茶酚胺释放抑制肽

• 批准号: 7430284
• 负责人: DANIEL T O'CONNOR
• 金额: $ 31.36万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7430284
• 关键词: 11q24-q25; Alleles; Anabolism; Antibiotic A23187; Axon; Beta Cell; Biochemical; Biogenesis; Blood Circulation; Blood Pressure; Blood Vessels; Calcium Channel; Catecholamines; Cells; Chloroquine; Cholinergic Agents; Cholinergic Antagonists; Cholinergic Receptors; Chromaffin Cells; Chromogranin A; Chromogranins; Chromosomes; Cleaved cell; Data; Diagnostic; Dose; Exons; Family; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Genetic Variation; Glucose; Haplotypes; Heritability; Human; Human Chromosomes; Human Genetics; Hypertension; In Vitro; Introns; Islets of Langerhans; Light; Luciferases; Mediating; Modeling; Muscle relaxants; Neurons; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Nicotinic Receptors; Oligopeptides; Organism; Peptides; Pharmaceutical Preparations; Phenotype; Physiology; Plasma; Plasmids; Population; Process; Proteins; Receptor Signaling; Regulation; Reporter; Research Design; Secretory Vesicles; Series; Signal Transduction; Specificity; Staging; Stimulus; Stress; Structure; System; Tannic Acid; Twin Multiple Birth; Untranslated Regions; Variant; Vesicle; cellular targeting; cholinergic; chromogranin A (344-364); chromogranin B; chromogranin C; epibatidine; in vivo; noradrenergic; novel; pancreastatin; promoter; research study; response; secretogranins; vasostatin; voltage

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（全部或全无），不仅释放儿茶酚胺，还释放储存儿茶酚胺的酸性蛋白：嗜铬粒蛋白/分泌粒蛋白，定量的主要成分是嗜铬粒蛋白 A (CHGA) 和嗜铬粒蛋白 B (CHGB)。 CHGA 和 CHGB 似乎都是儿茶酚胺分泌囊泡生物发生中的必要因素（“开/关”开关？）。 CHGA 被切割成生物活性片段，包括内源形成的“catestatin”？抑制儿茶酚胺和囊泡共递质的释放；其具体的抑制机制似乎是烟碱胆碱能拮抗作用。 HL58120 初始阶段收集的数据包括在 CHGA 和 CHGB 位点发现了实质性和功能性的人类遗传多样性（多态性），包括作为烟碱拮抗剂具有不同效力的 catestin 的 3 个新变体，以及 8 个常见的 CHGA 近端启动子 SNP，从而产生了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-988T）可预测血浆CHGA浓度。 CHGA (C+87T) 和 CHGB (C+85A) 中常见的 3?-UTR 多态性预测可遗传 人类双胞胎的应激血压反应存在差异。 CHGB 表达共分离 （LOD=5.84）在染色体 11q24-q25 上有一个新的位点，表明存在一个以前未表征的调节人类交感神经流出的主要基因。因此，我们将在 CHGA 上强调常见人类遗传变异（多态性）的影响 和 CHGB 位点的生物合成、释放、细胞靶标和自主神经后果。我们将描述儿茶素变体对烟碱胆碱能受体及其信号转导以及囊泡共递质释放的抑制作用。我们将探讨 CHGA/catestatin 和 CHGB 的多态性是否影响体内或体外儿茶酚胺的释放和自主生理学。为了探索此类多态性的重要性，我们提出了一系列 5 个具体目标，其中问题引发了可检验的假设，这些假设可以通过关键实验来证实或反驳。这些研究旨在揭示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影响，从而影响高血压的遗传风险。