In Vivo Chromaffin Granule depletion and Blood Pressure

体内嗜铬颗粒消耗和血压

• 批准号: 7844958
• 负责人: SUSHIL K MAHATA
• 金额: $ 24.11万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7844958
• 关键词: Acetylcholine; Adenosine Triphosphate; Adrenal Glands; Adrenal Medulla; African; Asians; Autonomic nervous system; Bacterial Artificial Chromosomes; Binding; Binding Sites; Biogenesis; Blood Pressure; Blood Vessels; CHGA gene; Cardiovascular Physiology; Catecholamines; Cations; Cattle; Cells; Chromaffin Cells; Chromaffin granule; Chromogranin A; Chromogranins; Circadian Rhythms; Complex; DNA Resequencing; Development; Diastolic blood pressure; Dimensions; Dopa; Drosophila pros protein; Environment; Ethnic group; European; Exhibits; Figs - dietary; Gene Expression; Genes; Heterozygote; Hormones; Human; Hypertension; Knock-out; Left; Membrane; Methods; Mexican Americans; Mus; Names; Neuroeffector Junction; Neuropeptides; Neurotransmitters; Nicotine; Nicotinic Antagonists; Organism; Peptides; Phenotype; Pheochromocytoma; Physiological; Plasma; Research Design; Research Personnel; Risk; Role; Smooth Muscle; Stress; Transgenes; Transgenic Mice; Transgenic Organisms; Variant; Vasodilator Agents; Ventricular; Vesicle; base; cholinergic; chromogranin A (344-364); coping; in vivo; mRNA Differential Displays; neuropeptide Y; novel; pancreastatin; research study; response; secretory protein; stressor; vasostatin

Chromogranin A (CHGA), a 48 kDa acidic secretory protein, is co-stored with neurotransmitters (catecholamines, ATP, and neuropetide Y [NPY]) in vesicles called chromaffin granules and co-released in response to nicotinic-cholinergic stimulation. CHGA is a proprotein giving rise to biologically active peptides including a catecholamine release inhibitory peptide (bovine CHGA344.364 and human CHGA352.372) that we discovered and named catestatin. Since genetically modified mice are becoming increasingly important in studies designed to understand basic mechanisms of cardiovascular function, we have generated systemic and conditional Chga knockout (Chga-/-) mice. The systemic Chga-/- mice displayed the following phenotypes: (i) Depletion of chromaffin granules accompanied by higher systolic and diastolic blood pressure (BP), (ii) "Non-dipping" BP (no diurnal variation), (iii) Increment of left ventricular dimension, (iv) Decrements of adrenal catecholamine, NPY and ATP levels, (v) Increments of plasma catecholamine and NPY levels, and (vi) Exaggerated BP response to treadmill stress. We have already generated bacterial artificial chromosome (BAG) transgenic mice containing the human CHGA gene (CHGA+/+) into the germline of Chga-/- mice (CHGA+/+;Chga-/-) to "rescue" Chga knockout phenotypes. The present proposal develops 3 specific aims: Aim I. Explore the mechanism of development of high BP (SBP and DBP) and "non-dipping" BP phenotypes in Chga-/- mice, including the role of cotransmitters. Aim II. "Rescue" the BP and "nondipping" BP phenotypes observed in Chga-/- mice by introduction of a BAG containing the human CHGA gene (CHGA+/+) into the germline of Chga-/- mice (CHGA+/+\Chga-/-). Aim III. Establish the role of a naturally occurring human catestatin variant in mice (expressing a BAC-catestatin variant transgene) in counteracting sympathoadrenal stress BP responses. These studies, utilizing unique knockout, transgenic, and human variants of catestatin, are likely to establish the role of CHGA fragment catestatin and catecholamine co-transmitters in the development of complex phenotypes such as hypertension, and the influence of naturally occurring catestatin variants in counteracting BP responses to sympathoadrenal stressors.

48 kDa酸性分泌蛋白Colomogranin A（Chga）与神经递质共同存储 （儿茶酚胺，ATP和Neuropetide Y [NPY]）在称为铬蛋白颗粒的囊泡中，并响应烟碱 - 胆碱能刺激而共同发行。 CHGA是一种普罗蛋白，引起了我们发现并命名为Catestatin的生物学活性肽（包括儿茶酚胺释放抑制性肽（牛CHGA344.364和Human CHGA352.372））。由于旨在了解心血管功能的基本机制的研究中，基因修饰的小鼠变得越来越重要，因此我们已经产生了系统性和条件的CHGA敲除（CHGA - / - ）小鼠。全身性CHGA - / - 小鼠显示以下表型：（i）铬脂颗粒的消耗，伴随着较高的收缩压和舒张压（bp），（ii）“非倾角” BP（无脂差异），（iii）左心室降低（III）左心室降低（IV）的增长，（IV）的necechornal and aremenal catechol and catechol and catecholam catecholaMine catecholaMine（IV血浆儿茶酚胺和NPY水平，以及（VI）夸张的BP对跑步机压力的反应。我们已经生成了含有人类CHGA基因（CHGA+/+）的细菌人造染色体（BAG）转基因小鼠进入Chga - / - 小鼠（CHGA+/+; CHGA - / - ）的种系中，以“ Rescue” Chga敲除表型。本提案开发了3个具体目的：AIM I.探索Chga - / - 小鼠中高BP（SBP和DBP）和“非浸入” BP表型的发展机制，包括共晶剂的作用。目标II。 “营救” BP和“非dippiptip” 通过引入包含人类的袋子，在Chga - / - 小鼠中观察到的BP表型 CHGA基因（CHGA+/+）进入Chga - / - 小鼠的种系（Chga+/+\ chga - / - ）。目标三。建立 自然存在的人猫蛋白变异在小鼠（表达BAC-catestatin变体转基因）中的作用在抵抗交感神经应力BP反应中的作用。这些研究利用了猫蛋白的独特敲除，转基因和人类变体，可能会确定CHGA片段片状猫蛋白酶和儿茶酚胺co递制剂在复杂表型（例如高血压）以及自然出现的catestatin变体中对同情反应的反应中的自然发生的表型的影响。