Sympathetic Neuroeffector Junctions & Blood Pressure

描述（由申请人提供）：自主神经系统的交感神经分支是血压的关键调节器。儿茶酚胺分泌囊泡通过胞外作用将共同储存的递质释放到血液或突触间隙中，在那里它们与心血管靶细胞接触。除了儿茶酚胺，分泌的“量子”还包括神经肽和嗜铬粒蛋白，它们是活性肽的前体，介导血管对交感肾上腺活化的反应，从而调节血压。我们的中心主题是：遗传变异和交感肾上腺共递质在血压调节中的作用。该计划将5个项目联系起来，研究这些递质的生物合成、释放和作用（突触前和突触后），整合它们对血压的影响。中心主题侧重于互动/协同努力。项目1和2包括人类研究，项目2和5探索转基因啮齿动物的机制，项目1和4阐明递质生物合成和释放的细胞机制，并利用项目1和2和核心C的离体生物材料进行表型分析。一个关键的主题是人类基因组DNA重测序，以确定控制交感神经活动的位点的等位基因变异谱，然后探索这些变异的功能作用。对人类双胞胎的研究探索了自主神经活动遗传改变的遗传基础（项目1&2；Core C），每个项目（1&5）都参与了由Core C&D衍生的独特的人类候选自主神经snp和单倍型的表型分析。在候选基因座上已经出现了重要的、新的遗传关联。核心设施提供标准化的人类表型和生物样本、细胞群、信号探针、基因分型、信息学、儿茶酚胺和血管活性肽分析以及成像。利用分子生物学和信息学工具，该项目旨在对交感神经效应器连接的动态复杂性，以及其组成部分如何导致血压的遗传变化，并最终导致人类高血压，达到一个新的理解水平。因此，该计划代表了一个独特的机会来定义人类自主神经功能控制血压调节的常见变异的遗传基础。

DESCRIPTION (provided by applicant): The sympathetic branch of the autonomic system is a key regulator of blood pressure. Catecholamine secretory vesicles release co-stored transmitters by exocytosis into the bloodstream or synaptic clefts, where they contact cardiovascular target cells. In addition to catecholamines, the secretory "quantum" includes neuropeptides and chromogranins, precursors of active peptides mediating vascular responses to sympathoadrenal activation, and hence blood pressure. Our central theme is: Genetic variation and sympathoadrenal co-transmitters in blood pressure regulation. This Program links 5 Projects to study biosynthesis, release, and actions (pre- and post-synaptic) of these transmitters, integrating their effects on blood pressure. Central themes focus interactive/synergistic efforts. Projects 1&2 include human studies, and Projects 2&5 probe mechanisms in transgenic rodents, while Projects 1&4 clarify cellular mechanisms in transmitter biosynthesis and release, and exploit ex vivo biological materials from Projects 1&2 & Core C for phenotyping. A crucial theme is human genomic DNA resequencing to define the spectrum of allelic variation at loci governing sympathetic activity, and then probing the functional role of such variants. Studies in human twin pairs probe the genetic basis of heritable alterations in autonomic activity (Projects 1&2; Core C), and each Project (1&5) participates in phenotyping unique human candidate autonomic SNPs & haplotypes derived by Cores C&D. Already, significant, novel genetic associations have emerged at candidate loci. 6 Core facilities provide standardized human phenotypes and biological samples, cell populations, signal probes, genotyping, informatics, catecholamine and vasoactive peptide assays, and imaging. Using molecular biologic and informatic tools, the program aims to achieve a new level of understanding of the dynamic complexity of the sympathetic neuroeffector junction, and how its components lead to heritable changes in blood pressure, and ultimately to human hypertension. The Program thus represents a unique opportunity to define the genetic basis of common variations in human autonomic function governing blood pressure regulation.