Homeostatic regulation of autonomic physiology by chromogranin A

描述（由申请人提供）：弥漫性神经内分泌系统的细胞具有普遍含有激素原嗜铬粒蛋白A（CHGA）的储存分泌颗粒。CHGA被加工成肽，肽是血压、心脏功能和葡萄糖代谢的稳态调节剂。巧合的是，高血压个体血浆中CHGA水平升高，而其catestatin（CST）片段减少。CST是CHGA的激素衍生物，其作为儿茶酚胺分泌抑制剂起作用。人类中的CHGA基因座具有常见的遗传变异，其导致CHGA的生物合成、加工、释放和其他体内功能的个体间差异。一般人群在CHGA和CST水平以及CST的主要序列中存在差异。约4.5%的人群具有变体Gly364Ser CST肽。 本研究将阐明CHGA水平升高导致CST降低，最终进入高血压状态的潜在机制。还将评价CST肽中氨基酸置换的体内功能意义。预期心脏功能（如心率及其变异性、压力感受器敏感性和外周血管扩张性）会受到CST序列变化的影响，并将对其进行评价。 新的转基因小鼠模型的嗜铬粒蛋白A基因座的“人源化”将用于解决本研究的目标。已经建立了小鼠模型来表达人CHGA基因（野生型和catestatin变体），在天然人元件的调节下。这是一种独特的体内方法，用于研究catestatin激素中单核苷酸多态性的相关性，允许验证体外发现，人群中的观察结果，并提供了在人体中不可能进行测试的方法。这项研究将揭示CHGA诱导的高血压对心脏自主控制的遗传基础。 我们预计，这些结果将引起广大受众的普遍兴趣：心脏病学家、血管生物学家、神经学家、神经生物学家、内分泌学家、生理学家和药理学家，以及探索影响人类自主神经功能的基因的复杂性状遗传学家。

DESCRIPTION (provided by applicant): Cells of the diffuse neuroendocrine system have storage secretory granules that ubiquitously contain the pro-hormone Chromogranin A (CHGA). CHGA is processed into peptides that are modulators of homeostasis of blood pressure, cardiac function and glucose metabolism. Paradoxically, the CHGA level is elevated in plasma of hypertensive individuals, whereas its catestatin (CST) fragment is diminished. CST is a hormone derivative of CHGA that functions as a catecholamine secretory inhibitor. The CHGA locus in humans has common genetic variations that result in inter- individual differences in biosynthesis, processing, release and other in vivo functions of CHGA. The general population has variation in both CHGA and CST levels, as well as in the primary sequence of CST. About 4.5% of the population has the variant Gly364Ser CST peptide. This study will delineate the underlying mechanism by which the elevated levels of CHGA result in diminished CST, eventuating into hypertensive state. It will also evaluate in vivo functional significance of the amino acid replacements in the CST peptide. Cardiac functions such as heart rate and its variability, baroreceptor sensitivity and peripheral blood vessel distensibility are expected to be affected by this variation in CST sequence and will be evaluated. Novel transgenic mouse models 'humanized' for the chromogranin A locus will be used to address the goals of this study. Mouse models have been created to express the human CHGA gene (wild-type and the catestatin variant), under regulation of the native human elements. This is a unique in vivo approach to study the relevance of single nucleotide polymorphisms in the catestatin hormone allowing validation of in vitro findings, observations in the human population and provides means for testing not possible in humans. The study will unravel the genetic underpinnings of CHGA-induced hypertension on cardiac autonomic control. We anticipate that the results will be of general interest to a wide audience: cardiologists, vascular biologists, neurologists, neurobiologists, endocrinologists, physiologists and pharmacologists, as well as complex trait geneticists probing genes that influence autonomic function in humans.