Central mechanisms and novel biomarkers of the salt-sensitivity of blood pressure

摘要 导致高血压的中心机制仍然存在，高血压是一种影响三分之一美国成年人的公共卫生危机 大部分未知。我们的初步数据表明，下丘脑室旁核（PVN）特异性Gαi2亚单位 蛋白质门控途径，其响应于高盐摄入被传入肾神经激活， 调节PVN抗炎反应和PVN小细胞神经元诱发的交感神经抑制， 钠尿对盐摄入的反应。此外，PVN特异性Gαi2蛋白上调是对抗PVN的需要。 盐敏感性高血压此外，我们的试点数据表明，GNIA 2多态性方差代表了一个 血压盐敏感性的新临床生物标志物。本应用程序将测试整体假设 膳食钠引起肾传入神经依赖性PVN Gαi2亚单位蛋白门控上调， 途径增强小细胞交感神经抑制反应，以对抗盐敏感性的发展 高血压和GNAI 2多态性变异是血液盐敏感性临床生物标志物 压力将进行以下具体目标来检验该假设-具体目标1：建立 PVN Gαi2亚单位蛋白调节PVN小细胞交感神经抑制性神经元激活， 炎症，以对抗盐敏感性高血压的启动。具体目标2：确定 肾传入神经刺激PVN Gαi2-亚单位蛋白上调，增强PVN小细胞 介导的交感神经抑制和利钠反应，以对抗盐敏感性高血压的起始。 具体目标3：确定GNAI 2基因的多态性变异是盐-尿激酶的临床生物标志物。 血压的敏感性。这些研究是国家心肺和血液中心使命的核心 研究所（NHLBI）和解决NHLBI战略计划中概述的所有目标和多个战略。这些 2014年NHLBI人类健康和疾病工作组的建议 对于1）需要进一步阐明盐可能 贡献，2）盐敏感性高血压作为优先研究课题，3）标准化的发展 在个体水平上确定血压的盐敏感性的协议。我们的研究目标是 由一个多学科的合作研究小组完成，该小组将抗盐和 盐敏感大鼠模型（目标1和2）和确定的盐敏感和盐抗性患者样品（目标3）， 同时产生机械洞察力和临床相关性。通过研究PVN Gαi2介导的 盐敏感性高血压的神经机制和GNAI 2多态性在确定高血压发生机制中的作用 血压的个体盐敏感性，我们的创新研究策略将定义一种新的饮食 防止盐敏感性高血压起始的钠敏感性机制（即，肾传入纤维 神经），开发临床诊断生物标志物（即，GNAI 2多态性方差）和鉴定机制 交感神经抑制治疗靶点（例如，Gαi2蛋白）用于治疗盐敏感性高血压。

ABSTRACT The central mechanisms that cause hypertension, a public health crisis that affects 1 in 3 U.S. adults, remain largely unknown. Our pilot data demonstrate that hypothalamic paraventricular (PVN) specific Gαi2-subunit protein-gated pathways, which are activated in response to high salt intake by the afferent renal nerves, modulate PVN anti-inflammatory responses and PVN parvocellular neuron evoked sympathoinhibitory and natriuretic responses to salt-intake. Additionally, PVN specific Gαi2 protein up regulation is required to counter salt-sensitive hypertension. Further, our pilot data suggests that GNIA2 polymorphic variance represents a novel clinical biomarker of the salt-sensitivity of blood pressure. This application will test the overall hypothesis that dietary sodium evoked afferent renal nerve-dependent up regulation of PVN Gαi2-subunit protein-gated pathways augments parvocellular sympathoinhibitory responses to counter the development of salt-sensitive hypertension and that GNAI2 polymorphic variance is a clinical biomarker of the salt-sensitivity of blood pressure. The following Specific Aims will be conducted to test this hypothesis - Specific Aim 1: To establish that PVN Gαi2-subunit proteins modulate PVN parvocellular sympathoinhibitory neuronal activation and inflammation to counter the initiation of salt-sensitive hypertension. Specific Aim 2: To establish that the afferent renal nerves stimulate PVN Gαi2-subunit protein up regulation to potentiate PVN parvocellular- mediated sympathoinhibitory and natriuretic responses to counter the initiation of salt-sensitive hypertension. Specific Aim 3: To establish that polymorphic variance in the GNAI2 gene is a clinical biomarker for the salt- sensitivity of blood pressure. These studies are central to the mission of the National Heart Lung and Blood Institute (NHLBI) and address all Goals and multiple Strategies outlined in the NHLBI Strategic Plan. These studies directly address the 2014 NHLBI Salt in Human Health and Sickness Working Group recommendations for 1) a need to further illuminate the biological mechanisms and pathological processes to which salt may contribute, 2) salt-sensitive hypertension as a priority research topic and, 3) the development of standardized protocols to determine the salt-sensitivity of blood pressure at an individual level. Our research goals will be accomplished by a multidisciplinary collaborative research team that combines the use of salt-resistant and salt-sensitive rat models (Aims 1 & 2) and defined salt-sensitive and salt-resistant patient samples (Aim 3) to generate mechanistic insight and clinical relevance simultaneously. By investigating the PVN Gαi2 mediated neural mechanisms underlying salt-sensitive hypertension and the utility of GNAI2 polymorphisms to determine the individual salt-sensitivity of blood pressure, our innovative research strategy will define a novel dietary sodium-sensitive mechanism that prevents the initiation of salt-sensitive hypertension (i.e., the afferent renal nerves), develop a clinical diagnostic biomarker (i.e., GNAI2 polymorphic variance) and identify mechanistic sympathoinhibitory therapeutic targets (e.g., Gαi2 proteins) for the treatment of salt-sensitive hypertension.