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

摘要 导致高血压的核心机制仍然存在，这是一种影响三分之一美国成年人的公共健康危机 很大程度上是未知的。我们的初步数据表明，下丘脑室旁核特异性G-αi2亚单位 蛋白门控通路，通过传入肾神经对高盐摄入做出反应而被激活， 调节PVN抗炎反应和PVN微小细胞神经元引起的交感神经抑制和 对食盐摄入的利钠反应。此外，pvn特异性Gαi2蛋白需要上调才能对抗 盐敏性高血压。此外，我们的试点数据表明，GNIA2的多态变异代表了 血压盐敏感性的新型临床生物标志物。这个应用程序将检验总体假设 膳食钠诱导肾传入神经依赖的PVN GαI2亚单位蛋白门控上调 通路增强微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GNAI2基因多态性是血液盐敏感性的临床生物标志物 压力。将进行以下具体目标来检验这一特定于假设的目标1： 下丘脑室旁核GαI2亚单位蛋白调节下丘脑室旁核小细胞交感神经抑制性神经元激活 炎症以对抗盐敏感型高血压的启动。具体目标2：确立 传入肾神经刺激室旁核GαI2亚单位蛋白上调，增强室旁核小细胞- 介导交感神经抑制和利钠反应以对抗盐敏感型高血压的启动。 具体目的3：建立GNAI2基因多态变异是盐中毒的临床生物标志物 血压的敏感度。这些研究是国家心脏、肺和血液中心的使命 研究所(NHLBI)并解决NHLBI战略计划中概述的所有目标和多重战略。这些 研究直接涉及2014年NHLBI盐对人类健康和疾病工作组的建议 1)需要进一步阐明盐可能引起的生物机制和病理过程 贡献，2)盐敏感性高血压作为优先研究主题，3)标准化的发展 在个体水平上确定血压对盐的敏感性的方案。我们的研究目标将是 由一个多学科合作研究团队完成，该团队结合了耐盐和 盐敏感大鼠模型(AIMS 1和2)和明确的盐敏感和耐盐患者样本(AIMS 3) 同时产生机械性的洞察力和临床相关性。通过对PVN GαI2介导的研究 盐敏感型高血压的神经机制及GNAI2基因多态性在诊断中的作用 由于个体对血压的盐敏感性，我们的创新研究策略将定义一种新的饮食 防止盐敏感型高血压(即传入肾)启动的钠敏感机制 神经)，开发临床诊断生物标记物(即，GNAI2多态变异)，并识别机制 用于治疗盐敏感型高血压的交感神经抑制治疗靶点(例如，GαI2蛋白)。

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.