Hypertension and Prostanoid Signaling in the Subfornical Organ of the Brain

大脑穹窿下器官中的高血压和前列腺素信号传导

• 批准号: 7760718
• 负责人: Robin L Davisson
• 金额: $ 36.07万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-05 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7760718
• 关键词: Angiotensin II; Attenuated; Automobile Driving; Baroreflex; Blood Pressure; Brain; Cardiovascular Diseases; Cardiovascular system; Cells; Chronic; Coupled; Data; Dinoprostone; Dose; Electrophysiology (science); Essential Hypertension; Fluorescent Dyes; Functional disorder; Gene Transfer; Generations; Homeostasis; Hormonal; Hormones; Human; Hypertension; Image; In Vitro; Infusion procedures; Knock-in Mouse; Knock-out; Knockout Mice; Lead; Link; Maps; Measures; Mediating; Modeling; Molecular; Mus; NADPH Oxidase; Neural Pathways; Neurons; Output; Oxidants; Phase; Physiological; Plasma; Play; Predisposition; Production; Prosencephalon; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Reactive Oxygen Species; Receptor Gene; Receptor Inhibition; Relative (related person); Research; Role; Signal Pathway; Signal Transduction; Site; Source; Staging; Structure; Subfornical Organ; Testing; Urine; Vasopressins; Viral; Viral Genes; Work; base; blood pressure regulation; cerebrovascular; cyclooxygenase 1; drinking; immunocytochemistry; in vivo; inhibitor/antagonist; insight; interdisciplinary approach; neurophysiology; novel therapeutic intervention; oxidant stress; paraventricular nucleus; patch clamp; prevent; receptor; receptor expression; recombinase; reconstitution; response; spatiotemporal; voltage

PROJECT 1 (Davisson): Hypertension and prostanoid signaling in the subfornical organ of the brain There is compelling evidence that human hypertension is characterized by neurohumoral dysfunction, and inappropriate angiotensin II (Angll) signaling in the CNS is a primary culprit. The subfornical organ (SFO), a forebrain structure considered a key "gateway" to the CNS for circulating Angll, provides extensive inputs to the paraventricular nucleus (PVN) and its output neurons mediating sympathetic activation and release of hormones, e.g., vasopressin. Our work shows that excessive reactive oxygen species (ROS) signaling in SFO are critical in "slow-pressor" Angll hypertension, a subpressor Angll infusion model that recapitulates critical features of essential hypertension. However, the signaling mechanisms within the SFO by which Angll and oxidant products initiate the neurohumoral dysfunction leading to the blood pressure elevation are not clear. Cyclooxygenase (COX)-derived prostaglandins, such as prostaglandin E2 (PGE2), have long been implicated in the signaling pathways of Angll, but their role in critical mechanisms in the SFO underlying slow-pressor Angll hypertension has not been elucidated. Our preliminary data suggest a crucial role of COX-1-derived PGE2 acting on PGE2 EPi receptors (EPiR) in Angll slow pressor hypertension. Project 1 will test the central hvpothesis that PGE9 provides an essential link between Angll, ROS and the maladaptive changes that occur in the SFO-PVN axis which lead to neurohumoral dysfunction in the Ang-ll slow-pressor model. Aim 1 will test the hypothesis that AT, receptors, NADPH oxidase subunits and PGE2-related molecules are co-localized in PVN-projecting SFO neurons in a manner consistent with their functional interaction. Aim 2 will test the hypothesis that administration of slow pressor doses of Angll elicits C0X1- dependent PGE2 production in the SFO. This aim will also determine whether ROS production is upstream or downstream of PGE2. Aim 3 will use single-cell electrophysiology and ROS imaging to test the hypothesis that COX-1-derived PGE2 is required for the enhancement of Ca^* currents and ROS production induced by Angll in PVN-projecting SFO neurons. Aim 4 will test the hypothesis that EPiR in SFO are necessary and sufficient to confer susceptibility to slow-pressor Angll neurohumoral dysfunction and hypertension. We will use a newly developed conditional EPiR null mouse in which EPiR expression can be regionally reconstituted by local delivery of Cre recombinase.

项目1（Davisson）：大脑副构造器官中的高血压和前列腺素信号传导 有令人信服的证据表明，人类高血压的特征是神经性功能障碍，并且 中枢神经系统中不适当的血管紧张素II（ANGLL）信号传导是主要的罪魁祸首。副脱机器官（SFO），一个 前脑结构被认为是CNS循环Angll的关键“网关”，为 室室核（PVN）及其输出神经元介导交感神经激活和释放 激素，例如加压素。我们的工作表明，过量的活性氧（ROS）信号传导 SFO对于“慢速” Angll高血压是至关重要的，这是一种概括的亚压输液模型 基本高血压的关键特征。但是，SFO内的信号传导机制 Angll和氧化剂产生导致血压升高的神经肿瘤功能障碍是 不清楚。环氧合酶（COX）衍生的前列腺素，例如前列腺素E2（PGE2），长期以来一直是 与Angll的信号传导途径有关，但它们在SFO基础的关键机制中的作用 尚未阐明慢速压力轴高血压。我们的初步数据表明 COX-1衍生的PGE2作用于Angll缓慢的压力高压中的PGE2 EPI受体（EPIR）。项目1将 测试PGE9提供Angll，ROS与适应不良的基本联系的中心HVPothesis SFO-PVN轴中发生的变化，导致Ang-ll慢速压力器中神经肿瘤功能障碍 模型。 AIM 1将检验以下假设：AT受体，NADPH氧化酶亚基和与PGE2相关的假设 分子以与其功能一致的方式共定位在PVN投影SFO神经元中 相互作用。 AIM 2将检验以下假设：慢速施用的施用引起慢速施加剂量。 SFO中的依赖性PGE2产生。此目标还将决定ROS的产生是上游还是 PGE2的下游。 AIM 3将使用单细胞电生理学和ROS成像来检验假设 COX-1衍生的PGE2是增强Ca^*电流和ROS产生所必需的 pvn推出的SFO神经元中的Angll。 AIM 4将检验以下假设：SFO中的EPIR是必要的，并且 足以赋予对缓慢压力的Angll神经肿瘤功能障碍和高血压的敏感性。我们将 使用新开发的条件EPIR NULL小鼠，其中EPIR表达可以在区域上表达 通过局部递送CRE重组酶重组。