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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

基本信息

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
项目类别：
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

项目摘要

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)：高血压和脑皮层下器官的前列腺素信号