Neurons expressing angiotensin type 2 receptors in the NTS as an access point for cardiovascular control.

NTS 中表达 2 型血管紧张素受体的神经元作为心血管控制的接入点。

基本信息

批准号：
10082461
负责人：
Eric Gerald Krause
金额：
$ 56.5万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10082461
关键词：
Acetates Affect Agonist Animal Model Antihypertensive Agents Area Attenuated Baroreflex Basic Science Blood Blood Pressure Blood Vessels Brain Brain Stem Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Cause of Death Cell Nucleus Cells DOCA Deoxycorticosterone Development Diabetes Mellitus Disease Enterobacteria phage P1 Cre recombinase Etiology GABA Receptor Gene Transfer Genetic Hypertension In Vitro Laboratories Lead Life Style Link Mediating Mediation Messenger RNA Metabolic syndrome Mus Nerve Neurons Neurosciences Neurotransmitters Nucleus solitarius Obesity Patients Pharmaceutical Preparations Pharmacology Phenotype Population Pressoreceptors Proteins Receptor Activation Receptor Gene Receptor Signaling Reflex control Reporter Reporting Research Resistance Resistant Hypertension Risk Factors Site Stroke Testing Therapeutic Therapeutic Intervention Tissues Transgenic Mice Translating Type 2 Angiotensin II Receptor Viral Virus Work base blood pressure reduction blood pressure regulation cardiovascular risk factor experimental study gamma-Aminobutyric Acid genetic approach improved in vivo indexing innovation mouse model neurogenic hypertension neurotransmission novel novel strategies novel therapeutic intervention novel therapeutics optogenetics pre-clinical receptor recombinase-mediated cassette exchange salt sensitive hypertension synthetic enzyme therapeutic target treatment strategy vasoconstriction

项目摘要

Project Summary Hypertension is the most important risk factor for the development of cardiovascular disease, the leading cause of death in the U.S. Despite therapeutic advancements, nearly 20-30% of hypertensive patients have uncontrolled high blood pressure. This resistant hypertension is associated with elevated sympathetic activity and abnormal baroreflex reflex control and thus is termed neurogenic hypertension. Animal models of neurogenic hypertension consistently implicate augmented release of GABA within the intermediate nucleus of the solitary tract (intNTS) as a contributing pathophysiological mechanism. Correcting this pathophysiological mechanism is a logical step towards decreasing high blood pressure of neurogenic origin. However, GABA and its receptors are poor therapeutic targets because GABA is the predominant inhibitory neurotransmitter in the CNS. To circumvent this impediment we began investigating whether neurons in the intNTS that express angiotensin type 2 receptors (AT2R) may serve as an access point for therapeutic interventions that relieve neurogenic hypertension. Using a novel transgenic mouse model (AT2R-eGFP reporter mouse) we discovered that GABA neurons in the intNTS robustly express AT2R and optogenetic excitation of these neurons significantly increases blood pressure. Intriguingly, DOCA-salt hypertension in mice increased indices of GABA synthesis in the intNTS but central delivery of the AT2R agonist, Compound 21 (C21), abrogated this hypertension and downregulated indices of GABA synthesis in the intNTS. Relevant to the proposed research, the antihypertensive effects of brain AT2R activation were abolished by deleting AT2R from GABA neurons. Based on these results we hypothesize that GABA neurons in the intNTS that express AT2R may be manipulated to reverse the onset of neurogenic hypertension. Two Specific Aims are proposed to substantiate or refute this hypothesis. Aim 1 combines genetic and pharmacological approaches to evaluate the consequences of deleting or stimulating AT2R on GABAergic neurons in the intNTS. Aim 1 tests the hypothesis that activation of AT2R expressed on GABAergic neurons in the intNTS alleviates DOCA-salt hypertension in mice by decreasing GABA synthetic enzymes within these neurons, which consequently decreases sympatho- excitation and improves baroreflex function. Aim 2 utilizes in vitro optogenetic and in vivo chemogenetic approaches to evaluate how DOCA-salt hypertension with or without C21 affects GABA neurotransmission within baroreflex circuits mediating cardiovascular function. Aim 2 tests the hypothesis that the activity of neurons within the intNTS that express AT2R control baroreflex sensitivity and sympathetic outflow and their selective inhibition mediates the reversal of hypertension. Execution of the proposed experiments will identify a discrete population of neurons that can be targeted to control blood pressure and provide preclinical evidence for the development of novel approaches for alleviating resistant hypertension.

项目概要高血压是心血管疾病发生的最重要的危险因素，也是心血管疾病的主要原因在美国，尽管治疗取得了进步，但仍有近 20-30% 的高血压患者死亡不受控制的高血压。这种顽固性高血压与交感神经活动升高有关压力反射控制异常，因此被称为神经源性高血压。动物模型神经源性高血压始终与中核内 GABA 的释放增加有关孤束（intNTS）作为一种病理生理机制。纠正这种病理生理该机制是降低神经源性高血压的合理步骤。然而，GABA 和它的受体不是很好的治疗靶点，因为 GABA 是体内主要的抑制性神经递质中枢神经系统。为了规避这个障碍，我们开始研究 intNTS 中的神经元是否表达血管紧张素 2 型受体 (AT2R) 可作为治疗干预的切入点，以缓解神经源性高血压。使用新型转基因小鼠模型（AT2R-eGFP 报告小鼠），我们发现 intNTS 中的 GABA 神经元强烈表达 AT2R 和这些神经元的光遗传学激发血压显着升高。有趣的是，DOCA-盐高血压小鼠的 GABA 指数增加 intNTS 中的合成，但 AT2R 激动剂化合物 21 (C21) 的中心递送消除了这一点高血压和 intNTS 中 GABA 合成指数下调。与拟议的研究相关，通过从 GABA 神经元中删除 AT2R，可以消除大脑 AT2R 激活的抗高血压作用。基于这些结果，我们假设 intNTS 中表达 AT2R 的 GABA 神经元可能是操纵以逆转神经源性高血压的发作。提出了两个具体目标证实或反驳这个假设。目标 1 结合遗传学和药理学方法来评估删除或刺激 intNTS 中 GABA 神经元 AT2R 的后果。目标 1 检验假设激活 intNTS 中 GABA 能神经元表达的 AT2R 可减轻 DOCA 盐高血压小鼠通过减少这些神经元内的 GABA 合成酶，从而降低交感神经兴奋并改善压力反射功能。目标 2 利用体外光遗传学和体内化学遗传学评估 DOCA-盐高血压（有或没有 C21）如何影响 GABA 神经传递的方法压力反射回路介导心血管功能。目标 2 检验神经元活动的假设在表达 AT2R 的 intNTS 中控制压力反射敏感性和交感神经流出及其选择性抑制介导高血压的逆转。执行所提出的实验将确定一个离散的可以靶向控制血压并提供临床前证据的神经元群开发缓解难治性高血压的新方法。