Angiotensin-(1-7) engages hypothalamic arcuate-paraventricular nucleus inhibitory pathways to lower blood pressure

血管紧张素-(1-7) 参与下丘脑弓状室旁核抑制通路来降低血压

基本信息

批准号：
10751682
负责人：
Victoria Lynn Vernail
金额：
$ 3.45万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10751682
关键词：
Address Animal Model Animals Antihypertensive Agents Area Attenuated Binding Blood Pressure Body Weight decreased Brain Cardiac Cardiovascular Diseases Cardiovascular system Cells Chronic Clinical Data Disease Electrophysiology (science)Epidemic Goals Health High Fat Diet Hormones Hypertension Hypothalamic structure Institution Insulin Knockout Mice Measures Melanocortin 4 Receptor Mentorship Metabolic Methods Molecular Mus Neurons Neurosciences Neurosciences Research Neurotransmitters Obese Mice Obesity Obesity Related Hypertension Pathway interactions Peripheral Pharmaceutical Preparations Physiological Pro-Opiomelanocortin Receptor Signaling Regulation Renin-Angiotensin System Research Research Personnel Rest Risk Rodent Saline Signal Pathway Signal Transduction Structure of nucleus infundibularis hypothalami Testing Tissues Transgenic Mice Work angiotensin I (1-7)antagonist blood pressure elevation blood pressure reduction career clinically relevant comparison control diet-induced obesity dietary control experimental study gamma-Aminobutyric Acid hypertension treatment hypertensive improved innovation insight insulin sensitivity lipid metabolism metabolic profile mouse model neural circuit neuromechanism neurotransmission new therapeutic target novel obesity treatment optimal treatments paraventricular nucleus patch clamp patient population pharmacologic presynaptic prevent receptor response side effect skills therapeutic target transmission process treatment comparison treatment guidelines treatment strategy

项目摘要

PROJECT SUMMARY Obesity is a global epidemic that greatly increases the risk for developing hypertension and cardiovascular disease. The molecular mechanisms connecting hypertension with obesity are poorly understood, however, and optimal treatment strategies are unclear as some antihypertensive drugs elicit adverse metabolic side effects. This illustrates the critical need to identify new therapeutic targets with a positive metabolic profile for treatment of obesity hypertension. We propose that angiotensin (Ang)-(1-7), a protective hormone of the renin- angiotensin system, provides this ideal target. Ang-(1-7) binds mas receptors (masR) to lower blood pressure and improve metabolic function in obese and hypertensive rodents; but the mechanisms involved are unknown. Our preliminary data show that Ang-(1-7) depressor effects require activation of masR within the arcuate nucleus of the hypothalamus (ARC). More specifically, we show that Ang-(1-7) masR are highly localized to proopiomelanocortin (POMC)-containing neurons that release the inhibitory neurotransmitter GABA. Activation of GABAergic POMC neurons by Ang-(1-7) could lower blood pressure by inhibiting downstream melanocortin-4 receptor (MC4R) signaling in the hypothalamic paraventricular nucleus (PVN), but this has not been explored. This proposal will test the central hypothesis that Ang-(1-7) stimulates ARC POMC neurons to enhance GABAergic neurotransmission onto PVN neurons to lower blood pressure. Aim 1 will determine if POMC masR are required for Ang-(1-7) to inhibit PVN neuronal activity and lower blood pressure. To test this, we will employ a novel transgenic mouse model to determine if deletion of masR from POMC neurons prevents the ability of Ang-(1-7) to enhance GABAergic activity in the PVN and lower blood pressure under normal conditions and in the context of high fat diet-induced obesity hypertension. Aim 2 will determine if high fat diet decreases, and Ang-(1-7) treatment restores, GABAergic transmission onto MC4R-expressing PVN neurons. To test this, we will employ MC4R-GFP mice to determine if: high fat diet decreases inhibitory neurotransmission in MC4R-expressing PVN neurons, Ang-(1-7) treatment reverses these effects, and changes in inhibitory neurotransmission in MC4R-PVN neurons correlate with blood pressure. The findings from this proposal will provide new insight into the neural mechanisms by which Ang-(1-7) lowers blood pressure as well as the potential for therapeutic targeting of Ang-(1-7) in obesity hypertension. Importantly, this proposal will logically build upon the PI’s background in molecular neuroscience and allow her to develop a new skillset in integrated molecular and whole animal physiological and pharmacological methods to assess neural mechanisms engaged by Ang-(1-7) for cardiovascular regulation. The PI will receive strong mentorship and a research framework to establish an independent and novel area of research to help meet her long-term career goal of becoming an independent investigator at an academic research institution where she can conduct collaborative and clinically relevant cardiovascular neuroscience research.

项目概要肥胖是一种全球流行病，大大增加患高血压和心血管疾病的风险然而，人们对高血压与肥胖之间的分子机制知之甚少。由于一些抗高血压药物会引起不良代谢副作用，因此最佳治疗策略尚不清楚这说明迫切需要确定具有积极代谢特征的新治疗靶点。我们建议使用血管紧张素 (Ang)-(1-7)，一种肾素的保护性激素。血管紧张素系统提供了这种理想的靶标，Ang-(1-7) 结合 mas 受体 (masR) 来降低血压。并改善肥胖和高血压啮齿动物的代谢功能；但所涉及的机制是我们的初步数据表明，Ang-(1-7) 抑制作用需要激活 masR。更具体地说，我们发现 Ang-(1-7) masR 高度活跃。定位于含有阿片黑皮质素原 (POMC) 的神经元，释放抑制性神经递质 Ang-(1-7) 激活 GABA 能 POMC 神经元可以通过抑制来降低血压。下丘脑室旁核 (PVN) 中的下游黑皮质素 4 受体 (MC4R) 信号传导，但是该提案将测试 Ang-(1-7) 刺激 ARC POMC 的中心假设。目标1将增强PVN神经元上的GABA能神经传递以降低血压。确定 Ang-(1-7) 是否需要 POMC masR 来抑制 PVN 神经元活动和降低血压。为了测试这一点，我们将采用一种新型转基因小鼠模型来确定是否从 POMC 中删除 masR 神经元阻止 Ang-(1-7) 增强 PVN 中 GABA 活性并降低血压的能力在正常情况下和高脂肪饮食引起的肥胖高血压的情况下，目标 2 将确定。高脂肪饮食减少，Ang-(1-7) 治疗恢复，GABA 能传输至 MC4R 表达为了测试这一点，我们将使用 MC4R-GFP 小鼠来确定：高脂肪饮食是否会降低抑制作用。表达 MC4R 的 PVN 神经元中的神经传递，Ang-(1-7) 治疗可逆转这些影响，并且 MC4R-PVN 神经元抑制性神经传递的变化与血压相关。该提案将为 Ang-(1-7) 降低血液的神经机制提供新的见解压力以及 Ang-(1-7) 治疗肥胖高血压的潜力。该提案将逻辑上建立在 PI 的分子神经科学背景之上，并允许她开发一种综合分子和整体动物生理和药理学方法评估的新技能 Ang-(1-7) 参与心血管调节的神经机制 PI 将得到强有力的指导。以及一个研究框架，以建立一个独立且新颖的研究领域，以帮助满足她的长期目标成为学术研究机构的独立研究员的职业目标，在那里她可以进行协作和临床相关的心血管神经科学研究。