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

项目总结 肥胖是一种全球性流行病，极大地增加了患高血压和心血管疾病的风险 疾病。然而，高血压和肥胖之间的分子机制却知之甚少。 由于一些降压药会引起不良代谢副作用，最佳治疗策略尚不清楚 效果。这表明，迫切需要确定新的治疗靶点，使其具有积极的代谢特征 肥胖型高血压的治疗。我们认为血管紧张素(Ang)-(1-7)是肾素的保护性激素-- 血管紧张素系统提供了这个理想的靶点。Ang-(1-7)与MAS受体(MASR)结合以降低血压 并改善肥胖和高血压啮齿动物的代谢功能；但涉及的机制是 未知。我们的初步数据显示，Ang-(1-7)降压效应需要激活MASR。 下丘脑弓状核(ARC)。更具体地说，我们证明了Ang-(1-7)MASR是高度 定位于释放抑制性神经递质的前阿片黑素皮质素(POMC)神经元 GABA。Ang-(1-7)激活GABA能POMC神经元可通过抑制血压降低血压 下丘脑室旁核(PVN)中的下游黑素皮质素-4受体(MC4R)信号，但 这一点还没有被探索过。这一提议将检验Ang-(1-7)刺激ARC POMC的中心假设 神经元增强GABA能神经传递到下丘脑室旁核神经元以降低血压。目标1将 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，我们将使用一种新的转基因小鼠模型来确定是否从POMC中删除了Masr 神经元拮抗Ang-(1-7)增强下丘脑室旁核GABA能活动和降低血压的作用 在正常情况下和在高脂饮食诱导的肥胖和高血压的背景下。目标2将决定是否 高脂饮食减少和Ang-(1-7)治疗恢复，GABA能传递到MC4R表达 室旁核神经元。为了测试这一点，我们将使用MC4R-GFP小鼠来确定：高脂肪饮食是否会减少抑制作用 在表达MC4R的下丘脑室旁核神经元中的神经传递，Ang-(1-7)处理逆转了这些效应，并且 MC4R-PVN神经元抑制性神经传递的变化与血压有关。调查结果 这一提议将为Ang-(1-7)降低血液的神经机制提供新的见解 血管紧张素-(1-7)在肥胖性高血压治疗中的作用。重要的是，这 从逻辑上讲，提案将建立在PI分子神经科学背景的基础上，并允许她开发一种 综合分子和整体动物生理学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，以建立一个独立和新颖的研究领域，以帮助满足她的长期 职业目标是成为学术研究机构的独立调查员，在那里她可以 开展合作和临床相关的心血管神经科学研究。

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.