Forebrain-hypothalamic mechanisms in obesity-induced hypertension

项目概要： 肥胖是一种日益严重的健康流行病，与高血压的发展直接相关。积累 来自人类和动物模型的证据表明，过度的中枢交感神经活动（SNA） 在肥胖相关的高血压中起致病作用。中枢神经系统（CNS） 导致SNA和动脉血压持续升高的网络和分子机制 在肥胖中的作用尚不清楚。越来越多的证据表明，内质网（ER）应激和 转录因子核因子-κ-B（NFκB）的激活参与肥胖。我们最近出版的 观察，以及令人兴奋的初步数据，是在支持这一点，并指出前脑下丘脑 网络是罪魁祸首。在饮食诱导的小鼠肥胖过程中，关键的发现揭示了强大的ER应激， 下丘脑室旁核（PVN）中NFκB的下游激活-一个关键的CNS区域 参与交感神经和心血管调节。我们还提供了新的证据表明， 病理生理学改变通过涉及穹窿下器官的兴奋性神经回路介导 (SFO)位于血脑屏障外的CNS脑室周围区域，其整合了循环 与自主神经系统的控制因素。使用一种结合基因组 介入，神经解剖回路分析，化学遗传学操作，创新的成像技术， 和综合生理学，我们将检验ER应激诱导NFκB活化的总体假设， 涉及SFO和PVN的前脑-下丘脑回路介导肥胖期间高血压的发展。 利用肥胖诱导的高血压小鼠模型，在目的1中，我们将剖析SFO兴奋性的作用， PVN ER应激中的信号传导。基于我们的证据，ER应激与NFκB活化直接交叉， 目的2：探讨肥胖相关性高血压时室旁核内质网应激与NF κB的相互作用。在Aim中 3.我们将研究SFO-PVN轴的功能作用，与ER应激和NFκB活化有关， 介导肥胖引起的交感神经过度活跃和高血压的发展。我们将使用一个 针对设计师药物技术设计的设计师受体，交叉病毒技术， 选择神经元群体，转基因小鼠模型，纵向体内生物发光成像，分子 生物学、最先进的扫描电子显微镜技术和综合心血管/自主神经 生理学，以完成拟议的研究。总的来说，这个项目将扩大我们对 肥胖者高血压发生的潜在神经回路和分子机制 条件

PROJECT SUMMARY: Obesity is a growing health epidemic and is directly linked to the development of hypertension. Accumulating evidence from humans and animal models indicate that excessive central sympathetic nerve activity (SNA) plays a pathogenic role in obesity-associated hypertension. However, the central nervous system (CNS) networks and molecular mechanisms that lead to sustained elevations in SNA and arterial blood pressure during obesity remain unclear. There is mounting evidence that endoplasmic reticulum (ER) stress and activation of the transcription factor nuclear factor-κ-B (NFκB) are involved in obesity. Our recently published observations, as well as exciting preliminary data, are in support of this and point to forebrain-hypothalamic networks as a culprit. Key findings, during diet-induced obesity in mice, have revealed robust ER stress and downstream activation of NFκB in the paraventricular nucleus of the hypothalamus (PVN) - a key CNS region involved in sympathetic and cardiovascular regulation. We also provide novel evidence that these pathophysiological alterations are mediated through an excitatory neural circuit involving the subfornical organ (SFO), a CNS circumventricular region located outside of the blood-brain-barrier that integrates circulating factors with the control of the autonomic nervous system. Using an approach that combines genomic interventions, neuroanatomical circuit analysis, chemogenetic manipulations, innovative imaging techniques, and integrative physiology, we will test the overall hypothesis that ER stress-induced NFκB activation in a forebrain-hypothalamic circuit involving the SFO and PVN mediates hypertension development during obesity. Using a murine model of obesity-induced hypertension, in Aim 1, we will dissect out the role of SFO excitatory signaling in PVN ER stress. Based on our evidence that ER stress intersects directly with NFκB activation, in Aim 2, we will interrogate ER stress-NFκB interactions in the PVN during obesity-related hypertension. In Aim 3, we will investigate the functional role of the SFO-PVN axis, as related to ER stress and NFκB activation, in mediating obesity-induced sympathetic overactivity and hypertension development. We will use an array of designer receptors engineered against designer drugs technology, intersectional viral techniques to target select neuron populations, transgenic mouse models, longitudinal in vivo bioluminescence imaging, molecular biology, state-of-the-art scanning electron microscopy techniques, and integrative cardiovascular/autonomic physiology to accomplish the proposed studies. Overall, this project will expand our knowledge of the underlying neurocircuitry and molecular mechanisms that contribute to hypertension development in obese conditions.