Molecular Mechanisms of Hypertension in the Microcirculation

说明(申请人提供)：血管紧张素II(Ang II)在高血压血管肥大和内皮功能障碍的病理生理学中起着核心作用，然而，对于导致高血压血管改变的细胞或分子机制知之甚少。Toll样受体是I型跨膜受体，在先天免疫中起关键作用。最近的证据表明，除了内毒素外，TLR4信号还可以被细胞应激和/或损伤过程中产生的内源性因素激活。我们的初步数据表明，TLR4缺乏限制了血管紧张素转换酶II诱导的内皮功能障碍的发展。雷帕霉素的哺乳动物靶标(MTOR)是磷脂酰肌醇3-激酶相关蛋白激酶家族的成员，最近被确定为细胞生长和肥大的重要调节因子。尽管mTOR被认为在细胞生长和肥大中起重要作用，但mTOR在高血压中的作用还没有被研究过。本实验室以往的研究表明，IL-6和NAD(P)H氧化酶在血管内皮功能障碍和血管肥厚与血管紧张素Ⅱ依赖型高血压相关中起着重要作用。我们的主要假设是TLR4和mTOR是相对于IL-6和NOx衍生的超氧化物歧化的关键分子机制，它们有助于高血压和高血压相关的血管和微血管后遗症。将涉及三个具体目标：目标1将测试TLR4激活是导致血管肥大和血管内皮功能障碍的血管II依赖型高血压的初始事件的假设。目的2将验证TLR4激活下游的mTOR激活有助于血管肥厚和血管内皮功能障碍的假说。目的3验证IL-6和NAD(P)H氧化酶衍生的超氧化物歧化在血管紧张素Ⅱ依赖性高血压中作为TLR4激活和mTOR下游激活之间的分子联系的假说。建议的研究是非常新颖和非常有意义的，因为他们代表了第一次对TLR4和mTOR信号在临床上与人类高血压相关的血管和微血管改变中所起作用的机制的研究。这些研究在高血压方面也具有翻译重要性，因为它们将为治疗干预确定新的分子靶点。 公共卫生相关性：高血压与心血管疾病和包括颈动脉疾病和中风在内的事件的发生率增加有关。这项建议中的研究旨在检查高血压免疫反应的特定成分的贡献和/或激活。拟议的研究具有临床和翻译重要性，因为它们旨在开发新的治疗靶点，为高血压患者开发新的治疗方法，并改善公众健康。

DESCRIPTION (provided by applicant): Angiotensin II (Ang II) plays a central role in the pathophysiology of vascular hypertrophy and endothelial dysfunction in hypertension, however very little is known regarding the cellular or molecular mechanisms that contribute to such vascular alterations in hypertension. Toll-like receptors (TLR) are type I transmembrane receptors that play a key role in innate immunity. Recent evidence suggests that, in addition to LPS, TLR4 signaling can be activated by endogenous factors produced during cell stress and/or injury. Our preliminary data indicate that TLR4 deficiency limits the development of Ang II-induced endothelial dysfunction. The mammalian target of rapamycin (mTOR; a member of the phosphoinositide 3-kinase-related kinase family of protein kinases) has recently been identified as an important regulator of cell growth and hypertrophy. Although mTOR has been implicated as playing an important role in cell growth and hypertrophy, the role of mTOR has not been previously examined in hypertension. Previous studies from our laboratory have implicated an important role for interleukin (IL)-6 and NAD(P)H oxidase in the endothelial dysfunction and vascular hypertrophy associated with Ang II-dependent hypertension. Our overarching hypothesis is that TLR4 and mTOR are key molecular mechanisms, vis-a-vis IL-6 and Nox-derived superoxide, that contribute to hypertension and hypertension-related vascular and microvascular sequelae. Three Specific Aims will be addressed: Aim 1 will test the hypothesis that TLR4 activation is an initial event that contributes to vascular hypertrophy and endothelial dysfunction in Ang II-dependent hypertension. Aim 2 will test the hypothesis that mTOR activation downstream of TLR4 activation contributes to vascular hypertrophy and endothelial dysfunction in Ang II-dependent hypertension. Aim 3 will test the hypothesis that IL-6 and NAD(P)H oxidase-derived superoxide serves as molecular links between TLR4 activation and downstream activation of mTOR in Ang II- dependent hypertension. The proposed studies are extremely novel and highly significant as they represent the first mechanistic examination of the roles of TLR4 and mTOR signaling in vascular and microvascular alterations that are clinically relevant to human hypertension. The studies also hold translational importance in hypertension as they will identify new molecular targets for therapeutic intervention. PUBLIC HEALTH RELEVANCE: Hypertension is associated with an increased incidence of cardiovascular disease and events including carotid artery disease and stroke. Studies in this proposal are designed to examine the contribution and/or activation of specific components of the immune response to hypertension. The proposed studies are of clinical and translational importance as they are aimed at developing new therapeutic targets for which new treatment could be developed for hypertensive patients and improving public health.