Molecular Mechanisms of Hypertension in the Microcirculation

描述（由申请人提供）：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中起着核心作用，然而，关于高血压血管改变的细胞或分子机制知之甚少。toll样受体（TLR）是一类跨膜受体，在先天免疫中起关键作用。最近的证据表明，除了LPS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子激活。我们的初步数据表明，TLR4缺陷限制了Ang ii诱导的内皮功能障碍的发展。哺乳动物雷帕霉素靶点（mTOR，磷酸肌肽3-激酶相关激酶家族蛋白激酶的成员）最近被确定为细胞生长和肥大的重要调节因子。尽管mTOR在细胞生长和肥大中起着重要作用，但mTOR在高血压中的作用尚未得到证实。我们实验室之前的研究表明，白细胞介素(IL)-6和NAD(P)H氧化酶在与angii依赖性高血压相关的内皮功能障碍和血管肥大中起重要作用。我们的总体假设是TLR4和mTOR是导致高血压和高血压相关血管和微血管后遗症的关键分子机制，相对于IL-6和nox衍生的超氧化物。目的1将验证TLR4激活是导致angii依赖性高血压血管肥大和内皮功能障碍的初始事件的假设。目的2将验证TLR4激活下游mTOR激活有助于angii依赖性高血压血管肥大和内皮功能障碍的假设。目的3将验证IL-6和NAD(P)H氧化酶衍生的超氧化物在Ang II依赖性高血压中TLR4激活和mTOR下游激活之间的分子联系。拟议的研究非常新颖，意义重大，因为它们首次对TLR4和mTOR信号在与人类高血压临床相关的血管和微血管改变中的作用进行了机制研究。这些研究在高血压方面也具有重要的翻译意义，因为它们将为治疗干预确定新的分子靶点。

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.