Opposing Mechanisms of Stabilizing and Destabilizing Receptors

描述（由申请人提供）：稳定和去稳定受体的相反机制。血管内皮屏障完整性的控制是医学的核心。从本质上讲，炎症的典型症状（发红、发热、疼痛、肿瘤）是屏障不稳定的产物。该资助申请的主要前提是存在竞争性配体-受体，其通过会聚途径发出信号，所述会聚途径决定内皮屏障的稳定性/不稳定性水平。具体来说，我们将研究的稳定和不稳定的影响，分别对内皮屏障的Robo 1受体和受体白细胞介素-1b（IL 1 R）。我们推测，这些受体的相反信号是由于相反的GT3激活蛋白（GAP）和鸟嘌呤核苷酸交换因子（GEF）的激活，分别决定了ARF 6的非活性和活性状态以及细胞-细胞相互作用的强度。我们怀疑我们的研究中得出的机制见解将对许多组织中的屏障功能和细胞-细胞相互作用产生广泛的影响。我们的工作将首次表明，有可能将细胞因子破坏组织屏障的能力与其对转录免疫调节途径的刺激分开。

DESCRIPTION (provided by applicant): Opposing mechanisms of stabilizing and destabilizing receptors. The control of barrier integrity in the vascular endothelium is central to medicine. In essence the classic signs of inflammation (rubor, calor, dolor, tumor) are products of a destabilized barrier. The main premise of this grant application is that there are competing ligand-receptors that signal through converging pathways that determine the level of stability/instability of the endothelial barrier. Specifically, we will study the stabilizing and destabilizing influences on the endothelial barrier of, respectively, the Robo1 receptor and the receptor for interleukin-1b (IL1R). We hypothesize that the opposing signals from these receptors are due to the activation of opposing GTPase activating proteins (GAP) and guanine nucleotide exchange factors (GEF) that determine, respectively, the inactive and active state of ARF6 and the strength of cell-cell interactions. We suspect that the mechanistic insights derived in our studies will have broad implications to barrier function and cell-cell interactions in many tissues. Our work will suggest for the first time that it may be possible to uncouple the ability o cytokines to disrupt tissue barriers from their stimulation of transcriptional immunomodulatory pathways.