Regulation of endothelial permeability in sepsis

描述（由申请人提供）：脓毒症仍然是当前的医学挑战。这种毁灭性疾病的频率正在增加，死亡率高达70%。它通常因水肿而加剧，水肿促进组织中的液体积聚，引起增强的炎症反应并诱导纤维化。随着时间的推移，这可能导致多器官衰竭和死亡。目前还没有用于阻断脓毒症中血管渗漏的疗法。这主要是因为调节血管通透性的分子机制尚未完全了解。关注血管通透性的机制可能为预防脓毒症引起的炎症和水肿的治疗干预提供有价值的靶点。我们已经确定了一种新的机制，血管屏障的完整性是保持。该提案的主要目标是进一步阐明这一机制，从而确定潜在的新的治疗靶点。我们以前曾报道过RRas和细丝蛋白A（FLN）之间的相互作用。RRas是一种细胞内GTP结合蛋白，主要在体内内皮细胞中表达，是动脉内皮功能的调节因子。细胞骨架蛋白FLN是血管发育中细胞间接触所必需的。事实上，FLN缺失小鼠死于血管缺陷。我们最近报道，在动脉内皮细胞内源性RRas与内源性FLN相互作用。此外，内皮屏障功能依赖于活性RRas以及RRas与FLN之间的关联。因此，我们提出了创新的假设，即RRas和FLN复合物是维持内皮屏障功能的主要驱动因素。该提案将集中在RRas和FLN复合物作为参与调节血管通透性的几种选择信号通路之间的整合点。本研究将测试这种RRas是否是脓毒症临床前小鼠模型中的治疗靶点。.!

DESCRIPTION (provided by applicant): Sepsis remains a current medical challenge. The frequency of this devastating disease is increasing and is associated with a death rate as high as 70%. It is often exacerbated by edema, which promotes fluid accumulation in tissues, causes an enhanced inflammatory response and induces fibrosis. Over time this can lead multiple organ failure and death. Currently there are no therapies for blocking vascular leakage in sepsis. This is primarily because the molecular mechanisms regulating vascular permeability are not completely understood. Focusing on the mechanisms of vascular permeability would potentially provide valuable targets for therapeutic intervention to prevent inflammation and edema due to sepsis. We have identified a novel mechanism by which vascular barrier integrity is maintained. The primary goal of this proposal is to elucidate this mechanism further and thereby identify potential new therapeutic targets. We have previously reported an interaction between RRas and Filamin A (FLN). RRas, an intracellular GTP-binding protein, is primarily expressed in endothelial cells in vivo and is a regulator of arterial endothelial function. The cytoskeletal protein FLN is required for cell-cell contact in vascular development. Indeed, FLN-null mice die of vascular defects. We have recently reported that in arterial endothelial cells endogenous RRas interacts with endogenous FLN. Furthermore, endothelial barrier function is dependent upon active RRas and an association between RRas and FLN. Thus, we propose the innovative hypothesis that the RRas and FLN complex is a primary driver in maintaining endothelial barrier function. This proposal will focus on the RRas and FLN complex as a point of integration between several select signaling pathways involved in regulating vascular permeability. This study will test whether this RRas is a therapeutic target in preclinical mouse models of sepsis. .!