New strategies for treating septic vasculopathy, inflammation and thrombosis

描述(申请人提供)：严重脓毒症的不良预后与微循环受损、多器官损伤和弥散性血管内凝血(DIC)有关，这是全身血管内炎、血管渗漏、微血管血栓形成和血小板减少等相互依存的机制的结果。目前，还没有药物可以同时治疗败血症的这些事件。我们最近发现VWF/GPIB-IX和整合素依赖的血小板黏附和血栓形成在脓毒症中起着重要作用(Yen ATVB2013)，并且G�/13异源三聚体G蛋白家族在血小板整合素内外信号转导中发挥关键作用(Gong等，科学，2010年，沈等自然，2013年)，并在血管内皮细胞的vWF分泌中发挥关键作用(Rusu等人血液，2014)。G�/13还负向调节钙粘素功能(Meigs JBC 2002)，并增加内皮通透性。此外，我们已经确认NOS1依赖的单核/巨噬细胞细胞因子信号抑制因子(SOCS1)表达的调节(Baig等人，Science Signal，修订中)是脓毒症诱导的血管炎症和高通透性的关键决定因素。在这里，我们将检验脓毒症可以通过同时使用不会导致出血和血管渗漏的新型药物的抗血栓、抗炎和抗高渗透治疗来有效治疗的假设。我们已经产生了新型的G�/�AP相互作用抑制肽，可以抑制内皮血管内皮细胞因子的分泌，以及G�-整合素和vWF-GPIB-IX相互作用的抑制剂，这些相互作用有效地抑制血栓形成，而不会导致不利的出血(沈等人，自然，2013年；殷等人，ATVB2013；Rusu等人，血液2013)。我们建议(1)确定在脓毒症中抑制GPIB和G-�/13/整合素信号通路的疗效；(2)确定G-�依赖的内皮细胞血管内皮因子分泌在脓毒症诱导的微血栓形成中的作用；(3)在抗血栓治疗的同时干预导致脓毒症内皮细胞高通透性的炎症反应。这项研究不仅将为脓毒症提供新的治疗概念，而且将这些概念转化为新的抗败血症药物和治疗方法。

DESCRIPTION (provided by applicant): Poor prognosis of severe sepsis is associated with impaired microcirculation, multiple organ injury and disseminated intravascular coagulation (DIC) as a result of interdependent mechanisms of systemic intravascular inflammation, vascular leakage, microvascular thrombosis, and thrombocytopenia. Currently, no drug is available to concomitantly treat these events in sepsis. We recently discovered an important role for VWF/GPIb-IX- and integrin-dependent platelet adhesion and thrombus formation in sepsis (Yin ATVB 2013), and that G�/13 family of heterotrimeric G proteins play critical roles in integrin outside-in signaling in platelets (Gong et al, Science 2010, Shen et al Nature 2013) and in vWF secretion by endothelial cells (Rusu et al Blood 2014). G�/13 also negatively regulates cadherin function (Meigs JBC 2002) and increases endothelial permeability. In addition, we have identified NOS1-dependent regulation of Suppressor of Cytokine Signaling (SOCS1) expression in monocytes/macrophages (Baig et al, Science Signaling, in revision) as a critical determinant of sepsis-induced vascular inflammation and hyperpermeability. Here, we will test the hypotheses that sepsis can be effectively treated by concomitant anti-thrombotic, anti-inflammatory and anti- hyperpermeability therapy with novel agents that do not cause hemorrhage and vascular leakage. We have generated novel inhibitory peptides of G�/�AP interaction that inhibit endothelial VWF secretion as well as inhibitors of G�-integrin and vWF-GPIb-IX interactions that potently inhibit thrombosis without adversely inducing hemorrhage (Shen et al, Nature 2013; Yin et al, ATVB 2013; Rusu et al., Blood 2013). We propose to (1) determine the therapeutic effect of inhibiting GPIb and G�/13/integrin signaling in sepsis; (2) determine the role of G�-dependent endothelial cell VWF secretion in sepsis-induced microthrombosis; and (3) interfere with the inflammatory response that induces endothelial hyperpermeability in sepsis concomitantly with anti-thrombotic therapy. This study will not only provide novel therapeutic concepts in sepsis, but also translate these concepts into new anti-sepsis drugs and treatments.