TARGETING SIGNALING OF THE TISSUE FACTOR PATHWAY

描述（由申请人提供）： 凝血和细胞信号传导的启动在生理学和病理学的多个水平上交叉。 组织因子（TF）是凝血和炎症界面的关键分子，但我们的数据显示， 证明了TF凝血起始阶段信号传导如何分支的惊人复杂性 PAR1和PAR2激活的下游。选择性途径将PAR2信号传导与TF联系起来 胞质结构域磷酸化和血管病理学结果表明，TF 磷酸化标志着TF信号的紊乱。依赖于TF的信令的某些方面是 因此是治疗干预的有吸引力的靶点。初步数据显示，抗凝活性很难预测如何有效地TF定向抑制剂中断信号。本申请的中心目标是确定TF依赖性信号传导通过PAR 1和PAR 2的哪些方面被TF定向抑制剂阻断，并阐明下游凝血反应（传统抗凝剂的靶点）是否影响TF依赖性信号传导。在目标1中，我们将提供一个全面的目录TF起始复合物信号介导的反应，并确定这些反应是否是由PAR1或PAR2介导的，并由TF胞质结构域磷酸化控制。目的2是建立TF三元复合物抑制剂如何中断TF信号传导反应的库，目的是提供新的诊断标记物，以帮助靶向TF的转化研究。目的3是确定下游凝血信号如何影响TF信号，从而阐明传统抗凝策略对凝血起始相信号的影响。这些实验将解决凝血抑制剂如何干扰TF信号传导的重要未解决问题，从而确定新的诊断工具和潜在的治疗靶点，使TF在炎症和血栓形成中的复杂作用能够成功地进行临床干预。

DESCRIPTION (provided by applicant): Initiation of coagulation and cell signaling intersect at multiple levels in physiology and pathology. Tissue factor (TF) is a key molecule at the interface of coagulation and inflammation, but our data demonstrate surprising complexity of how TF coagulation initiation phase signaling branches out downstream of PAR1 and PAR2 activation. A selective pathway links PAR2 signaling to TF cytoplasmic domain phosphorylation and findings in vascular pathology suggests that TF phosphorylation marks deranged TF signaling. Certain aspects of signaling dependent on TF are thus attractive targets for therapeutic intervention. Preliminary data show that anticoagulant activity poorly predicts how efficiently TF-directed inhibitors interrupt signaling. The central goal of this application is to define which aspects of TF-dependent signaling through PAR1 and PAR2 are blocked by TF-directed inhibitors and to elucidate whether the downstream coagulation reaction, the target for traditional anticoagulants, influences TF-dependent signaling. In Aim 1, we will provide a comprehensive catalogue of TF initiation complex signaling mediated responses and define whether these responses are mediated by PAR1 or PAR2, and are controlled by TF cytoplasmic domain phosphorylation. Aim 2 is to establish how TF ternary complex inhibitors interrupt the repertoire of TF signaling responses with the goal to provide new diagnostic markers that aid translational research to target TF. Aim 3 is to define how downstream coagulation signaling influences TF signaling and thus elucidate the influence of traditional anticoagulant strategies on signaling of the coagulation initiation phase. These experiments will address important unresolved issues of how coagulation inhibitors interfere with TF signaling and thus identify novel diagnostic tools and potential therapeutic targets that enable the successful clinical intervention with the complex role of TF in inflammation and thrombosis.