TARGETING SIGNALING OF THE TISSUE FACTOR PATHWAY

描述(由申请人提供)： 凝血的启动和细胞信号在生理和病理上是多层次交叉的。 组织因子(Tf)是凝血和炎症交界处的关键分子，但我们的数据 展示TF凝血起始期信号如何分支的惊人复杂性 PAR1和PAR2激活下游。一条选择性通路将PAR2信号与转铁蛋白联系起来 胞浆结构域的磷酸化和血管病理研究表明，转铁蛋白 磷酸化标志着转铁蛋白信号的错乱。依赖于TF的信令的某些方面包括 因此，治疗干预的目标很有吸引力。初步数据显示，抗凝活性不能很好地预测转铁蛋白导向的抑制物阻断信号的效率。这项应用的中心目标是确定通过PAR1和PAR2的哪些方面的TF依赖的信号被TF指导的抑制剂阻断，并阐明下游的凝血反应，传统抗凝剂的靶标，是否影响TF依赖的信号。在目标1中，我们将提供一个全面的Tf起始复合体信号介导的反应目录，并确定这些反应是由PAR1还是PAR2介导的，并由Tf胞浆区域的磷酸化控制。目的2是为了确定转铁蛋白三元复合体抑制剂是如何干扰转铁蛋白信号反应的，目的是提供新的诊断标记物来帮助靶向转铁蛋白的研究。目的3确定下游凝血信号如何影响转铁蛋白信号，从而阐明传统的抗凝策略对凝血起始阶段信号的影响。这些实验将解决凝血抑制物如何干扰TF信号的重要悬而未决的问题，从而确定新的诊断工具和潜在的治疗靶点，使成功的临床干预能够利用TF在炎症和血栓形成中的复杂作用。

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.