TARGETING SIGNALING OF THE TISSUE FACTOR PATHWAY

Scripps Research Institute, The, La Jolla CA

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Abstract

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.