Cellular Mechanisms of Inflammation, Hemostasis, and Thrombosis

ABSTRACT Continued support is requested for an interdisciplinary effort to understand the key molecular and developmental events that regulate blood and vascular cells in inflammation, hemostasis and thrombosis with a focus on adhesive signaling. The four Projects will: 1) Test the hypothesis that an alternative IL-2 signaling pathway controls the immunological landscape and outcomes of vascular diseases associated with inflammation and thrombosis. 2) Test the hypothesis that an extended, but low affinity form of integrin αIIbβ3 mediates the clearance of platelets with dysregulated activation of Rap1 and can serve as a biomarker of thrombosis. 3) Test the hypothesis that chronic inflammation leads to changes in chromatin structure that result in a persistently activated endothelial cell predisposed to thrombosis and inflammation. 4) Test the hypothesis that recruitment of talin-1 and kindlin-3 in primary neutrophils are associated with marked differences in their adhesive behavior and kinetics of conformational changes in integrins. A scientific Core Unit A, led by a leader in multi-omic analysis of leukocytes, will provide the individual projects with expertise for experimental design required to establish the spatial molecular imaging of transcriptomes and proteomes of blood and vascular cells in situ and the technical capability to do so.