Interactions and convergence of innate inflammation and extrinsic coagulation pathways

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Project Summary It is well established that vascular diseases involve and can be characterized by altered inflammatory and thrombotic processes. In the past, these processes were thought to be distinct and unrelated but emerging evidence suggests that there are important connections between inflammatory and thrombotic activities. gC1qR has surfaced as a salient receptor for many innate inflammatory disease processes and there have been links identified between gC1qR activity and intrinsic coagulation. However, it has never been investigated whether or not gC1qR activity, as mediated by C1q, leads to altered extrinsic coagulation, the physiologically and pathologically relevant coagulation system. We have shown for the first time that C1q activation of gC1qR expressed on vascular smooth muscle cell and adventitial fibroblasts enhances the expression of tissue factor. Tissue factor expression is the salient rate limiting step for extrinsic coagulation activation. Our long-term goal is to elucidate the relevance and significance of this converged inflammatory/thrombotic signaling on vascular disease progression. In parallel to this, we aim to identify the underlying mechanism(s) responsible for the observed alterations on vascular health and vascular disease progression. The specific objective for this proposal is to investigate the significance of gC1qR activity on tissue factor expression and subsequent activation/progression of extrinsic coagulation to the level of prothrombin activation. We will observe these interactions using our in vitro models of vascular health, utilizing relevant smooth muscle cells, fibroblasts and platelets to characterize disease progression. Our global hypothesis is that activation of the innate immune system leads to altered gC1qR activity/signaling, which subsequently induces altered tissue factor expression and extrinsic coagulation activation. This work would show, for the first time, a distinct and specific link and convergence of innate inflammatory pathways with the extrinsic coagulation pathways; while characterizing the underlying mechanisms responsible for these responses. We further hypothesize that these changes are mediated by altered Akt signaling within vascular smooth muscle cells and adventitial fibroblasts. Guided by our preliminary work, we will test our hypothesis by pursing 2 specific aims: 1) evaluate complement regulation of vascular smooth muscle cell and adventitial fibroblast tissue factor expression and to elucidate the underlying mechanisms responsible for observed changes and 2) evaluate thrombotic changes in response to altered vascular smooth muscle cell and adventitial fibroblast tissue factor expression. The proposed work is innovative because we will determine whether or not gC1qR acts as a transitional link between innate inflammation and extrinsic coagulation and furthermore, we will illustrate that changes to innate immunity can lead to altered extrinsic coagulation activity. We believe that the success of this proposal will have a significant positive impact on the understanding of vascular disease development, provide new insight into vascular disease progression and may help us to identify new candidate targets for disease intervention.