Interactions and convergence of innate inflammation and extrinsic coagulation pathways

项目摘要 已经确定血管疾病涉及改变的炎性和炎症性改变，并且其特征可以在于改变的炎性和炎症性改变。 血栓形成过程。在过去，这些过程被认为是不同的和不相关的，但新兴的 有证据表明，在炎症和血栓形成活动之间存在重要的联系。 gC 1 qR作为许多先天性炎症性疾病过程的显著受体而出现， gC 1 qR活性和内源性凝血之间的联系。但从未被查处 无论由C1 q介导的gC 1 qR活性是否导致外源性凝血改变， 和病理相关的凝血系统。我们首次证明了gC 1 qR的C1 q激活 在血管平滑肌细胞和外膜成纤维细胞上表达的p53增强了组织因子的表达。 组织因子表达是外源性凝血激活的显著限速步骤。我们的长期目标 目的是阐明这种融合的炎症/血栓形成信号在血管内皮细胞上的相关性和意义， 疾病进展。与此同时，我们的目标是确定负责 观察到血管健康和血管疾病进展的改变。具体目标是 建议是研究gC 1 qR活性对组织因子表达的意义， 外源性凝血激活/进展至凝血酶原激活水平。我们将观察这些 使用我们的血管健康体外模型，利用相关的平滑肌细胞，成纤维细胞和 血小板来表征疾病进展。我们的总体假设是先天免疫的激活 系统导致改变的gC 1 qR活性/信号传导，其随后诱导改变的组织因子表达 和外源性凝血激活。这项工作将首次显示出一种独特而具体的联系， 先天性炎症途径与外源性凝血途径的融合;同时表征 负责这些反应的潜在机制。我们进一步假设，这些变化是 通过血管平滑肌细胞和外膜成纤维细胞内改变的Akt信号传导介导。指导 在我们的初步工作中，我们将通过追求2个具体目标来验证我们的假设：1）评估补体调节 血管平滑肌细胞和外膜成纤维细胞组织因子的表达，并阐明 负责观察到的变化的潜在机制和2）评价血栓形成的变化， 血管平滑肌细胞和外膜成纤维细胞组织因子表达改变。拟议的工作是 创新，因为我们将确定gC 1 qR是否作为先天之间的过渡联系， 炎症和外源性凝血，此外，我们将说明先天免疫的变化可以 导致外源性凝血活性改变。我们认为，这一建议的成功将产生 对了解血管疾病的发展产生了重大的积极影响， 血管疾病的进展，并可能帮助我们确定新的候选目标的疾病干预。

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.