Role of Tissue Factor in Atherosclerosis

动脉粥样硬化是一种复杂的进行性炎症性疾病，其特征在于 巨噬细胞和淋巴细胞的积聚，血管平滑肌细胞增殖， 动脉壁中的脂质沉积。组织因子（TF）是细胞内主要的启动因子， 凝固蛋白酶级联。TF：FVII复合物激活FX和FXI，产生凝血酶 生成、纤维蛋白沉积和血小板活化。此外，TF：FVIIa复合物是 促炎性，部分是通过产生凝血酶，凝血酶通过裂解 蛋白酶激活受体1（PAR-1）。在这个建议中，我们将使用遗传和药理学 探讨TF和PAR-1在动脉粥样硬化形成中的作用。我们将使用动脉粥样硬化易感小鼠LDLR-/-和ApoE-/-确定降低总TF表达对动脉粥样硬化的影响。我们将通过用来自低TF或TF缺失小鼠的骨髓重建LDLR-/-小鼠的骨髓来检查巨噬细胞TF在动脉粥样硬化中的作用。我们将使用有效的抗人TF抗体来抑制TF人源化小鼠中的TF活性。我们将产生高水平TF的小鼠，这可能会增加血栓形成并改变病变的表型。PAR-1在动脉粥样硬化中的作用将通过PAR-1-/-小鼠与ApoE-/-小鼠杂交来分析。最后，我们将分析增加或减少TF表达或消除PAR-1表达对动脉粥样硬化病变小鼠动脉粥样硬化前基因（如IL-6、MCP-1和Gro-α）表达的影响。这些全面的研究将阐明TF在动脉粥样硬化形成中的作用。这些信息可能提供重要的科学数据，可能导致使用新的抗TF药物在动脉粥样硬化的临床治疗。

Atherosclerosis is a complex and progressive inflammatory disease characterized by an accumulation of macrophages and lymphocytes, vascular smooth muscle cell proliferation and deposition of lipids in the arterial wail. Tissue factor (TF) is the primary cellular initiator of the coagulation protease cascades. The TF:FVII complex activates FX and FXI leading to thrombin generation, fibrin deposition and platelet activation. In addition, the TF:FVIla complex is proinflammatory, in part, by generating thrombin that activates vascular cells by cleavage of protease activated receptor 1 (PAR-1). In this proposal, we will use genetic and pharmacological approaches to elucidate the roles of TF and PAR-1 in atherogenesis. We will determine the effects of reducing total TF expression on atherosclerosis using the atherosclerosis-prone mice LDLR-/- and ApoE-/-. We will examine the role of macrophage TF on atherosclerosis by reconstituting the bone marrow of LDLR-/- mice with bone marrow from either low TF or TF null mice. We will use a potent anti-human TF antibody to inhibit TF activity in mice humanized for TF. We will generate mice with high levels of TF, which may increase the thrombogenicity and change the phenotype of the lesions. The role of PAR-1 in atherosclerosis will be analyzed by crossing PAR-1-/- mice with ApoE-/- mice. Finally, we will analyze the effects of increasing or decreasing TF expression or abolishing PAR-1 expression on the expression of pro-atherogenic genes, such as IL-6, MCP-1 and Gro-alpha, in the aortas of mice with atherosclerotic lesions. These comprehensive studies will elucidate the role of TF in atherogenesis. This information may provide important scientific data that may lead to the use of novel anti-TF drugs in the clinical treatment of atherosclerosis.