ROLE OF TISSUE FACTOR IN HEMOSTASIS & THROMBOSIS

组织因子（TF）是凝血蛋白酶级联反应的主要细胞起始因子。它扮演着重要的角色， 止血作用。然而，在病理条件下，血管内TF表达异常， 与血栓形成有关。本提案的目的是确定TF在止血和 血栓形成在目标1中，我们将确定单核细胞、内皮细胞和 血小板对LPS诱导的凝血的影响。脓毒症是重症监护室的主要死亡原因 单位在美国。在人类中，先天免疫系统已经进化到通过以下方式感知感染： 检测来自病原体的少量产物，例如LPS。然而，过度的反应 血液中LPS的存在与弥散性血管内凝血（DIG）有关。 单核细胞和内皮细胞在内毒素血症动物模型中表达TF， 败血症最近，我们发现LPS诱导血小板TF表达。在aim 2中，我们将同时使用 遗传学和药理学方法来研究磷脂酰肌醇-3-激酶（PI 3 K）的作用， 蛋白激酶B（Akt）途径在体内外抑制LPS诱导的基因表达中的作用。 我们发现PI 3 K-Akt通路抑制LPS诱导TF和炎症基因的表达， 在单核细胞和内毒素血症小鼠中表达。重要的是，几种减少这两种药物的药物 内毒素血症和脓毒症动物模型中的凝血和炎症激活该途径。在目标3中， 我们将研究外源性（TF和FVII）和内源性（FXII、FXI、FIX和FVIII）凝血的作用 组织特异性止血和伤口愈合的途径。最近的一项研究表明， 小鼠中的FVIIa水平由于心脏和肺中的血栓形成而导致过早死亡。我们将跨越高空 FVIIa小鼠与低TF小鼠或心脏中TF表达增加和减少的小鼠。的 不同小鼠的表型将检验外源性途径介导心脏特异性 止血。 相关性（参见说明）： 这些研究应该为止血和血栓形成的机制提供新的见解， 刺激新的治疗策略的发展，以治疗这些疾病的患者。

Tissue factor (TF) is the primary cellular initiator of the coagulation protease cascades. It plays an essential role in hemostasis. Under pathological conditions, however, aberrant TF expression within the vasculature is associated with thrombosis. The goals of this proposal are to determine the roles of TF in hemostasis and thrombosis. In aim 1, we will determine the relative contribution of monocytes, endothelial cells, and platelets to LPS-induced coagulation in a mouse model. Sepsis is the major cause of death in intensive care units in the United States. In humans, the innate immune system has evolved to sense an infection by detecting small amounts of products from the pathogens, such as LPS. However, an excessive response to the presence of LPS in the blood is associated with disseminated intravascular coagulation (DIG). Monocytes and endothelial cells have been shown to express TF in animal models of endotoxemia and sepsis. More recently, we found that LPS induced TF expression in platelets. In aim 2, we will use both genetic and pharmacologic approaches to investigate the role of the phosphatidylinositol-3-kinase (PI3K)- protein kinase B (Akt) pathway in the suppression of LPS-induced gene expression both in vitro and in vivo. We have found that the PI3K-Akt pathway suppresses LPS induction of TF and inflammatory gene expression in monocytic cells and in endotoxemic mice. Importantly, several agents that reduce both coagulation and inflammation in animal models of endotoxemia and sepsis activate this pathway. In aim 3, we will investigate the role of the extrinsic (TF and FVII) and intrinsic (FXII, FXI, FIX and FVIII) coagulation pathways in tissue-specific hemostasis and wound healing. A recent study showed that expression of high levels of FVIIa in mice leads to premature death due to thrombosis in the heart and lung. We will cross high FVIIa mice with either low TF mice or mice with increased and decreased TF expression in the heart. The phenotypes of the different mice will test the hypothesis that the extrinsic pathways mediates heart-specific hemostasis. RELEVANCE (See instructions): These studies should provide novel insights into the mechanisms of hemostasis and thrombosis that may stimulate the development of novel therapeutic strategies to treat patients with these disorders.