ROLE OF TISSUE FACTOR IN HEMOSTASIS & THROMBOSIS

组织因子在止血中的作用

• 批准号: 7667048
• 负责人: Nigel Mackman
• 金额: $ 30.64万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7667048
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Angiopoietin-1; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Blood; Blood Platelets; Blood Vessels; Cause of Death; Cells; Cessation of life; Choristoma; Classification; Coagulation Process; Defect; Development; Disease; Disseminated Intravascular Coagulation; Endothelial Cells; Endotoxemia; Gene Expression; Genetic; Goals; Heart; Hemostatic Agents; Hemostatic function; Human; Immune system; In Vitro; Infection; Inflammation; Inflammatory; Instruction; Insulin; Intensive Care Units; Lead; Lung; Mediating; Mediator of activation protein; Mus; Pathway interactions; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Phenotype; Play; Protective Agents; Proto-Oncogene Proteins c-akt; Reducing Agents; Relative (related person); Role; Sepsis; Source; Testing; Thromboplastin; Thrombosis; Tissues; United States; Vascular Endothelial Growth Factors; Wound Healing; cell type; design; improved; in vivo; inhibitor/antagonist; insight; macrophage; monocyte; mouse model; novel; novel therapeutics; pathogen; premature; response; treatment strategy

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.

组织因子（TF）是凝结蛋白酶级联反应的主要细胞引发剂。它扮演着必不可少的 在止血中的作用。然而，在病理条件下，脉管系统内的异常TF表达是 与血栓形成有关。该提案的目标是确定TF在止血中的作用 血栓形成。在AIM 1中，我们将确定单核细胞，内皮细胞和 小鼠模型中的血小板至LPS诱导的凝结。败血症是重症监护的主要原因 美国的单位。在人类中，先天免疫系统已经发展为感染的感染 从病原体（例如LPS）中检测少量产品。但是，对 血液中LPS的存在与散布的血管内凝血有关（DIG）。 已经证明单核细胞和内皮细胞在内毒素血症的动物模型和 败血症。最近，我们发现LP诱导血小板中的TF表达。在AIM 2中，我们将同时使用 研究磷脂酰肌醇-3-激酶（PI3K） - 蛋白激酶B（AKT）途径在体外和体内抑制LPS诱导的基因表达。 我们发现PI3K-AKT途径抑制了TF和炎症基因的LPS诱导 单核细胞和内毒素小鼠的表达。重要的是，有几种减少两者的代理商 内毒素血症和败血症动物模型中的凝结和炎症激活了这一途径。在AIM 3中， 我们将研究外部（TF和FVII）和内在（FXII，FXI，FIX和FVIII）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，高 小鼠的FVIIA水平导致由于心脏和肺的血栓形成导致过早死亡。我们将越高 患有低TF小鼠或小鼠的FVIIA小鼠心脏中TF表达增加和降低。这 不同小鼠的表型将检验以下假设：外部途径介导心脏特异性 止血。 相关性（请参阅说明）： 这些研究应提供有关止血和血栓形成机制的新见解，可能 刺激治疗这些疾病患者的新型治疗策略的发展。