Circulating Tissue Factor: Characterization and Interactions with Factor IX

循环组织因子：特征及其与因子 IX 的相互作用

基本信息

批准号：
7898959
负责人：
Lisa Diane Wilsbacher
金额：
$ 2.56万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7898959
关键词：
Ablation Alleles Antigens Attention Birth Bleeding time procedure Blood Blood Pressure Blood Vessels Carotid Arteries Cells Coagulation Process Data Disease Disseminated Intravascular Coagulation Endothelial Cells Endotoxemia Endotoxins Epithelium Exposure to Factor IX Factor Xa Female Generations Genes Genetic Hematopoietic Hemorrhage Hemostatic Agents Hemostatic function Homeostasis Human Inflammation Inflammatory Knock-out Knockout Mice Link Measures Membrane Glycoproteins Messenger RNA Modeling Mus Pathway interactions Pericytes Placentation Play Protocols documentation Relative (related person)Role Stimulus System Tail Testing Thrombin Thromboplastin Thrombosis Thrombus Time Transgenes Vascular Permeabilities Wild Type Mouse base ferric chloride hematopoietic tissue implantation mRNA Expression mouse model response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Tissue factor (TF) is an integral membrane glycoprotein that initiates the coagulation cascade after exposure to blood components. In classical models, TF is constitutively expressed in epithelia and vascular adventitial cells so as to create a "hemostatic envelope" around but separated from blood. However, endothelial cells and hematopoietic cells can express TF especially after inflammatory stimuli, and it has been postulated that activation of circulating TF is important for clot propagation. We have used a Tie2-Cre transgene to excise a floxed Tf allele to generate mice in which hematopoietic and endothelial cell Tf has been ablated ('Tf hem/endo knockout"). Data using such mice suggest that endothelial and hematopoietic Tf is necessary for disseminated intravascular coagulation in mouse models of endotoxemia. However, the normal role of endothelial and hematopoietic TF in homeostasis and in inflammatory states is unknown. We shallask: Specific Aim 1. Is endothelial and hematopoietic TF important for hemostasis and thrombosis? In Tf hem/endo knockout mice, we will assess ablation of circulating TF by quantitative RT- PCR for Tf mRNA. Hemostasis and thrombosis will be tested in mice using well-validated protocols. Specific Aim 2. Does induction of endothelial and hematopoietic TF by inflammatory stimuli promote hemostasis and thrombosis? We will induce TF mRNA expression via exposure to endotoxin and then examine bleeding times and thrombosis. Enhanced hemostasis and/or thrombosis would support the hypothesis that endothelial and hematopoietic TF may provide a link between inflammation and thrombosis. Specific Aim 3. Might mice lacking factor IX provide a sensitized system in which we might detect normal roles for circulating TF? We will test the hypothesis that these systems are partially redundant by examining hemostasis and thrombosis in mice that lack both circulating TF and factor IX. Our study seeks to define the role of circulating TF, which is increased in important human inflammatory disease states, and its interaction with the intrinsic coagulation pathway. These studies may provide attractive therapeutic targets for treatment of these inflammatory states.

描述（由申请人提供）：组织因子（TF）是一种完整的膜糖蛋白，在接触血液成分后启动凝血级联反应。在经典模型中，TF在上皮细胞和血管外膜细胞中组成型表达，从而在血液周围形成“止血包膜”但与血液分离。然而，内皮细胞和造血细胞可以表达 TF，尤其是在炎症刺激后，并且推测循环 TF 的激活对于凝块增殖很重要。我们使用 Tie2-Cre 转基因切除 floxed Tf 等位基因，以产生造血细胞和内皮细胞 Tf 已被消融的小鼠（“Tf hem/endo 敲除”）。使用此类小鼠的数据表明，内皮细胞和造血细胞 Tf 对于然而内毒素血症小鼠模型中弥散性血管内凝血对内皮和造血TF的正常作用。我们将问：具体目标 1. 内皮和造血 TF 对止血和血栓形成重要吗？在 Tf hem/endo 敲除小鼠中，我们将通过定量 RT-PCR 评估循环 TF 的消融情况。将使用经过充分验证的方案在小鼠中测试止血和血栓形成。是否诱导内皮和造血。炎症刺激下的 TF 促进止血和血栓形成？我们将通过接触内毒素诱导 TF mRNA 表达，然后检查出血时间和血栓形成的增强，这将支持内皮和造血 TF 可能在炎症和血栓形成之间提供联系的假设。。具体目标 3. 缺乏因子 IX 的小鼠是否可能提供一个敏感系统，我们可以在其中检测循环 TF 的正常作用？我们将通过检查缺乏循环 TF 和因子 IX 的小鼠的止血和血栓形成来检验这些系统部分冗余的假设。我们的研究旨在明确循环 TF 的作用（它在重要的人类炎症性疾病状态下增加）及其与内在凝血途径的相互作用。这些研究可能为治疗这些炎症状态提供有吸引力的治疗靶点。