Type-2 Tissue Factor Pathway Inhibitor

2 型组织因子途径抑制剂

• 批准号: 6897301
• 负责人: Walter Kisiel
• 金额: $ 26.25万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6897301
• 关键词: SCID mouse; X ray crystallography; angiogenesis; asthma; athymic mouse; blood coagulation; cell migration; enzyme inhibitors; extracellular matrix; extracellular matrix proteins; gene expression; genetic regulatory element; homeostasis; laboratory mouse; lymphocyte; macrophage; metastasis; neoplastic growth; protein protein interaction; protein structure function; respiratory system; serine proteinases; thromboplastin; tissue /cell culture; transfection; vascular endothelium

DESCRIPTION (provided by applicant): Extracellular matrix (ECM) is a complex mixture of proteoglycans that function in cell adhesion, migration, growth and differentiation. In addition, the ECM serves as a reservoir for a number of growth factors, proteinases and proteinase inhibitors essential for ECM homeostasis. Our studies have shown that one of the serine proteinase inhibitors found in the ECM is a 32 kDa glycoprotein consisting of three tandemly- arranged Kunitz-type proteinase inhibitor domains homologous to tissue factor pathway inhibitor, an important negative regulator of blood coagulation. This novel inhibitor, designated as type-2 tissue factor pathway inhibitor, or TFPI-2, in synthesized and secreted into the ECM by endothelial cells, smooth muscle cells, fibroblasts, keratinocytes and urothelium. TFPI-2 readily inhibits several serine proteinase in vitro, strongly inhibited the trypsin or plasmin-mediated activation of promatrix metalloproteinases, and suppressed production of active MMP-2 in tumor cells transfected with the TFPI-2 expression vector. In addition, TFPI-2 expression is up regulated in human atherosclerotic coronary arteries, and its expression in solid tumors inversely correlates with the degree of malignancy. Thus, ECM-associated TFPI-2 may play a pivotal role in the regulation of ECM remodeling, a process essential for angiogenesis, atherogenesis and tumor invasion. The purpose of the studies proposed in this application is to examine in greater detail structure-function relationships in TFPI-2, its inhibitory properties in association with ECM structural proteins, and its role in tumor growth, vascularization and metastasis. Our preliminary data also show that TFPI-2 inhibits mononuclear cell transepithelial migration into airways in a murine model of allergic asthma, and studies are proposed to investigate its mechanism of action in this setting. The long range objectives of this proposal are to accomplish a comprehensive characterization of TFPI-2 in order to delineate its biological role in normal and pathological ECM turnover.

描述（由申请人提供）：细胞外基质（ECM）是在细胞粘附，迁移，生长和分化中起作用的蛋白聚糖的复杂混合物。此外，ECM充当许多生长因子，蛋白酶和蛋白酶抑制剂对ECM稳态必不可少的储层。我们的研究表明，在ECM中发现的丝氨酸蛋白酶抑制剂之一是32 kDa糖蛋白，该糖蛋白由三个串联布置的kunitz-type蛋白酶抑制剂结构域组成，该蛋白酶抑制剂结构域与组织因子途径途径抑制剂同源，这是一个重要的血液凝结剂。这种新型抑制剂被指定为2型组织因子途径抑制剂，或TFPI-2，并被内皮细胞，平滑肌细胞，成纤维细胞，角质形成细胞和尿皮细胞合成并分泌到ECM中。 TFPI-2很容易在体外抑制几种丝氨酸蛋白酶，强烈抑制了胰蛋白酶或纤溶酶介导的promatrix金属蛋白酶的激活，并抑制了用TFPI-2表达载体转染的肿瘤细胞中活性MMP-2的产生。另外，在人动脉粥样硬化冠状动脉中TFPI-2表达受到调节，其在实体瘤中的表达与恶性肿瘤的程度成反比。因此，与ECM相关的TFPI-2可能在ECM重塑的调节中起关键作用，这是血管生成，动脉粥样硬化和肿瘤侵袭必不可少的过程。在本应用中提出的研究的目的是更详细地检查TFPI-2中的结构 - 功能关系，其抑制特性与ECM结构蛋白有关，及其在肿瘤生长，血管化和转移中的作用。我们的初步数据还表明，TFPI-2在过敏性哮喘的鼠模型中抑制了单核细胞transepitherial迁移到气道中，并提出了研究以研究其在这种情况下的作用机理。该提案的远距离目标是完成TFPI-2的全面表征，以描绘其在正常和病理ECM周转中的生物学作用。