HUMAN TISSUE FACTOR AND ITS PLASMA INHIBITOR

通过凝血因子VII-组织启动血液凝固 因子途径不仅对正常止血很重要， 很可能在病理性血栓形成中也起作用。 蜂窝 TF的表达与感染，炎症， 和肿瘤疾病，并可能是部分负责 不仅这些疾病的血栓栓塞并发症，而且 静脉血栓栓塞和肺栓塞发生在 其他方面正常的人也一样。 血浆含有VII-TF复合物的内源性抑制剂， 我们叫LACI 它与血浆中的脂蛋白有关， 需要Xa的存在才能表达其反馈抑制， VII-TF. 我们计划通过分离其cDNA来进一步表征LACI， 测定其蛋白酶抑制的光谱和动力学， 并对LACI的结构功能关系进行了研究 分子与脂蛋白的结合， Xa的抑制作用及其与其他组分的关系 推定的VII-TF-Xa-LACI抑制复合物。 其他研究 还将研究TF和LACI的细胞合成， 确定TF/LACI在正常组织中的免疫组织化学定位 和病理组织，并评估TF 和LACI血液浓度与临床疾病的关系。 这些研究将使用纯化的TF和LACI进行， 通过蛋白水解或化学处理产生的它们的片段 （CnBr），它们的分离的cDNA，基于它们的合成肽， 预测的氨基酸序列，以及适当的单克隆和 多克隆抗体。 这些实验旨在提供信息，现在缺乏， 关于凝结的启动和控制， 古典“外在”与“内在”的相互关系 途径。 研究结果应该会增进我们对这两个问题的理解 正常止血和病理性血栓栓塞。

The initiation of blood coagulation through the factor VII-Tissue Factor pathway is not only important for normal hemostasis, but likely plays a role in pathological thrombosis as well. Cellular expression of TF has been correlated with infectious, inflammatory, and neoplastic disease, and may be responsible in part for the thromboembolic complications of not only these illnesses, but also the venous thromboembolic and pulmonary embolism occurring in otherwise normal individuals as well. Plasma contains an endogenous inhibitor of the VII-TF complex which we call LACI. It is associated with the lipoproteins in plasma and requires the presence of Xa to express its feedback inhibition of VII-TF. We plan to further characterize LACI by isolating its cDNA, determining the spectrum and kinetics of its protease inhibition, and investigating the structure function relationships of the LACI molecule vis a vis its association with lipoproteins, its inhibition of Xa, and its relationship to the other components in the putative VII-TF-Xa-LACI inhibitory complex. Additional studies will also investigate the synthesis of TF and LACI by cells, determine the immunohistochemical localization of TF/LACI in normal and pathological tissues, and assess the relationship between TF and LACI blood concentrations and clinical disease. These studies will be performed using purified TF and LACI, fragments of them produced by proteolysis or chemical treatment (CnBr), their isolated cDNAs, synthetic peptides based on their predicted amino acid sequence, and appropriate monoclonal and polyclonal antibodies. The experiments are designed to provide information, now lacking, concerning the initiation and control of coagulation and the interrelationship between the classical "extrinsic" and "intrinsic" pathways. The results should enhance our understanding of both normal hemostasis and pathologic thromboembolism.