HUMAN PLASMINOGEN ACTIVATOR-INHIBITOR PAI-1 GENE

纤溶作用在一定程度上受组织类型之间的平衡调节。 纤溶酶原激活物(TPA)及其特异性、快效性 抑制物、纤溶酶原激活物抑制物(PAI-1)。PAI-1合成 发生在许多组织中，包括血管内皮细胞 细胞，通过一个复杂的过程调节，涉及多个 各种因素。血浆PAI-1水平异常与 患有各种血栓栓塞性疾病的男性。这些研究 本提案中概述的目的是确定 人PAI-1基因对PAI-1基因调控的研究 在分子水平上表达，研究两者之间的关系 PAI-1的结构和功能之间的关系，并开始研究PAI-1的 PAI-1遗传性异常的分子遗传学基础。在……里面 初步研究，全长人纤溶酶原激活物-1基因已被 从lambda gt11基因文库中分离出其全长 顺序已确定。人纤溶酶原激活物抑制物-1基因已定位 PAI-1序列显示出广泛的同源性 丝氨酸蛋白酶抑制剂(SERPIN)的其他成员 表观基因家族。纤溶酶原激活物-1基因调控的初步研究 显示PAI-1mRNA水平下降约10倍 在肝素和内皮细胞生长因子存在的情况下。如果 这种肝素影响在体内也会发生，这可能会显著增加 肝素通过增加tPA活性对临床的影响 随后的纤溶增加。在这项提案中，这些 观察结果将在分子水平上进一步表征 通过定量的mRNA研究和引入重组 载体以评估特定调控序列的作用。这个 人类PAI-1基因的详细结构将通过以下方式确定 重组人纤溶酶原激活物-1特异性克隆的研究 人λ噬菌体基因组DNA文库。两个版本的比较 推导的外显子/内含子结构和启动子序列 其他基因，特别是SERPIN基因家族，可能有 协调控制相关基因和基因的主要意义 基因家族的进化。1个PAI-1基因限制性内切酶长度 多态(RFLP)已在初步研究中被确定 并将寻求更多的机会。这些工具最终可以 在遗传性家系遗传连锁分析中的应用 血栓栓塞性疾病。

Fibrinolysis is regulated, in part, by a balance between tissue-type plasminogen activator (tPA) and its specific, rapidly acting inhibitor, plasminogen activator inhibitor (PAI-1). PAI-1 synthesis occurs in a number of tissues including the vascular endothelial cell and is regulated via a complex process involving multiple factors. Abnormal plasma levels of PAI-1 have been associated with a variety of thromboembolic disorders in man. The studies outlined in this proposal aim to determine the structure of the human PAI-1 gene, characterize the regulation of PAI-1 gene expression at the molecular level, investigate the relationship between PAI-1 structure and function, and begin to study the molecular genetic basis of hereditary abnormalities in PAI-1. In preliminary studies, full-length human PAI-1 cDNA has been isolated from a lambda gt11 cDNA library and its complete sequence determined. The human PAI-1 gene has been localized to chromosome 7. The PAI-1 sequence shows extensive homology to other members of the serine protease inhibitor (SERPIN) supergene family. Preliminary studies of PAI-1 gene regulation show PAI-1 mRNA levels to be decreased approximately 10-fold in the presence of heparin and endothelial cell growth factor. If this heparin affect also occurs in vivo, this could add significantly to heparin's clinical affect by increasing tPA activity with a subsequent increase in fibrinolysis. In this proposal, these observations will be further characterized at the molecular level by quantitative mRNA studies and introduction of recombinant vectors to assess the role of specific regulatory sequences. The detailed structure of the human PAI-1 gene will be determined by the study of PAI-1 specific clones isolated from a recombinant human lambda phage genomic DNA library. Comparison of the deduced exon/intron structure and promotor sequences to those of other genes, particularly the SERPIN gene family, may have major implications for coordinate control of related genes and the evolution of gene families. One PAI-1 gene restriction length polymorphism (RFLP) has been identified in preliminary studies and additional ones will be sought. These tools can eventually be applied to genetic linkage analysis in families with hereditary thromboembolic disease.