ENDOTHELIAL-SPECIFIC GENE EXPRESSION

血管内皮细胞在血管内皮细胞的调节中起重要作用 心血管系统。位于循环部件之间的 在血液和底层的平滑肌细胞中， 血管内皮细胞基因可能是 血管壁的病理生理学。例如，在 功能失调产生的动脉粥样硬化分泌产物 内皮细胞可能启动血管的迁移和增殖 病变特有的平滑肌细胞。在高血压患者中， 内皮细胞产生松弛因子的能力是 钝化，而它产生收缩因素的能力是 增加了。参与这些过程的蛋白质介体的研究 转基因小鼠的生产将促进这一过程 内皮细胞选择性过度表达的模型 这些蛋白质。然而，适当转基因的发展 模型需要这些介体的内皮特异性表达。 在建议的研究中，我们会把 选择性血管内皮细胞-白细胞黏附分子-1基因 由内皮细胞表达，并定义调控元件 这使得血管内皮细胞特异的基因表达。同时，我们 将表征血管细胞黏附分子-1基因 在所有类型的细胞因子激活的细胞中高效表达 内皮细胞。可能的脱氧核糖核酸结合蛋白(S) 内皮特异的转录调控过程将是 已定义。这些信息将有助于我们设计表达 选择性靶向表达外源基因的构建体 在转基因小鼠模型中将基因转移到内皮细胞。通过 从基因上操纵血管内皮细胞，或许有可能 确定这种细胞在脑白质瘤病理生物学中所起的作用 血管壁。此外，对这两个问题的描述 顺式要素和交易因素对 血管内皮细胞特异性基因的表达可能允许发生 识别有血管风险的患者的新策略 疾病。

Endothelium plays an important role in the regulation of the cardiovascular system. Situated between the circulating components of the blood and underlying smooth muscle cells, the products of endothelial genes can be critical determinants in the pathophysiology of the vessel wall. For example, in atherosclerosis secretory products produced by dysfunctional endothelium might initiate the migration and proliferation of smooth muscle cells characteristic of the lesion. In hypertension, the ability of the endothelium to produce relaxing factors is blunted, while its ability to produce contracting factors is increased. Study of the protein mediators involved in these processes would be facilitated by production of transgenic mouse models in which the endothelial cell selectively over-expresses these proteins. However, development of appropriate transgenic models requires endothelial-specific expression of these mediators. In the proposed studies, we will characterize the endothelial-leukocyte adhesion molecule-1 gene that is selectively expressed by endothelial cells and define the regulatory elements that confer endothelial-specific gene expression. In parallel we will characterize the vascular cell adhesion molecule-1 gene which is efficiently expressed in all types of cytokine-activated endothelium. The putative DNA binding protein(s) responsible for the endothelial-specific transcriptional control process will be defined. This information will assist us in designing expression constructs which will selectively target expression of exogenous genes to the endothelial cell in the transgenic mouse model. By genetically manipulating the endothelium, it may be possible to determine what role this cell plays in the pathobiology of the vessel wall. Furthermore, characterization of both the cis-elements and transacting factors responsible for endothelial-specific gene expression may permit the development of new strategies for identifying patients at risk of vascular disease.