VASCULAR FUNCTIONS OF NEUTROPHINS

初步结果表明，血管平滑肌细胞亚群 肌细胞表达生长因子的NGF家族的受体 （神经营养因子）。 神经营养因子由平滑肌细胞产生， 血小板，并通过交感神经元支配的 脉管系统 神经营养因子在血管内皮细胞中的作用 发展和对伤害的反应将被检查。 原位 将采用杂交和免疫组织化学技术， 表征神经营养因子（NGF，BDNF，NT-3， NT-4）。 神经营养素对体外培养的 检查血管平滑肌细胞。 培养能力 大鼠交感神经元将神经营养素沿轴突运输， 评估。 神经营养因子在体内的功能将通过 产生转基因小鼠，其中嵌合基因由以下组成： BDNF编码序列上游的多巴胺β-羟化酶启动子 和NT-3引起交感神经细胞中这些因子的表达增强， 神经元 阻断神经营养素对血管平滑肌的影响 将评估体内的肌细胞。 这将通过 产生转基因小鼠，其中神经营养因子受体突变体具有 显性负作用在平滑肌细胞中表达， 控制hNGFR基因的启动子区和/或平滑肌 α肌动蛋白基因

Preliminary results demonstrate that subpopulations of vascular smooth muscle cells express receptors for the NGF family of growth factors (neurotrophins). Neurotrophins are produced by smooth muscle cells, by blood platelets, and by the sympathetic neurons which innervate the vasculature. The functional role of neurotrophins in vascular development and response to injury will be examined. In situ hybridization and immunohistochemical techniques will be employed to characterize the pattern of expression of neurotrophins (NGF, BDNF, NT-3, NT-4) in developing mice. The effects of neurotrophins on cultured vascular smooth muscle cells will be examined. The capacity of cultured rat sympathetic neurons to transport neurotrophins down axons will be assessed. Functions of neurotrophins in vivo will be assessed by generating transgenic mice in which chimeric genes consisting of the dopamine beta-hydroxylase promoter upstream of coding sequences for BDNF and NT-3 cause enhanced expression of these factors in sympathetic neurons. The effects of blocking neurotrophin action on vascular smooth muscle cells in vivo will be assessed. This will be accomplished by generating transgenic mice in which neurotrophin receptor mutants with dominant negative action are expressed in smooth muscle cells under control of the promoter region of the hNGFR gene and/or the smooth muscle alpha actin gene.