Analysis of mechanisms which regulate differential expression of gene, espcsially neuronal specificity

为了阐明基因表达既以区域特异性方式调控又以刺激特异性方式调控的机制，研究了几种富集于特定脑区蛋白的基因调控。A2a亚型腺苷受体在上丘中富集，其激活引起视觉输入增强。硒蛋白RHO基因结构分析。被确认为神经元存活伸长因子，表明其表达受金属响应元件、干扰素相关元件等调控。形式剥夺性近视引起视网膜一氧化氮合酶（NOS）基因的差异调控，即iNOS和bNOS mRNA下调，而eNOS mRNA不下调F。除了神经元外，我们还研究了基因调控的改变，即克隆出了与成骨细胞分化相关的硫酸异常增生转运蛋白，而受虐儿童淋巴细胞中MHC-II抗原下调。另一方面，这种分子生物学方法被应用于职业健康，特别是为了阐明几种化学物质的神经毒性。烷基乙酸酯的麻醉活性与它们的疏水性有关，即它们改变膜流动性的有效性。腈虫表现出神经毒性，包括行为异常，其毒性涉及特定神经元的凋亡。我们现在正在研究哪种凋亡级联是腈的主要靶点。此外，我们正在将这种方法应用于癌症特异性基因表达的研究，以阐明癌症进展机制，估计每种癌症的恶性程度等。

In order to elucidate the mechanisms why gene expression was regulated not only in a region-specific manner but also in a stimuli-specific manner, gene regulation of several proteins which were enriched in specific brain region was examined. Adenosine receptor subtype A2a was enriched in superior colliculs and its activation caused enhancement in visual input. Analysis of gene structure of selenoprotein RHO.which was recognized to be a survival elongation factor of neuron, displayed that its expression was regulated by metal-responsive-elements, interferon-related-elements, etc. Form-deprivation myopia caused differential regulation in nitric oxide synthase (NOS) gene in retina, namely, down regulation in iNOS and bNOS mRNAs but not F in eNOS mRNA.Aside from neurons, alteration in gene regulation was investigated, i.e., diastrophic dysplasia su1fate transporter was cloned because it was up-regulated in association with osteoblastic differentiation, while MHC-II antigens were down-regulated in lymphocytes of abused children. On the other hand, such molecular biological approach was applied to occupational health, especially, in order to elucidate neuronal toxicity of several chemicals. Anesthetic activity of alkyl acetates were associated with their hydrophobicity, namely their availability to change membrane fluidity. In case of nitriles which displayed neuronal toxicity, including behavioral abnormality, their toxicity involved in apoptosis to specific neurons. We are now investigating which apoptotic cascade is a major target to nitriles. Moreover, we are applying such approach to investigation in cancer-specific gene expression in order to clarify the mechanism of cancer progression, to estimate malignancy of each cancer, etc.