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

为了阐明基因表达不仅以区域特异性方式而且以刺激特异性方式调节的机制，检测了在特定脑区域富集的几种蛋白质的基因调节。腺苷受体亚型A2 a在上级丘中富集，其激活引起视觉输入的增强。对神经元存活延长因子硒蛋白RHO基因结构的分析表明，其表达受金属反应元件、干扰素相关元件等的调控。形觉剥夺性近视导致视网膜一氧化氮合酶（NOS）基因的差异性调控，即iNOS和bNOS mRNA下调，而eNOS mRNA无F表达。研究了基因调控的改变，即，由于在成骨细胞分化中表达上调，而在受虐待儿童的淋巴细胞中MHC-II抗原表达下调，因此克隆了一种硫转运蛋白。另一方面，这种分子生物学方法被应用于职业健康，特别是，为了阐明神经毒性的几种化学品。乙酸烷基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可用性。在腈类化合物表现出神经元毒性的情况下，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反应是腈类的主要靶点。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，以阐明癌症进展的机制，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.