Comprehension and application of biological information system based on the analysis of molecular mechanisms of stress response

本研究计划旨在揭示细胞将信号的数量差异转化为反应的质量差异的分子机制。我们研究了ASK家族蛋白在理化胁迫下的应激反应，重点研究了其调节机制。1)氧化应激和内质网应激诱导ASK1的激活机制，2)ASK1活性监测系统的建立，3)寻找抑制ASK1活性的小分子化合物，4)ASK家族蛋白的激活机制，5)ASK家族基因敲除小鼠的建立，6)ASK1基因缺失对基因表达、蛋白修饰和细胞命运的影响。基于这些实验，我们发现ASK1下游激活蛋白的持续时间在细胞反应的质的差异的产生中起着重要的作用。这些良好的结果表明，通过ASK家族对应激反应的研究可能会导致神经退行性疾病和炎症的革命性治疗药物的开发。

This research program aimed at disclosing the molecular mechanisms by which cells convert quantitative difference of signals into qualitative difference of responses. We investigated the stress responses with main focuses on the regulatory mechanisms of ASK family proteins by physico-chemical stresses. More concretely, following studies have been performed ; 1)oxidative stress- and endoplasmic reticulum stress-induced activation mechanisms of ASK1, 2)development of monitoring system of ASK1 activity, 3)search for small compounds which inhibit ASK1 activity, 4)activation mechanisms of ASK family proteins, 5)establishment of knockout mice of ASK family genes, 6)the effects of ASK1 gene deletion on the gene expression, protein modification and cell fate. Based on these experiments, we found that durations of activated proteins downstream of ASK1 play important roles in generation of qualitative differences of cellular responses. These excellent results suggested that the studies of stress responses through ASK family may lead to the development of revolutionary therapeutic drugs for neurodegenerative diseases and inflammation.