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Research on the fundamental molecules in relation to controlling brain aging : From neuronal cytoskeleton regulation to neuronal longevity control

控制脑衰老的基础分子研究：从神经元细胞骨架调节到神经元寿命控制

基本信息

批准号：
19300130
负责人：
MORI Nozomu
金额：
$ 12.15万
依托单位：
Nagasaki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2007
资助国家：
日本
起止时间：
2007 至 2009
项目状态：
已结题

项目摘要

While I previously established N-Shc gene deficient mouse, the so-called KO mouse, we now made N-Shc and Grit/RICS double KO mouse. In norder to understand molecular mechanisms of actin dynamics regulation via N-Shc, we examined the role of Homer/Cupidin, an anchoring molecule to actins at neuronal synapses. We also analyzed the transcriptional regulatory mechanisms of BDNF promoter by NRSF/REST. In aged brains, it has been well known that various functions, particularly in hippocampus and cerebram, do decrease, but little is known about the cerebellar function. We, therefore, asked whether synaptic LTP in cerebellum changes or not in aging, and found that it indeed declined with age. We further found that the reduction of LTP is strongly affected by oxidative stress. Since the LTP at parallel fiber-Purkinje cell synapse depend on NO (nitric oxide), we assumed and finally demonstrated that this NO-dependent LTP is impaired by oxidative stress during aging. We also analyzed the effects of HDAC6 and SIRT2 in the protein aggregate turnover in neurons, and found that HDAC6 stimulated poly glutamin-mdiated protain aggregation in neuronal cells, which may be relevant to the studies of age-related neurodegenerative diseases. Finally, we established Asian research consortium on aging.

虽然我以前建立了N-Shc基因缺陷小鼠，即所谓的KO小鼠，但我们现在建立了N-Shc和Grit/RICS双KO小鼠。为了了解N-Shc调控肌动蛋白动力学的分子机制，我们研究了Homer/Cupidin在神经元突触中对肌动蛋白的锚定分子的作用。我们还利用NRSF/REST分析了BDNF启动子的转录调控机制。在老年人的大脑中，许多功能，特别是海马和大脑，确实会下降，但对小脑的功能知之甚少。因此，我们询问小脑突触LTP是否随年龄增长而变化，发现它确实随年龄增长而下降。我们进一步发现，LTP的减少受到氧化应激的强烈影响。由于平行纤维浦肯野细胞突触的LTP依赖于NO（一氧化氮），我们假设，并最终证明，这种NO依赖的LTP受损的氧化应激在老化过程中。我们还分析了HDAC 6和SIRT 2在神经元蛋白聚集体周转中的作用，发现HDAC 6刺激神经元细胞中聚精氨酸介导的蛋白聚集，这可能与年龄相关的神经退行性疾病的研究有关。最后，我们成立了亚洲老龄化研究联盟。