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Effects of PPARγ and its mew on the development of central nervous system.

PPARγ及其对中枢神经系统发育的影响。

基本信息

批准号：
15590227
负责人：
WADA Koichiro
金额：
$ 2.3万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590227/
关键词：
PPARγ Central nervous system Neural stem cell Proliferation Lentiviral vector Cell cycle Apoptosis Knockout mouse 細胞増殖細胞分化

项目摘要

Most self-renewal in the central nervous system is dependent upon neural stem cells (NSCs) that are multi-potent and self-renewing progenitor cells. NSCs are expected to be of utility in the treatment of neurodegenerative disorders, such as Parkinson's disease, Huntington's disease, and multiple sclerosis. However, detailed mechanisms that control proliferation and differentiation of NSCs are still unclear. Therefore, we investigated the effects of various molecules that potentially affect the NSC proliferation and differentiation.We found high-level expression of PPARγ in embryo mouse brain and NSCs. In contrast, extremely low levels were observed in adult mouse brain. Inhibition of PPARγ pathway by specific antagonist or lentiviral vector-siRNA caused apoptosis of NSCs. Homozygous PPARγ-knockout mice showed disorder of the development of central nervous system. Those results indicate the importance of PPARγ pathway on the NSC proliferation and the development of central nervous system.We also investigated the effects of endocrine disruptors (EDs) or non-steroidal anti-inflammatory drugs (NSAIDs) on the proliferation of NSCs, because the both of them are closely related with the field of dentistry potentially affect the NSC proliferation. Diclofenac, but not other NSAIDs, caused apoptosis of NSCs. Nonylphenol, one of the EDs, also caused apoptosis of NSCs. Cell cycle arrest was involved in the mechanisms of both apoptosis.Together with those results, various molecules, such as PPARγ, EDs, and NSAIDs, affect the proliferation or differentiation of NSCs, and may influence the development of central nervous system.

大多数中枢神经系统的自我更新依赖于神经干细胞（NSCs），神经干细胞是一种多能和自我更新的祖细胞。NSCs有望用于神经退行性疾病的治疗，如帕金森病、亨廷顿病和多发性硬化症。然而，控制NSCs增殖和分化的详细机制尚不清楚。因此，我们研究了可能影响NSC增殖和分化的各种分子的作用。我们发现PPARγ在胚胎小鼠脑和NSCs中高水平表达。相比之下，在成年小鼠的大脑中观察到极低的水平。特异性拮抗剂或慢病毒载体sirna抑制PPARγ通路导致NSCs凋亡。纯合子ppar γ敲除小鼠出现中枢神经系统发育障碍。这些结果提示PPARγ通路在NSC增殖和中枢神经系统发育中的重要作用。我们还研究了内分泌干扰物（EDs）或非甾体抗炎药（NSAIDs）对NSCs增殖的影响，因为它们都与牙科领域密切相关，可能会影响NSCs的增殖。双氯芬酸引起NSCs凋亡，而非其他非甾体抗炎药。壬基酚也可引起NSCs的凋亡。细胞周期阻滞参与了这两种凋亡机制。综上所述，各种分子如PPARγ、ed、NSAIDs等影响NSCs的增殖或分化，并可能影响中枢神经系统的发育。