The analysis of PDGFR-β deficient brain

PDGFR-β缺陷脑的分析

• 批准号: 17590338
• 负责人: ISHII Yoko
• 金额: $ 2.47万
• 依托单位: University of Toyama
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17590338/
• 关键词: platelet-derived growth factor; receptor; conditional knockout; neurotrophic factor; injury; excitotoxicity; differentiation; cell culture

Platelet-derived growth factors (PDGFs) and PDGF receptors (PDGFRs) are widely expressed in the mammalian CNS, though their functional significance remains unclear. To clarify PDGFR function in CNS, we developed novel mutant mice in which the gene encoding the b subunit of PDGFR (PDGFR-b) was genetically deleted in CNS neurons to elucidate the role of PDGFR-b, particularly in the post-natal stage and analyzed the mutant mice.1) The cerebral damage after cryogenic injury was severely exacerbated in the mutants compared with controls. Furthermore, TdT-mediated dUTP-biotin nick end labeling (TUNEL)- positive neuronal cell death and lesion formation in the cerebral hemisphere were extensively exacerbated in our mutant mice after direct injection of NMDA without altered NMDA receptor expression. Our results clearly demonstrate that PDGFR-b expressed in neurons protects them from cryogenic injury and NMDA-induced excitotoxicity.2) We examined the inhibitory effect of PDGF-BB on the AMPA rece … More ptor function in the nucleus tractus solitarius (NTS) by using slice patch-clamp techniques. PDGF-BB significantly reduced the amplitude of AMPA-induced currents in NTS neurons, which showed that PDGF-BB could suppress the AMPA receptor-mediated excitatory input via the postsynaptic mechanism. The inhibitory effect of PDGF-BB on EPSCs was not observed in mutant mice with conditional deletion of the PDGFR-β gene in neurons. These studies suggest that the PDGF-B/PDGFR-β axis inhibits the AMPA receptormediated synaptic transmission that comprises the major part of the primary afferent to the NTS second-order neuron. The detected inhibitory action may be involved in the CNS regulation of the respiratory response.3) PDGFRB-/-neural stem cells showed a higher rate of apoptosis without any significant decrease in proliferation. They demonstrated reduced capacities of migration and neuronal differentiation in response to not only PDGF-BB but also bFGF. bFGF increased the activity of the PDGFRB promoter as well as the expression and phosphorylation of PDGFRB. These results suggest the presence of the signaling convergence between PDGF and FGF. PDGFRB is needed for survival, and the effects of bFGF in migration and neural differentiation of the cells may be potentiated by induction of PDGFRB. Less

血小板衍生生长因子(PDGFs)及其受体(PDGFRs)在哺乳动物中枢神经系统中广泛表达，但其功能意义尚不清楚。为了阐明PDGFR在中枢神经系统中的功能，我们建立了编码PDGFR b亚单位基因(PDGFR-b)在CNS神经元中的基因缺失的新型突变小鼠，以阐明PDGFR-b在出生后阶段的作用，并对突变小鼠进行了分析：1)与对照组相比，突变小鼠低温损伤后的脑损伤严重加重。此外，在我们的突变小鼠中，在没有改变NMDA受体表达的情况下，直接注射NMDA后，TdT介导的dUTP-生物素缺口末端标记(TUNEL)阳性神经细胞死亡和大脑半球病变形成的情况广泛加剧。我们的结果清楚地表明，在神经元中表达的PDGFFR-b可以保护神经元免受低温损伤和N-甲基-D-天冬氨酸诱导的兴奋性毒性。2)我们检测了PDGF-BB对AMPA受体…的抑制作用应用薄片膜片钳技术研究孤束核(NTS)内更多的ptor功能。PDGF-BB可显著降低AMPA诱发的NTS神经元电流的幅度，表明PDGF-BB可能通过突触后机制抑制AMPA受体介导的兴奋性传入。在神经元中PDGFFR-β基因有条件缺失的突变小鼠中，未观察到PDGFR-BB对EPSCs的抑制作用。这些研究表明，PDGF-B/PDGFR-β轴抑制了AMPA受体介导的突触传递，该突触传递构成了NTS二级神经元初级传入的主要部分。该抑制作用可能与中枢神经系统对呼吸反应的调节有关。3)PDGFRb-/-神经干细胞表现出较高的凋亡率，但增殖能力没有明显下降。它们的迁移能力和神经元分化能力不仅受到PDGF-BB的影响，而且还受到碱性成纤维细胞生长因子的影响。碱性成纤维细胞生长因子增强了PDGFRb启动子的活性以及PDGFRb的表达和磷酸化。这些结果提示PDGF和成纤维细胞生长因子之间存在信号融合。PDGFRb是细胞存活所必需的，诱导PDGFRb可增强bFGF在细胞迁移和神经分化中的作用。较少

项目成果

Neuroprotective Role of Transgenic PAF-Acetylhydrolase II in Mouse Models of Focal Cerebral Ischemia

• DOI: 10.1161/01.str.0000257981.09329.d2
• 发表时间: 2007-03
• 期刊: Stroke
• 影响因子: 8.3
• 作者: K. Umemura;I. Kato;Y. Hirashima;Y. Ishii;Takao Inoue;J. Aoki;N. Kono;T. Oya;N. Hayashi

Transgenic PAF-acetylhydrolase II protects neurons in mouse models of transient focal cerebral ischemia.

转基因 PAF-乙酰水解酶 II 可以保护短暂性局灶性脑缺血小鼠模型中的神经元。

• 发表时间: 2007
• 作者: Hirashima;Y;Kurimoto;M;Hayashi;N;Umemura;K;Hori;E;Origasa;H;Endo;S;Ichsan AM.;Hirashima Y.;Hirashima Y.;Nagai S.;Hamada H.;Hori E.;Kuwayama N.;Hayakawa Y.;Kanekiyo K.;Hirashima Y.;Hayashi N.;Kurosaki K.;Hirashima Y.;Shibata T.;Tada M.;鈴木ひかり;柴田 孝;柴田 孝;加藤一郎;川口 博;Mohafez O. M.;鈴木ひかり;鈴木 ひかり;加藤一郎;鈴木ひかり;鈴木 ひかり;Kato I.
• 通讯作者: Kato I.

A novel model for diabetic retinopathy

糖尿病视网膜病变的新模型

• 发表时间: 2006
• 作者: Ichsan;A. M.;Kato;I.;Oya;T.;Tomi;M.;Takasawa;S.;Okamoto;H.;Sasahara;M.;Hayasaka S.;Hosoya K.;Hiraga;K
• 通讯作者: K

「研究成果報告書概要(和文)」より

摘自《研究结果报告摘要（日文）》

• 发表时间: 2005
• 作者: Kawauchi;et. al.;Nishimura et al.;Dezawa et al.;Yoshizawa et al.;星野 幹雄;星野 幹雄
• 通讯作者: 星野 幹雄

Expression of constitutively active form of CaM kinase II in pancreatic betacells of transgenic mice leads to severe diabetes mellitus.

CaM 激酶 II 的组成型活性形式在转基因小鼠的胰腺 β 细胞中表达会导致严重的糖尿病。

• 发表时间: 2006
• 作者: 石岡千加史;千葉奈津子;酒寄真人;下平秀樹;山崎隆志;川村しのぶ;中川加奈子;Ichsan A.M.;Kato I.
• 通讯作者: Kato I.