A functional analyses of PDGF expressed in CNS

CNS中PDGF表达的功能分析

• 批准号: 16390114
• 负责人: SASAHARA Masakiyo
• 金额: $ 9.8万
• 依托单位: University of Toyama (2005-2007)Toyama Medical and Pharmaceutical University (2004)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390114/
• 关键词: PDGF; Conditional knockout; Cre; loxP; Brain; Behavior analyses; Neurotrophic factor; Receptor; Neuronal differentiation; Crelox P; 血小板由来増殖因子; knockout; conditional; 線維芽細胞; Akt; MAP kinase

Platelet-derived growth factors (PDGFs) and the receptors (PDGFRs) appear to the internal organs of the whole body, and they are distributed in the brain tissue especially widely, and abundantly. They are potent biological molecules with multiple functions, being involved in diverse biological phenomena of our body, and the application to the medical treatment has been hoped for. The present project aimed to understand the functional relevance of PDGFs expressed in the brain through a set of the expression intervention studies.To evade the neonatal lethality in null knockout model, we established the mouse lines of PDGFR-β conditional knockout by Cre-loxP method. This, for the first time, allowed us the functional analyses of the gene in postnatal life. The mutant mice survived after birth and grown up normally, so far examined. However, the mice in which PDGFR-β gene was deleted in neuroepithelium-derived cells, showed increased vulnerability of the brain to the excitotoxicity and cryogenic injuries in which oxidative stress is one of the major cause of death. We could show that PDGF system in the CNS is neuroprotective, and that the effects were mediated by PDGFR-β expressed in neurons in adult mouse brain. We further extended in vivo studies to in vitro, in which we could induce the PDGFR-β gene deletion in cultured cells with non-invasive and stable manner. We could show that the two types of PDGFRs convey similar and distinctive effects in different cells. PDGFR-β but not PDGFR-α specifically mediated migratory response of fibroblasts and the neuronal differentiation of neural stem cells, but inhibited the osteogenic differentiation of mesenchymal stromal cells.Thus, due to the establishment of novel system to appreciate the PDGFR-β gene function, we are starting to reveal the functions that have not been reported. Our project should further give us new vistas to understand the growth factor function in our body.

血小板衍生生长因子(PDGFs)及其受体(PDGFRs)广泛存在于全身各脏器，尤其在脑组织中分布广泛、丰富。它们是具有多种功能的强效生物分子，参与人体的各种生物现象，在医学治疗中的应用前景广阔。为了解PDGFs在脑内表达的功能相关性，采用Cre-loxP方法建立了PDGFR-β条件性基因敲除小鼠模型，避免了零基因敲除模型中新生儿死亡的发生。这使得我们第一次能够对基因在出生后的生活进行功能分析。到目前为止，这些突变小鼠在出生后存活下来，并正常长大。然而，在神经上皮源性细胞中PDGFR-β基因缺失的小鼠，大脑对兴奋性毒性和低温损伤的易感性增加，而氧化应激是导致死亡的主要原因之一。结果表明，中枢神经系统中的血小板衍生生长因子系统具有神经保护作用，这种作用是由成年小鼠脑内神经元表达的血小板衍生生长因子受体β介导的。我们进一步将体内研究扩展到体外，以非侵入性和稳定的方式在培养细胞中诱导PDGFR-β基因缺失。我们可以证明，这两种类型的PDGFRs在不同的细胞中传递相似而不同的作用。PDGFR-β不能特异性地介导成纤维细胞的迁移反应和神经干细胞的神经分化，但能抑制间充质基质细胞的成骨分化。因此，随着PDGFR-α基因功能新体系的建立，我们开始揭示未见报道的功能。我们的项目应该会进一步给我们提供新的视角来了解生长因子在我们体内的功能。

项目成果

CaMKII alpha-transgenic Mice Shows Pathological Changes of Diabetic Nephropathy with Enhanced Expression of PDGF-B Chain and PDGF-beta Receptor.

CaMKII α 转基因小鼠显示糖尿病肾病的病理变化，PDGF-B 链和 PDGF-β 受体表达增强。

• 发表时间: 2007
• 作者: Kato;I.;Umemura;K.;Ishii;Y.;Inoue;T.;Aoki;J.;Kono;N.;Oya;T.;Arai;H.;Hayashi;N.;Hamada;H.;Endo;S.;Hirashima;Y.;Hiraga;K;Suzuki H.
• 通讯作者: Suzuki H.

The analysis of the PDGF- p function in fibroblasts using Cre-loxP knockout system

利用Cre-loxP敲除系统分析成纤维细胞中PDGF-p的功能

• 发表时间: 2005
• 作者: Oya;T.;Gao;Z.;Ishu;Y.;Sasaoka;T.;Sabit;H.;Tokunaga;A. Zheng;L.;Ishizawa;S.;Fujimori;T.;Sasahara;M
• 通讯作者: M

Attenuation of focal cerebral ischemic injury in transgenic mice overexpressing PAF-acetylhydrolase II(PAF-AH(II))in neurons

神经元过表达PAF-乙酰水解酶II（PAF-AH（II））转基因小鼠局灶性脑缺血损伤的减轻

• 发表时间: 2005
• 作者: Umemura;K.;Hirashima;Y.;Endo;S.;Kawai;N.;Inoue;T.;Aoki;J.;Arai;Y.;Kuchi;H.;Oda;M.;Ishu;Y.;Kato;I.;Hiraga;K
• 通讯作者: K

Expression analysis of ATBF1 and ZFH4, the zinc-finger and homeodomain family proteins(ZFH family proteins), in developing rat brains.

锌指和同源域家族蛋白（ZFH 家族蛋白）ATBF1 和 ZFH4 在发育中的大鼠大脑中的表达分析。

• 发表时间: 2004
• 作者: Umemura;K.;Hirashima;Y.;Endo;S.;Kawai;N.;Inoue;T.;Aoki;J.;Arai;Y.;Kuchi;H.;Oda;M.;Ishu;Y.;Kato;I.;Hiraga;K;和田芳直;Gzo Z.;高澤久美;Ishii Y.
• 通讯作者: Ishii Y.

Expression analysis of ATBF1 and ZFH4, the zinc-finger and homeodomain family proteins(ZFH family proteins), in developing rat brains

锌指和同源域家族蛋白（ZFH 家族蛋白）ATBF1 和 ZFH4 在发育中的大鼠大脑中的表达分析

• 发表时间: 2004
• 作者: Ishii;Y.;Nogami;S.;Kawaguchi;M.;Oya;T.;Sasahara;M
• 通讯作者: M