Functional analysis on the role of platelet-derived growth factor in CNS development after birth using knockout model.

利用敲除模型对血小板衍生生长因子在出生后中枢神经系统发育中的作用进行功能分析。

基本信息

批准号：
12470053
负责人：
SASAHARA Masakiyo
金额：
$ 8万
依托单位：
TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2003
项目状态：
已结题

项目摘要

1)Establishment of the model animal.We have found that the CNS is one of the organs that express platelet-derived growth factor(PDGF) and its receptors at high levels. However, their function still remains undetermined in CNS in vivo. To understand the function, we established conditional knockout mouse of PDGF beta-receptor(PDGFR-b) using Cre-loxP system in this project. Mice with foxed PDGFR-b allele do not show apparent abnormality. Now study is under process on the mice in which PDGFR-b is conditionally ablated only in CNS by the crossbreeding with Cre transgenic mice. These mice survive and grow up until adult, indicating that the model established in current study is useful for the functional study of PDGFR-b.2)Other studiesIn neonatal rat, we found that the PDGF-B chain expressed in CNS is important physiological modulator of the vulnerability of brain to excitotoxicity, which vulnerability is specific to neonatal period in both rodent and human. It was suggested that the enforcement of PDGF-B/PDGFR-b could protect the immature brain at risk of hypoxic and ischemic injury.We demonstrated that PDGF-B expression was induced in the process of sciatic nerve regeneration after crush injury. Furthermore, the active form of Src, a signaling molecule at the downstream of PDGFR, is also induced at the same time. Separately, we showed that the PDGF-B induced tubular epithelial cell regeneration via the activation of Src after ischemic insult of kidney. These findings obtained indicate that induction of PDGF-B signaling is important for the regeneration of nerve and kidney.We conducted studies on basic aspects of brain development focusing on the expression of ZFH transcription factors. Also we studied on FGF, Klotho gene.In summary, we established mouse model to study the function of PDGF based on Cre/loxP system. We are starting to obtain data indicating the significance of PDGF in CNS. Further study would be required.

1)模型动物的建立。我们发现中枢神经系统是高水平表达血小板源性生长因子(PDGF)及其受体的器官之一。然而，它们在体内中枢神经系统中的功能仍未确定。为了了解其功能，本项目利用Cre-loxP系统建立了PDGFβ受体（PDGFR-b）条件敲除小鼠。具有 Foxed PDGFR-b 等位基因的小鼠没有表现出明显的异常。目前正在对小鼠进行研究，通过与 Cre 转基因小鼠杂交，仅在中枢神经系统中条件性地消除 PDGFR-b。这些小鼠存活并长大直至成年，表明本研究建立的模型对于PDGFR-b的功能研究是有用的。2）其他研究在新生大鼠中，我们发现CNS中表达的PDGF-B链是重要的生理调节剂大脑对兴奋性毒性的脆弱性，这种脆弱性是啮齿动物和人类新生儿时期所特有的。提示PDGF-B/PDGFR-b的增强可以保护处于缺氧和缺血性损伤风险中的未成熟大脑。我们证明PDGF-B的表达在挤压损伤后的坐骨神经再生过程中被诱导。此外，PDGFR下游信号分子Src的活性形式也同时被诱导。另外，我们发现 PDGF-B 在肾脏缺血损伤后通过激活 Src 诱导肾小管上皮细胞再生。获得的这些发现表明PDGF-B信号传导的诱导对于神经和肾脏的再生很重要。我们对大脑发育的基本方面进行了研究，重点关注ZFH转录因子的表达。我们还对FGF、Klotho基因进行了研究。综上所述，我们基于Cre/loxP系统建立了小鼠模型来研究PDGF的功能。我们开始获得表明 PDGF 在 CNS 中重要性的数据。需要进一步研究。