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

1)模型动物的建立：我们发现中枢神经系统是血小板源性生长因子（PDGF）及其受体高水平表达的器官之一。然而，它们在体内CNS中的功能仍然不确定。为了了解PDGF β受体的功能，本课题利用Cre-loxP系统建立了PDGF β受体（PDGFR-b）条件性基因敲除小鼠。PDGFR-b等位基因缺失的小鼠没有表现出明显的异常。目前，通过与Cre转基因小鼠杂交，对仅在CNS中条件性消融PDGFR-b的小鼠的研究正在进行中。2）其他研究在新生大鼠中，我们发现B链在中枢神经系统中的表达是脑对兴奋性毒性易感性的重要生理调节因子，这种易感性在啮齿类动物和人类都是新生期特有的。提示PDGF-B/PDGFR-b的表达对缺血缺氧性损伤的未成熟脑组织具有保护作用。此外，PDGFR下游的信号分子Src的活性形式也同时被诱导。另外，我们发现PDGF-B通过激活Src诱导肾小管上皮细胞在肾缺血损伤后再生。这些结果表明，PDGF-B信号的诱导对于神经和肾脏的再生是重要的。我们对脑发育的基本方面进行了研究，重点是ZFH转录因子的表达。综上所述，我们建立了基于Cre/loxP系统的PDGF功能研究的小鼠模型。我们开始获得表明PDGF在CNS中的意义的数据。需要进一步研究。

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.