A functional analyses of PDGF expressed in CNS

血小板源性生长因子（PDGFs）及其受体（PDGFRs）广泛分布于全身各器官，在脑组织中的分布尤为广泛和丰富。它们是具有多种功能的有效生物分子，参与我们身体的多种生物现象，并且希望应用于医学治疗。本研究旨在通过一系列表达干预研究来了解PDGFs在脑内表达的功能相关性，为避免null敲除模型的新生儿致死性，我们采用Cre-loxP方法建立了PDGFR-β条件性敲除小鼠品系。这是第一次，让我们在出生后的生活基因的功能分析。到目前为止，突变小鼠在出生后存活并正常长大。然而，PDGFR-β基因在神经上皮来源的细胞中缺失的小鼠表现出大脑对兴奋性毒性和低温损伤的脆弱性增加，其中氧化应激是死亡的主要原因之一。我们可以表明，PDGF系统在中枢神经系统是神经保护，并在成年小鼠脑神经元中表达的PDGFR-β介导的效果。我们进一步将体内研究扩展到体外，在体外以非侵入性和稳定的方式诱导培养细胞中PDGFR-β基因缺失。我们可以证明，这两种类型的PDGFRs在不同的细胞中具有相似而独特的作用。PDGFR-β而非PDGFR-α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元分化，但抑制间充质基质细胞的成骨分化，因此，由于建立了新的研究PDGFR-β基因功能的系统，我们开始揭示尚未报道的功能。我们的项目将进一步为我们了解生长因子在我们体内的功能提供新的前景。

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.