A functional analyses of PDGF expressed in CNS

血小板衍生生长因子（Platelet-derived growth factors, PDGFs）及其受体（Platelet-derived receptor, PDGFRs）出现在全身的内脏器官中，尤其在脑组织中分布广泛而丰富。它们是一种具有多种功能的强效生物分子，参与人体的多种生物现象，在医学上的应用备受期待。本项目旨在通过一系列的表达干预研究来了解PDGFs在大脑中表达的功能相关性。为了避免零敲除模型的新生儿死亡，我们采用Cre-loxP法建立PDGFR-β条件敲除小鼠系。这是我们第一次能够对出生后的生命进行基因功能分析。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，在神经上皮细胞中缺失PDGFR-β基因的小鼠，大脑对兴奋性毒性和低温损伤的易感性增加，其中氧化应激是导致死亡的主要原因之一。我们可以证明PDGF系统在中枢神经系统中具有神经保护作用，其作用是由PDGFR-β在成年小鼠脑神经元中表达介导的。我们进一步将体内研究扩展到体外，我们可以在培养细胞中以非侵入性和稳定的方式诱导PDGFR-β基因缺失。我们可以证明这两种类型的PDGFRs在不同的细胞中具有相似和独特的作用。PDGFR-β而非PDGFR-α特异性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PDGFR-β基因功能的新系统的建立，我们开始揭示未被报道的功能。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.