Molecular biology of form cell generation in atherosclerosis

原癌基因c-fms编码巨噬细胞集落刺激因子受体(M-CSF)，调节单核巨噬细胞的分化、成熟和增殖。该基因位于PDGF-β受体基因旁边，在正常情况下，它只在单核巨噬细胞中表达，在血管平滑肌细胞等间充质细胞中不表达。这两个基因调节这些基因在细胞中表达的特异性，而不是在正常的血管壁中共表达。我们报道了这两种受体在动脉粥样硬化病变来源的细胞中共表达。结果表明，在动脉粥样硬化过程中，M-CSF和PDGF-β共同作用促进了细胞的转化，即泡沫细胞的形成。最近，我们研究了c-fms表达的转录调控，发现在基因的上游存在抑制基因转录和刺激基因的位置，报道了PU1、E2a和Id2转录因子的参与。在血管壁细胞的病理反应的背景下，似乎存在与细胞增殖相关的基因的正常调控失败，我们认为需要通过这两个基因的表达和调控机制的分析来阐明细胞在管壁中的增殖和转化机制。通过建立c-FMS基因敲除小鼠和高表达M-CSF小鼠，阐明M-CSF在动脉粥样硬化过程中作用的病理学意义。然后，通过检测c-FMS基因敲除小鼠细胞中泡沫细胞的形成机制，阐明M-CSF/PDGF系统在发病机制中的意义。

Proto-oncogene, c-fms is the gene which encodes the receptor of macrophage colony-stimulating factor (M-CSF) which regulates differentiation, maturation, and proliferation of the monocyte-macrophages. This gene locates next to the PDGF-beta receptor gene, and in the normal condition it is expressed only in the monocyte-macrophages and is not expressed in the mesenchymal cell such as vascular smooth muscle cell. These two genes regulate the specificity of those gene expression in cells without coexpressing in the normal vessel wall. We reported that both receptors are coexpressed in cells derived from atherosclerotic lesions. It was indicated that the transformation of cells, namely the foam cell formation, was stimulated through the action of both M-CSF and PDGF-beta during the atherosclerotic process. Recently, we examined the transcriptional control of the c-fms expression, and it is recognized that there are the position which suppresses the gene transcription and stimulating position in the upstream of gene, and the involvement of transcription factors of PU.1, E2A, and Id2 was reported.In the background of the pathological reaction of the vessel wail cells, the failure of normal regulation of the gene concerning cell proliferation seemed to exist, and we considered that it was required to clarify the mechanism of proliferation and transformation of the cell in the vessel wall through these two gene expression and analysis of the regulation mechanism. By producing knockout mouse of c-fms and M-CSF overexpression mouse, we intends to clarify the pathological significance of M-CSF action in the atherosclerotic process. Then, by examining mechanism of foam cell formation in cells lucking c-fms derived from knockout mouse, we intends to clarify the significance of M-CSF/PDGF system in athorogenesis.