HEMOPOIETIC STEM CELL DIFFERENTIATION TO MACROPHAGES

描述：（改编自研究者摘要）集落刺激 因子-1（CSF-1）调节细胞的存活、增殖和分化 单核吞噬细胞的功能和女性的其他细胞的功能 生殖道 它要么作为糖蛋白或软骨素分泌 含硫酸盐的蛋白聚糖，两者都存在于生物学中， 在循环中的活性浓度，或在生物学上表达 在细胞表面作为跨膜糖蛋白的活性形式。 的 细胞表面CSF-1和蛋白聚糖CSF-1可以在局部的 方式，前者通过与靶细胞的直接细胞-细胞相互作用，或通过 可溶性生长因子从细胞表面的局部蛋白水解释放， 和蛋白聚糖CSF-1通过其螯合到特定的细胞外 矩阵 骨硬化（csfm-op/csfm-op）突变小鼠的研究， 在CSF-1基因中具有失活突变，表明CSF-1是 单核吞噬细胞产生的主要调节因子。 他们还 表明CSF-1通过其对靶细胞局部和体液作用， 调节许多对正常发育至关重要的过程， 各种非造血组织和器官的功能，包括 骨骼、大脑、真皮和生殖器官。 此外，其他研究 表明CSF-1在脑缺血再灌注中起重要自分泌或旁分泌作用， 白血病和女性生殖系统的肿瘤。 这项提案的总体目标是进一步了解生物学 CSF-1和CSF-1受体（CSF-1 R）的作用。 将寻求答案， 以下问题：1）哪些细胞类型在体内合成CSF-1？ 如何 这些细胞类型的CSF-1合成受到调节吗？ 3)什么是CSF-1 （分泌的糖蛋白、蛋白聚糖或细胞表面）调节各种 CSF-1靶细胞？ 4)CSF-1的所有作用是否都是通过 已知CSF-1 R（c-fms原癌基因产物）？ 5)这种受体是否受到调节 通过其他配体？ 6)CSF-1如何参与小鼠的发育 辐射诱导的白血病表现出CSF-1的自分泌调节？ 的 具体目的是：1.鉴定体内合成CSF-1的细胞。 2. 目的：探讨CSF-1基因表达的调控机制。 3.确定 不同的CSF-1应答细胞的调节机制， 不同的组织，并分析它们的功能。 4.扰乱老鼠 CSF-1 R基因敲除小鼠的表型分析。 5. 阐明 CSF-1在SJL/J放射性白血病发生中的作用 小鼠

DESCRIPTION: (Adapted from investigator's abstract) Colony stimulating factor-1 (CSF-1) regulates the survival, proliferation and differentiation of mononuclear phagocytes and the function of other cells of the female reproductive tract. It is either secreted as a glycoprotein or chondroitin sulfate-containing proteoglycan, both of which are found in biologically active concentrations in the circulation, or expressed in biologically active form at the cell surface as a membrane spanning glycoprotein. The cell surface CSF-1 and the proteoglycan CSF-1 can act in a localized fashion, the former by direct cell-cell interaction with target cells or by local proteolytic release of soluble growth factor from the cell surface, and the proteoglycan CSF-1 by its sequestration to particular extracellular matrices. Studies with the osteopetrotic (csfm-op/csfm-op) mutant mouse, that possesses an inactivating mutation in the CSF-1 gene, indicate that CSF-1 is the primary regulator of mononuclear phagocyte production. They also indicate that CSF-1, via its local and humoral action on target cells, regulates many processes that are vital for the normal development and function of a variety of non-hematopoietic tissues and organs, including bone, brain, dermis and the reproductive organs. In addition, other studies indicate that CSF-1 plays an important autocrine or paracrine role in leukemias and in neoplasias of the female reproductive system. The overall aim of this proposal is to further understand the biological roles of CSF-1 and the CSF-1 receptor (CSF-1R). Answers will be sought to the following questions: 1) Which cell types synthesize CSF-1 in vivo? How is CSF-1 synthesis by these cell types regulated? 3) What forms of CSF-1 (secreted glycoprotein, proteoglycan or cell surface) regulate the various CSF-1 target cells? 4) Are all of the effects of CSF-1 mediated via the known CSF-1R (c-fms protooncogene product)? 5) Is this receptor regulated by other ligands? 6) How is CSF-1 involved in the development of mouse radiation-induced leukemias that exhibit autocrine regulation by CSF-1? The specific aims are: 1.To identify the cells that synthesize CSF-1 in vivo. 2. To elucidate the regulation of CSF-1 gene expression. 3.To determine the mechanism of regulation of the various CSF-1 responsive cells in different tissues and to analyze their functions. 4.To disrupt the mouse CSF-1R gene and analyze the phenotype of CSF-1R-null mice. 5. To elucidate the role of CSF-1 in the development of radiation-induced leukemias of SJL/J mice.