HEMOPOIETIC STEM CELL DIFFERENTIATION TO MACROPHAGES

描述：(改编自调查人员摘要)群体刺激 因子-1(CSF-1)调节细胞的存活、增殖和分化 单核巨噬细胞和雌性其他细胞的功能 生殖道。它是以糖蛋白或软骨素的形式分泌的。 含有硫酸盐的蛋白多糖，这两种物质都存在于生物学上 循环中的活性浓度，或在生物学上表现出来的 以跨膜糖蛋白的形式活跃在细胞表面。这个 细胞表面CSF-1和蛋白多糖CSF-1可在局部发挥作用 时尚，前者通过细胞与目标细胞的直接细胞相互作用或通过 细胞表面的可溶性生长因子的局部蛋白分解释放， 和蛋白多糖CSF-1通过其对特定细胞外的隔离 矩阵。 对骨质疏松症(CSFM-OP/CSFM-OP)突变小鼠的研究 在CSF-1基因中存在失活突变，表明CSF-1是 单核巨噬细胞产生的主要调节因子。他们也 表明CSF-1通过其对靶细胞的局部和体液作用， 调节许多对正常发育和 各种非造血组织和器官的功能，包括 骨骼、脑、真皮和生殖器官。此外，其他研究 提示脑脊液-1在脑出血中起重要的自分泌或旁分泌作用。 白血病和女性生殖系统肿瘤。 这项建议的总体目标是进一步了解生物 脑脊液-1及其受体的作用。将寻求答案，以 以下问题：1)哪些细胞类型在体内合成CSF-1？多么 这些类型的细胞对CSF-1的合成有调节作用吗？3)哪些形式的CSF-1 (分泌的糖蛋白、蛋白多糖或细胞表面)调节各种 CSF-1靶细胞？4)CSF-1的所有作用都通过 已知的csf-1R(c-fms原癌基因产物)？5)该受体受调控吗？ 通过其他配体？6)CSF-1如何参与小鼠的发育 表现出自分泌调节的放射诱导白血病？这个 其具体目的是：1.鉴定体内合成CSF-1的细胞。 2.阐明脑脊液中脑脊液-1基因表达的调控。3.确定 脑脊液中多种反应细胞的调节机制 不同的组织并分析它们的功能。4.扰乱鼠标 并对CSF-1R基因缺失小鼠进行表型分析。5.澄清 脑脊液-1在SJL/J放射性白血病发生发展中的作用 老鼠。

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.