Hemopoietic Stem Cell Differentiation to Macrophages

说明(申请人提供)：集落刺激因子-1(CSF-1)是 细胞存活、增殖和分化的主要调节因子 单核巨噬细胞，包括组织巨噬细胞和破骨细胞 它们在组织的发育和功能中的关键作用 住下来。CSF-1在生育方面也很重要，它调节睾丸巨噬细胞。 以及女性生殖道的细胞，包括蜕膜细胞， 滋养层细胞、卵母细胞、胚胎细胞和巨噬细胞。不足为奇的是， 因此，Csf1op/Csf1op基因缺失的Csf1op小鼠具有多效性表型。 局部产生的CSF-1有助于巨噬细胞的局部积聚 慢性炎症性疾病，如关节炎和自身免疫性肾小球 肾炎。此外，CSF-1还具有重要的自分泌和/或旁分泌作用。 髓系、淋巴系和女性生殖系统的肿瘤。 CSF-1以糖蛋白或含有硫酸软骨素的形式分泌 蛋白多糖，这两种物质都在生物活性浓度中被发现 循环，或表示为具有生物活性的跨膜 糖蛋白。细胞表面的CSF-1和蛋白多糖CSF-1可以作用于 局部化方式，前者通过细胞与目标细胞的直接相互作用 或通过细胞表面可溶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。局部CSF-1合成和蓄积部位的阐明 组织巨噬细胞已经提出了这些脑脊液-1功能的范例 新近研究的生理和疾病中的同工酶 小鼠模型系统。 Csf-1的作用是通过csf-1受体(csf-1R)介导的，csf-1R是原癌基因c-fms编码的一种约165 kDa的酪氨酸激酶。的表型 脑脊液-1R基因缺失的小鼠比脑脊液-1基因缺失的表型更严重 老鼠。因此，尽管CSF-1的所有作用都是通过这种受体介导的， 其他作用可能是通过非依赖于CSF-1的CSF-1R激活来实现的。 该提案的总体目标是利用最近开发的新型鼠标 理解CSF-1及其受体在发育过程中作用的模型系统 和疾病。具体目的是：1.分析脑脊液-1异构体在脑出血中的作用 发展和疾病。2.确定不当行为的后果 脑脊液-1的自分泌调节。3.阐明中美之间存在差异的基础 脑脊液-1和脑脊液-1R-缺合子小鼠之间的表型。4.鉴定脑脊液-1受体 调节单核巨噬细胞承诺和分化的突变。

DESCRIPTION (provided by applicant): Colony Stimulating Factor-1 (CSF-1) is the primary regulator of the survival, proliferation and differentiation of mononuclear phagocytes, including tissue macrophages and osteoclasts, that play critical roles in the development and function of the tissues in which they reside. CSF-1 is also important in fertility, regulating testicular macrophages and cells of the female reproductive tract, including decidual cells, trophoblast, oocytes, embryonic cells and macrophages. Not surprisingly, therefore, CSF-1-nullizygous Csf1op/Csf1op mice have a pleiotropic phenotype. Local production of CSF-1 contributes to the local accumulation of macrophages in chronic inflammatory diseases, such as arthritis and autoimmune glomerular nephritis. In addition, CSF-1 has important autocrine and/or paracrine roles in neoplasias of the myeloid, lymphoid and female reproductive systems. CSF-1 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 as a biologically active 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. Elucidation of the sites of local CSF-1 synthesis and of accumulation of tissue macrophages have suggested paradigms for the function of these CSF-1 isoforms in physiology and disease that can be studied in recently developed mouse model systems. The effects of CSF-1 are mediated via the CSF-1 receptor (CSF-1 R), an approximately 165-kDa tyrosine kinase encoded by the c-fms protooncogene. The phenotype of CSF-1R-nullizygous mice is more severe than the phenotype of CSF-1-nullizygous mice. Thus, while all of the effects of CSF-1 are mediated by this receptor, other effects may be mediated by CSF-1 -independent CSF-1 R activation. The overall aim of the proposal is to utilize recently developed, novel mouse model systems to understand the roles of CSF-1 and the CSF-1 R in development and disease. The specific aims are: 1. To analyze the role of CSF-1 isoforms in development and disease. 2. To determine the consequences of inappropriate autocrine regulation by CSF-1. 3. To elucidate the basis of the difference in phenotype between CSF-1 - and CSF-1 R-nullizygous mice. 4. To identify CSF-1 R mutations regulating mononuclear phagocyte commitment and differentiation.