MURINE STK RECEPTOR AND MACROPHAGE ACTIVATION

描述：(改编自研究人员摘要)一氧化氮(NO) 许多细胞因子诱导的巨噬细胞的主要介体 在细胞介导的免疫反应中的活动，包括杀死 感染性病原体和肿瘤细胞。然而，NO水平的升高会导致 与许多常见的慢性炎症性疾病有关，如 如糖尿病、类风湿性关节炎、哮喘和炎症性肠病。 因此，激活的巨噬细胞对NO合成的调节对 在有效的免疫反应和 破坏组织的炎症和细胞死亡。这一平衡是通过一个 巨噬细胞正负效应因子的复杂相互作用 激活。巨噬细胞刺激蛋白--STK受体的配体 酪氨酸激酶抑制干扰素-γ激活的巨噬细胞产生NO 在试管中。随后，缺乏STK受体的小鼠表现出增加 炎症、组织损伤和死亡发生后的细胞介导的 免疫反应。拟议的研究将探索通过什么机制 STK受体调节巨噬细胞的激活和NO的产生 结合生物、生化和遗传分析。第一, 来自STK基因敲除小鼠的干扰素-γ激活的巨噬细胞将用于 进一步研究STK受体缺失对细胞周期的影响 巨噬细胞在体外和体内的激活。第二，巨噬细胞 将建立表达STK受体的细胞系，以便研究 巨噬细胞激活中STK的信号特性，以及 它改变这些细胞对干扰素-伽马的反应的机制。 最后，STK缺陷小鼠将与其他基因敲除的小鼠杂交 已知的巨噬细胞激活调节因子，从干扰素开始 伽马受体，以及缺乏诱导型一氧化氮合酶的小鼠 (Inos)。将对这些小鼠的巨噬细胞进行研究，以确定哪些 信号位于相同的路径中，以及这些信号如何相交。通过 更详细地了解巨噬细胞激活的调节， PI希望开始确定抑制组织破坏的目标 在不影响宿主免疫反应的情况下，减轻炎症的影响。

DESCRIPTION: (Adapted from investigator's abstract) Nitric oxide (NO) is the principal mediator of many of the cytokine-inducible macrophage activities during a cell-mediated immune response, including the killing of infectious pathogens and tumor cells. However, elevated levels of NO have been associated with a number of common chronic inflammatory diseases such as diabetes, rheumatoid arthritis, asthma and inflammatory bowel disease. Thus, regulation of NO synthesis by activated macrophages is critical to maintaining a balance between an effective immune response and tissue-damaging inflammation and cell death. This balance is achieved by a complex interplay between positive and negative effectors of macrophage activation. Macrophage-stimulating protein, the ligand for the STK receptor tyrosine kinase, suppresses NO production by IFN-gamma-activated macrophages in vitro. Subsequently, mice lacking the STK receptor exhibit increased inflammation, tissue damage and death following the onset of a cell-mediated immune response. The proposed studies will explore the mechanism by which the STK receptor regulates macrophage activation and NO production using a combination of biological, biochemical and genetic analyses. First, IFN-gamma-activated macrophages from the STK knockout mice will be used to further examine the effect the absence of the STK receptor has on the activation of macrophages both in vitro and in vivo. Second, macrophage cell lines expressing the STK receptor will be generated in order to study the signaling properties of STK in the context of macrophage activation, and the mechanism by which it alters the response of these cells to IFN-gamma. Finally, the STK deficient mice will be crossed with knockouts of other known regulators of macrophage activation, starting with the interferon gamma receptor, as well as mice lacking inducible nitric oxide synthase (iNOS). Macrophages from these mice will be studied to determine which signals lie in the same pathway, and how these signals intersect. By understanding, in more detail, the regulation of macrophage activation, the PI hopes to begin to identify targets for suppression of the tissue-damaging effects of inflammation without compromising the host immune response.