MURINE STK RECEPTOR AND MACROPHAGE ACTIVATION

描述：（改编自研究者摘要）一氧化氮（NO）是 许多精氨酸诱导的巨噬细胞的主要介质 在细胞介导的免疫应答期间的活性，包括杀死 感染性病原体和肿瘤细胞。 然而，NO水平升高， 与许多常见的慢性炎症性疾病有关， 如糖尿病、风湿性关节炎、哮喘和炎症性肠病。 因此，活化的巨噬细胞对NO合成的调节对于 维持有效免疫反应和 组织损伤性炎症和细胞死亡。 这种平衡是通过一个 巨噬细胞正负效应子间复杂的相互作用 activation. 巨噬细胞刺激蛋白，STK受体的配体 酪氨酸激酶，抑制IFN-γ激活的巨噬细胞产生NO 体外 随后，缺乏STK受体的小鼠表现出增加的 炎症，组织损伤和死亡后的发病细胞介导的 免疫反应 拟议的研究将探讨 STK受体通过调节巨噬细胞的活化和NO的产生， 生物学、生物化学和遗传学分析的组合。 第一、 来自STK敲除小鼠的IFN-γ活化的巨噬细胞将用于 进一步研究STK受体的缺乏对 在体外和体内激活巨噬细胞。 第二，巨噬细胞 将产生表达STK受体的细胞系以研究 STK在巨噬细胞活化背景下的信号传导特性，以及 它改变这些细胞对IFN-γ反应的机制。 最后，将STK缺陷小鼠与其他STK基因敲除小鼠杂交。 已知的巨噬细胞活化调节剂，从干扰素开始， γ受体，以及缺乏诱导型一氧化氮合酶的小鼠 （iNOS）。 将研究这些小鼠的巨噬细胞，以确定 信号位于同一路径，以及这些信号如何交叉。 通过 为了更详细地了解巨噬细胞活化的调节， PI希望开始确定抑制组织损伤的靶点， 炎症的影响，而不损害宿主的免疫反应。

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.