PROTEIN TYROSINE KINASES IN LEUKO PROLIF AND APOPTOSIS

(改编自申请人的摘要)基本的细胞过程 增殖、分化和凋亡受 多肽和脂类因子。配体激活的胞浆蛋白酪氨酸 蛋白酪氨酸激酶(PTK)调节这些反应。PTK在以下方面发挥着核心作用 白细胞的功能，它介导炎症和组织损伤， 以及直接止血和组织损伤的血小板。多重 酪氨酸激酶存在于任何特定的细胞中。中的一个非常重要的问题 细胞生物学是将特定的功能(S)归因于特定的激酶。 广泛的细胞因子导致其中一种酪氨酸的磷酸化 与JAK相关的PTK，目前的教义认为Jak是 细胞因子受体的主要信号转导通路。然而， 调查人员已经确认LYN是一种快速激活的信号 粒细胞巨噬细胞集落刺激因子分子，2 白血球发育的重要生长因子。林恩是会员 属于蛋白酪氨酸激酶的Src家族。最近的研究在 他们的实验室有野生型B细胞和他们诱变的LYN- 已稳定转染人G-G基因的缺陷型细胞系 脑脊液受体的研究表明，G-CSF诱导DNA合成需要 LYN和JAK2的JAK1的激活不足以 回应。他们假设LYN和JAK2引导不同的途径 白细胞增殖和凋亡。这样做的具体目的是 应用：1)确定LYN和LYN的结构机制 JAK2与G-CSFR相互作用，2)定义LYN的相对贡献 和JAK2在白细胞信号转导中的作用 阴性形式及Lyn缺乏对G-CSF影响的分析 增殖和凋亡中的信号转导；3)鉴定LYN特异性和 酵母双杂交技术在白细胞JAK2信号转导中的应用 系统。两个长期目标是理解分子缺陷 低增殖性和高增殖性白细胞疾病及其发展 基于蛋白酪氨酸激酶信号通路的药物干扰 白细胞被激活。 这项NIH K02奖将允许申请人补充他的美国人 癌症协会独立研究员资助并保护他的实验室 时间至少达到85%，这将巩固他作为一个 独立科学家。

(Adapted from applicant's abstract) The fundamental cellular processes of proliferation, differentiation, and apoptosis are under control by polypeptide and lipid factors. Ligand-activated cytosolic protein tyrosine kinases (PTK) regulate these responses. PTKs play a central role in the functioning of leukocytes, which mediate inflammation and tissue injury, and platelets, which direct hemostasis and tissue injury. Multiple tyrosine kinases exist in any particular cell. A very important problem in cell biology is to attribute a specific function(s) to a specific kinase. A wide range of cytokines lead to the tyrosine phosphorylation of one of the Jak-related PTK, and current dogma holds that the Jaks are the principal signalling PTK for cytokine receptors. However, the investigator's have identified Lyn as a rapidly activated signalling molecule for granulocyte macrophage colony-stimulating factor (G-CSF), two important growth factors for white blood cell development. Lyn is a member of the Src family of protein tyrosine kinases. More recent studies in their laboratory with wild-type B cells and their mutagenized lyn- deficient cell lines, which have been stably transfected with the human G- CSF receptor, have shown that G-CSF's induction of DNA synthesis requires Lyn and that the activation of Jak1 of Jak2 is not sufficient for that response. They hypothesize that Lyn and Jak2 direct different pathways for leukocyte proliferation and apoptosis. The specific aims of this application are 1) Determine the structural mechanisms whereby Lyn and Jak2 interact with the G-CSFR, 2) Define the relative contributions of Lyn and Jak2 in leukocyte signalling by transfecting cells with their dominant negative forms and by analyzing the effects of lyn-deficiency on G-CSF signalling in proliferation and apoptosis and 3) identify Lyn-specific and Jak2-specific signalling partners in leukocytes by the yeast two-hybrid system. Two long-term goals are to understand the molecular defects in hypo- and hyper-proliferative white blood cell disorders and to develop drugs based on protein tyrosine kinase signalling pathways to interrupt leukocyte activation. This NIH K02 award will permit the applicant to supplement his American Cancer Society independent investigator grants and protect his laboratory time to at least 85%, this will solidify his establishment as an independent scientist.