PROTEIN TYROSINE KINASES IN LEUKO PROLIF AND APOPTOSIS

（改编自申请人的摘要） 细胞增殖、分化和凋亡受 多肽和脂质因子。配体激活胞浆蛋白酪氨酸 激酶（PTK）调节这些反应。PTK在这方面发挥着核心作用， 介导炎症和组织损伤的白细胞的功能， 和血小板，其指导止血和组织损伤。多 酪氨酸激酶存在于任何特定的细胞中。中一个非常重要的问题 细胞生物学是将特定功能归因于特定激酶。 广泛的细胞因子导致酪氨酸磷酸化的一个 杰克相关的PTK，目前的教条认为，杰克是 细胞因子受体的主要信号转导PTK。但 研究人员已经确定林恩是一种快速激活信号 粒细胞巨噬细胞集落刺激因子（G-CSF）分子，两个 白色血细胞发育的重要生长因子。林恩是 蛋白酪氨酸激酶Src家族。最近的研究， 他们的实验室用野生型B细胞及其诱变的林恩- 缺陷细胞系，其已经用人G- CSF受体的研究表明，G-CSF对DNA合成的诱导需要 林恩和激活的Jak 1的Jak 2是不够的， 反应他们假设林恩和Jak 2指导不同的途径， 白细胞增殖和凋亡。具体目标是 应用是1）确定结构机制，其中林恩和 2）定义林恩的相对贡献 和Jak 2在白细胞信号传导中的作用， 阴性形式，并通过分析lyn缺乏对G-CSF的影响， 在增殖和凋亡中的信号传导和3）鉴定Lyn-specific和 利用酵母双杂交技术研究白细胞中Jak 2特异性信号伴侣 系统两个长期目标是了解 低增殖性和高增殖性白色血细胞病症并发展成 基于蛋白酪氨酸激酶信号通路的药物， 白细胞活化 这个NIH K 02奖将允许申请人补充他的美国 癌症协会独立调查员赠款和保护他的实验室 时间到至少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.