GENETIC AND BIOCHEMICAL APPROACHES TO TYROSINE KINASE FUNCTION

酪氨酸激酶功能的遗传和生物化学方法

• 批准号: 6290333
• 负责人: PAMELA SCHWARTZBERG
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6290333
• 关键词: protein tyrosine kinase

Our laboratory studies the functions of non-receptor tyrosine kinases, molecules required for intracellular signaling pathways involved in normal cellular growth and differentiation as well as abnormal growth and development involved in the formation and progression of cancer. We apply a combination of mouse genetics, cellular biology and protein biochemistry to the study of these molecules. Our work has concentrated on how these molecules contribute to normal function of cells of the immune system and the skeletal system and how lessons we learn from these systems can be extended to other celltypes in which these molecules function. Our recent work has concentrated on studies of the Btk family of kinases. Btk has previously been shown to be required for normal function of B cells and mutation of Btk is responsible for the human genetic disorder X-linked agammmaglobulimemia. We have recently shown that mutation of other Btk family kinases can severely impair T lymphocyte function in mice, thereby establishing for the first time a role for these kinases in T cell mediated immune responses. In particular, we have demonstrated that mutation of two Btk family kinases, Rlk and Itk leads to marked defects in T cell responses to stimulation in culture and to infectious agents in the animal. We have also continued work on the study of Src family kinases in bone cell function. We have recently shown that expression of a truncated mutant of Src can act as a dominant-negative molecule and lead to programmed cell death or apoptosis. We have extended this work to show that this mutant can alter cell survival pathways required for angiogenesis and tumor growth. Recent work has demonstrated that the SH2 (Src homology 2) domain is important for these cell survival pathways. This work provides a model for the use of inhibitors of Src function in the treatment of certain tumors. - Genetics, Immunology, Infectious Diseases, Tropical Diseases, Osteoporosis

我们的实验室研究非受体酪氨酸激酶的功能，这是参与正常细胞生长和分化的细胞内信号通路所需的分子，以及参与癌症形成和发展的异常生长和发育。我们结合了小鼠遗传学、细胞生物学和蛋白质生物化学来研究这些分子。我们的工作集中在这些分子如何促进免疫系统和骨骼系统细胞的正常功能，以及我们从这些系统中学到的教训如何扩展到这些分子发挥作用的其他细胞类型。我们最近的工作集中在对BTK激酶家族的研究上。BTK此前已被证明是B细胞正常功能所必需的，BTK的突变是导致人类遗传性疾病X连锁无丙种球蛋白血症的原因。我们最近发现，其他BTK家族激酶的突变可以严重损害小鼠的T淋巴细胞功能，从而首次确立了这些激酶在T细胞介导的免疫反应中的作用。特别是，我们已经证明了两个BTK家族激酶RLK和ITK的突变导致T细胞对培养中的刺激和动物中的感染性病原体的反应明显缺陷。我们还继续研究Src家族蛋白在骨细胞功能中的作用。我们最近发现，一个截短的Src突变体的表达可以作为一个显性负性分子，导致细胞程序性死亡或凋亡。我们已经扩展了这项工作，以表明该突变体可以改变血管生成和肿瘤生长所需的细胞生存途径。最近的工作表明，SH2(Src同源2)结构域对于这些细胞生存途径是重要的。这项工作为使用Src功能抑制剂治疗某些肿瘤提供了一个模型。-遗传学、免疫学、传染病、热带病、骨质疏松症