NEURONAL AND LYMPHOID LTK PROTEIN KINASE

我们克隆了一个非常不寻常的新成员的细胞生长， 分化控制受体酪氨酸激酶家族，称为LTK， 在成年小鼠前脑神经元中特异性表达， 淋巴细胞 因为ltk很可能控制着重要的信号 通路，我们提出的这种受体的进一步分析可能不会 不仅提高了对淋巴和神经生物学的理解，而且 为神经和淋巴疾病的病因提供线索。 的 我们建议的研究的具体目标是： 1.为了证实淋巴和神经ltk cDNA预测蛋白质， 很大程度上不同的细胞外结构域。 这一前所未有的发现 提示ltk可能是不同淋巴和神经细胞的受体 配体。 我们还将扩大我们的发现，淋巴ltk不是 表达于转染细胞表面。 我们将这种缺乏 表面表达到缺乏一个必要的亚基，导致 接收器装配不正确。 我们将测试转染的神经元 ltk是细胞质的，是否有额外的淋巴和神经元cDNA 恢复表面表达ltk。 2.为了分析ltk发挥作用的信号通路， ltk缺陷小鼠通过ES细胞基因靶向。 这些老鼠可能会揭示 淋巴ltk是否是前B细胞生长的受体， 分化因子 这种因子可能是一种有用的治疗剂 用于治疗B细胞恶性肿瘤。 如果我们推测ltk控制了 细胞的存活是正确的，ltk缺陷小鼠可能表现出进行性的 并提供人类神经退行性疾病的线索 紊乱 3.利用ltk的高表达，筛选出与细胞凋亡相关的核因子， 可能控制淋巴细胞和神经细胞的重要方面， 发展 这项工作可能导致启动子元件的鉴定 它允许靶基因在有丝分裂后的大脑神经元中表达， 转基因动物

We have cloned a highly unusual new member of the cell growth and differentiation controlling receptor tyrosine kinase family, called ltk, which is specifically expressed in adult mouse forebrain neurons and pre-B lymphocytes. Because ltk is likely to control important signalling pathways, the further analysis of this receptor as proposed by us may not only improve the understanding of lymphoid and neuronal biology, but also provide clues about causes of neuronal and lymphoid disorders. The specific aims of our proposed research are: 1. To confirm that lymphoid and neuronal ltk cDNAs predict proteins with largely different extracellular domains. This unprecedented finding suggests that ltk may be the receptor for different lymphoid and neuronal ligands. We shall also expand on our finding that lymphoid ltk is not expressed on the surface of transfected cells. We attribute this lack of surface expression to the absence of an essential subunits, leading to incorrect receptor assembly. We shall test whether transfected neuronal ltk is cytoplasmic, and whether additional lymphoid and neuronal cDNAs restore surface expression ltk. 2. To analyze the signaling pathways in which ltk functions, by creating ltk deficient mice via ES cell gene targeting. These mice may reveal whether lymphoid ltk is the receptor for a pre-B cell growth or differentiation factor. Such a factor might be a useful therapeutic agent for B cell malignancies. If our speculative hypothesis that ltk controls the survival of cells is correct, ltk-deficient mice may show progressive neurodegeneration and provide clues about human neurodegenerative disorders. 3. To use the highly expression of ltk, to identify nuclear factors that are likely to control important aspects of lymphocyte and neuronal development. This work may lead to the identification of promoter elements that allow targeted gene expression in postmitotic cerebral neurons of transgenic animals.