CEK8--A NOVEL NEURAL RECEPTOR TYROSINE KINASE

CEK8--一种新型神经受体酪氨酸激酶

• 批准号: 3735494
• 负责人: ELENA B PASQUALE
• 金额: --
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY 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/3735494
• 关键词: antireceptor antibody; binding proteins; biological signal transduction; cadherins; cell cell interaction; chick embryo; developmental neurobiology; embryo /fetus tissue /cell culture; enzyme activity; genetic library; growth cones; laboratory rabbit; laboratory rat; ligands; molecular cloning; neural cell adhesion molecules; neurogenesis; neuronal guidance; neurons; phosphorylation; protein structure function; protein tyrosine kinase; proteoglycan; receptor expression; western blottings

Cek8 (Chicken embryo kinase 8) is a recently identified receptor-type tyrosine kinase of the Eph subclass which is preferentially expressed in neural tissues. The extracellular domain of Cek8 contains motifs characteristic of cell adhesion molecules, while the cytoplasmic domain comprises a typical tyrosine kinase catalytic domain. Preliminary data indicate that Cek8 and its mammalian homologs may function to regulate cellular interactions and axonal growth in the developing nervous system. Furthermore, Cek8 may be implicated in the formation of tumors of the nervous system. The objectives of the proposed research are to provide insight into the neural functions of Cek8 by using a variety of different molecular approaches. The cellular and subcellular localization of Cek8 in the nervous system of the developing embryo and in dissociated neural cultures will be studied in detail, together with the developmental regulation and level of catalytic activation of Cek8 in vivo. For example, the possibility that Cek8 may be concentrated in growth cones and implicated in axonal guidance will be explored. These studies will provide the initial clues about the functions of Cek8. The molecular components of the signaling pathways in which Cek8 is implicated will be dissected by investigating the interactions of Cek8 with molecules that have a similar localization in the nervous system. Neuronal adhesion molecules, proteoglycans and cytoplasmic tyrosine kinases are among the known molecules that may participate in functional interactions with Cek8. Other molecules interacting with Cek8, such s ligands or substrates, will also be searched for based on their ability to bind to Cek8. Finally, the expression and activity of Cek8 will be perturbed with antibodies, a dominant negative form of Cek8, Cek8 antisense sequences and, if identified, the Cek8 activating lignad. These studies will be performed in vivo and in vitro to address directly the functions of Cek8, particularly during axonal growth. The characterization of Cek8 and of the molecules that interact with it, which will be addressed in the proposed studies, will provide the information necessary to manipulate the neural signal transduction pathways in which Cek8 is implicated. Thus, the studies proposed are likely to form the basis for the development of treatments to ameliorte specific developmental neural pathologies and degenerative diseases of the nervous system.

Cek8（鸡胚激酶8）是最近发现的一种受体类型 Eph 亚类酪氨酸激酶，优先表达于 神经组织。 Cek8 的胞外结构域包含基序 细胞粘附分子的特征，而细胞质结构域 包含典型的酪氨酸激酶催化结构域。 初步数据 表明 Cek8 及其哺乳动物同源物可能具有调节 发育中的神经系统中的细胞相互作用和轴突生长。 此外，Cek8可能与肿瘤的形成有关。 神经系统。 拟议研究的目标是提供 通过使用各种不同的方法来深入了解 Cek8 的神经功能 分子方法。 Cek8 的细胞和亚细胞定位 发育中胚胎的神经系统和分离的神经系统 将详细研究文化以及发展 Cek8 体内催化激活的调节和水平。 例如， Cek8 可能集中在生长锥中的可能性 将探讨与轴突引导有关的问题。 这些研究将提供 关于 Cek8 功能的初步线索。 的分子成分 Cek8 所涉及的信号传导途径将被剖析 研究 Cek8 与具有相似分子的相互作用 在神经系统中的定位。 神经元粘附分子， 蛋白聚糖和细胞质酪氨酸激酶是已知的 可能参与与 Cek8 功能相互作用的分子。 其他 与 Cek8 相互作用的分子，例如配体或底物，也将被 根据其与 Cek8 的结合能力进行搜索。 最后， Cek8 的表达和活性将受到抗体的干扰，a Cek8 的显性失活形式、Cek8 反义序列，并且，如果 鉴定出 Cek8 激活配体。 这些研究将在 体内和体外直接解决 Cek8 的功能，特别是 轴突生长过程中。 Cek8 及其分子的表征 与之相互作用，这将在拟议的研究中得到解决， 将提供操纵神经信号所需的信息 Cek8 涉及的转导途径。 因此，研究 所提出的可能成为开发治疗方法的基础 amelorte 特定的发育神经病理学和退行性 神经系统疾病。