ORGANIZATION OF ACTIVE ZONE WITHIN PRESYNAPTIC TERMINALS ON HIPPOCAMPAL NEURONS

海马神经元突触前末梢内活动区的组织

• 批准号: 6220673
• 负责人: THOMAS SCHIKORSKI
• 金额: $ 3.85万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-15 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6220673
• 关键词: Mammalia; aging; biomedical resource; microscopy; nervous system; substance abuse related disorder; technology /technique

During the development of the nervous system, a number of cellular processes which include cell proliferation, cell differentiation, cell adhesion, cell migration and cell death are required for the correct formation of neural structures and to obtain functional and reproducible connectivity between them. In the nervous system some of these cellular processes have been shown to be mediated or modulated by growth factors and their receptors. The receptors transduce responses upon activation its ligand through their tyrosine kinase domain the cytoplasmic tail. Examples of such growth factors/receptor pairs are NGF/trk, BDNK/trkB, and NT3/trkC. A yet uncharacterized receptor Tyro-3, belongs to this class and is the subject of our study. The overall goal of this project is to understand some of the functions, primarily in cell adhesion and to identify signal transduction pathways affected by the tyrosine kinas Tyro-3. This receptor has two immunoglobulin-like repeats and two fibronectin type-III repeats in its extracellular portion and intracellularly a functional tyrosine kinase domain, shown to be phosphorylated upon binding of its known ligand gas-6. We will determine the ultrastructural localization of Tyro-3 in the hoppocampus, in order to establish a possible role of Tyro-3 in synaptogenesis and synaptic plasticity. Preliminary data suggests that the Tyro-3 protein and mRNA are preferentially localizd in the dendritic layer of CA1 neurons. This structure has been demonstrated to be crucial for the establishment of short term memory and to be affected in Alzheimers disease. We will also analyze the cell adhesive properties of Tyro-3 and the ability of this adhesion to affect its kinase activity. Cel l adhesion plays a major role in neuronal patterning during development and can affect remodeling of synaptic connections in the adult CNS. We will study the observation that Tyro-3 is phosphorylated upon addition of glutamate to hippocampal neurons in culture. Through these efforts we hope to understand the role of Tyro-3, one of the few nervous ysstem specific tyrosine kinases described so far, and gain insight into the role played by tyrosine kinases in general in the signal transduction events important for the development and functioning of the nervous system.

在神经系统的发育过程中，许多细胞 包括细胞增殖、细胞分化、细胞 黏附、细胞迁移和细胞死亡是正确的 神经结构的形成，并获得功能性和 它们之间可重现的连通性。在神经系统中，一些 这些细胞过程已被证明是由中介或调节的。 由生长因子及其受体决定。受体转导 通过酪氨酸激酶激活其配体时的反应 胞质尾部的区域。这类生长因子/受体的例子 对是NGF/trk、BDNK/trkB和NT3/trkC。一个尚未定格的人物 受体Tyro-3，属于这一类，是我们 学习。本项目的总体目标是了解一些 功能，主要是在细胞黏附和识别信号 酪氨酸激酶Tyro-3影响的转导通路。这 受体有两个免疫球蛋白样重复序列和两个纤维连接蛋白 III型在其胞外部分和细胞内a重复 功能性酪氨酸激酶结构域，显示其被磷酸化 其已知配体GAS-6的结合。我们将确定 Tyro-3在跳跃校园中的超微结构定位 建立Tyro-3在突触发生和突触中的可能作用 可塑性。初步数据显示，Tyro-3蛋白和 MRNA优先定位于CA1的树突层 神经元。这种结构已经被证明是对 阿尔茨海默病患者短期记忆的建立及其影响 疾病。我们还将分析Tyro-3的细胞黏附特性 以及这种粘附性影响其激酶活性的能力。赛尔·L 黏附在发育过程中对神经元构型起主要作用 并可影响成年中枢神经系统突触连接的重塑。 我们将研究观察到的Tyro-3被磷酸化 谷氨酸对培养的海马神经元的影响。穿过 我们希望通过这些努力来了解Tyro-3的作用，它是为数不多的 到目前为止描述的神经系统特异性酪氨酸激酶，并获得 深入了解酪氨酸激酶在心脏疾病中的作用 信号转导事件对发育和 神经系统的功能。