REGULATION OF SYNAPTIC DEVELOPMENT AND FUNCTION BY NEUROTROPHIC FACTORS

神经营养因子对突触发育和功能的调节

• 批准号: 7470542
• 负责人: Louis French Reichardt
• 金额: $ 19.49万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7470542
• 关键词: Age; Aging; Animals; Cells; Cerebellum; Chromosome Pairing; Communication; Dendrites; Development; Disease; Golgi Apparatus; Health; Interneurons; Mediating; Molecular; Mus; Neocortex; Neuraxis; Neurons; Phenotype; Photoreceptors; Protein Tyrosine Kinase; Proteins; Purkinje Cells; Pyramidal Cells; Receptor Protein-Tyrosine Kinases; Regulation; Retina; Role; Signal Transduction; Synapses; Vertebral column; cell type; neurotrophic factor; receptor; synaptogenesis

The major objectives of this project are to identify the cell types that require TrkB-mediated signaling for normal development and synapse formation and function in the retina, cerebellum and neocortex. We will continue studies that have documented deficits in synaptic communication from photoreceptors to the inner retina in the absence of trkB signaling, attempting to determine which cells in the retina must express trkB for normal development and function of photoreceptors. We will also characterize the molecular changes that result in the observed synaptic deficit. Within the cerebellum, we will characterize the phenotypes caused by absence of TrkB signaling on development of Purkinje cell spines and expression of GABAergic proteins and development of synapses by Golgi interneurons. Again, we will identify the cells where absence of trkB results in these phenotypes and will attempt to identify proteins and mRNAs altered by absence of TrkB signaling that are candidates to explain these phenotypes. We will characterize further the progressive deficit observed in the cortex of mice in which TrkB has been eliminated from the majority of cortical pyramidal cells. We will determine whether it becomes more and more progressive as animals age, determine whether there are additional secondary effects on neurons not targeted directly, and will try to identify proteins and mRNAs known to be involved in dendrite formation that depend upon TrkB signaling for normal expression. Receptor tyrosine kinase signaling obviously mediates many diverse actions in the central nervous system. It is hoped that studies on this one important tyrosine kinase will result in conclusions applicable to understanding the roles of other tyrosine kinases in addition to the Trk receptors in regulating neuronal development, function, and aging in the central nervous system in both health and disease.

该项目的主要目标是确定视网膜、小脑和新皮质中正常发育以及突触形成和功能需要 TrkB 介导的信号传导的细胞类型。我们将继续进行研究，记录在缺乏 trkB 信号传导的情况下从光感受器到内部视网膜的突触通讯缺陷，试图确定视网膜中的哪些细胞必须表达 trkB 以保证光感受器的正常发育和功能。我们还将描述导致观察到的突触缺陷的分子变化。在小脑内，我们将描述由以下原因引起的表型： 浦肯野细胞棘的发育、GABA能蛋白的表达以及高尔基体中间神经元的突触发育中TrkB信号传导的缺失。同样，我们将鉴定缺乏 trkB 导致这些表型的细胞，并尝试鉴定因缺乏 TrkB 信号而改变的蛋白质和 mRNA，这些蛋白质和 mRNA 是解释这些表型的候选者。我们将进一步描述在小鼠皮质中观察到的渐进性缺陷，其中 TrkB 已从大多数皮质锥体细胞中消除。我们将确定随着动物年龄的增长，它是否会变得越来越进步，确定是否对非直接靶向的神经元有额外的次级影响，并将尝试识别蛋白质和 已知参与树突形成的 mRNA 依赖于 TrkB 信号传导来正常表达。受体酪氨酸激酶信号传导显然介导中枢神经系统中的许多不同的作用。希望对这一重要酪氨酸激酶的研究能够得出适用于理解除 Trk 受体之外的其他酪氨酸激酶在健康和疾病中调节中枢神经系统神经元发育、功能和衰老中的作用的结论。