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.

该项目的主要目的是确定需要TRKB介导的信号传导以进行正常发育和突触形成和功能的细胞类型，在视网膜，小脑和新皮层中。我们将继续进行研究，这些研究记录了在没有TRKB信号传导的情况下从感光体到内部视网膜的突触通信中缺陷，试图确定视网膜中的哪些细胞必须表达TRKB，以进行光感受器的正常发育和功能。我们还将表征导致观察到的突触不足的分子变化。在小脑内，我们将表征由 缺乏TRKB信号传导在Purkinje细胞刺的发育和GABA能蛋白的表达以及高尔基神经中神经元的突触中的发展。同样，我们将确定缺乏TRKB导致这些表型的细胞，并试图鉴定由于缺乏TRKB信号传导而改变的蛋白质和mRNA，这些蛋白质和mRNA是候选者解释这些表型的候选者。我们将进一步表征在大多数皮质金字塔细胞中消除TRKB的小鼠皮层中观察到的渐进性缺陷。我们将确定随着动物的年龄的增长，它是否变得越来越渐进，确定是否对未直接靶向的神经元有其他次要影响，并将尝试鉴定蛋白质和 已知与trkb信号传导正常表达有关的树突形成的mRNA。受体酪氨酸激酶信号传导显然介导了中枢神经系统中的许多不同作用。希望对这一重要的酪氨酸激酶的研究将得出适用于理解其他酪氨酸激酶在调节健康和疾病中中枢神经系统中的神经元发育，功能和衰老的结论。