FUNCTION OF RETINAL TRKB RECEPTOR ISOFORMS

描述（改编自申请人的摘要）：长期目标 本研究旨在了解神经营养生长因子是如何调节 脊椎动物视觉系统的正常发育和功能。 的 神经营养因子BDNF支持视网膜和顶盖神经元的存活， 以及引导轴突和树突过程的局部生长， 以活性依赖的方式调节突触功能。 的行动 BDNF主要由trkB受体介导，广泛表达于脑组织中。 视网膜、顶盖和其他视觉核团。 一个悬而未决的关键问题是， trkB受体介导这些对BDNF的多效性反应。 的 本申请人发现了trkB受体的复杂剪接， 视觉系统表明，受体结合和信号转导是 在受体结构水平上受到严格调控。 推进我们 了解BDNF在视觉系统中的不同作用将需要 的功能特性和表达模式的表征 trkB受体亚型。 具体目标集中在三个方面 在视觉系统中表达的trkB剪接变体的主要类别。 要求1 将研究细胞外结合结构域中的选择性剪接 (ED基序）调节神经营养蛋白特异性和受体活化。 目的 2将确定细胞质插入（JI基序）对 受体激酶活性、信号传导途径和下游的活化 细胞反应。 目的3将确定激酶缺失的表达 (KD)同种型在视网膜和他们的潜在作用，作为抑制剂， 全长（FL）受体在体外和体内的功能。 BDNF是一种 促进视网膜细胞存活和视神经的有前途的试剂 眼睛损伤和疾病后的再生。 了重要贡献 其治疗潜力的发展将来自于 trkB受体同种型及其功能特性的表征。

DESCRIPTION (Adapted from applicant's abstract): The long-term goals of this study are to understand how neurotrophin growth factors regulate the normal development and function of the vertebrate visual system. The neurotrophin BDNF supports the survival of retinal and tectal neurons, as well as guiding the local growth of axonal and dendritic processes and regulates synaptic function in an activity-dependent manner. The actions of BDNF are mediated principally by the trkB receptor, expressed widely in the retina, tectum and other visual nuclei. A critical unresolved issue is how the trkB receptor mediates these pleiotropic responses to BDNF. The applicant's discovery of the complex splicing of trkB receptors in the visual system indicates that receptor binding and signal transduction are tightly regulated at the level of receptor structure. Advancing our understanding of the diverse roles of BDNF in the visual system will require the characterization of the functional properties and expression patterns of the trkB receptor isoforms. The specific aims are focused on the three major classes of trkB splice variants expressed in the visual system. Aim 1 will examine how alternative splicing in the extracellular binding domain (ED motif) regulates neurotrophin specificity and receptor activation. Aim 2 will determine the effects of a cytoplasmic insertion (JI motif) on receptor kinase activity, activation of signaling pathways and downstream cellular responses. Aim 3 will determine the expression of Kinase Deletion (KD) isoforms in the retina and their potential role as inhibitors of the full length (FL) receptor function in vitro and in vivo. BDNF is a promising agent for promoting retinal cell survival and optic nerve regeneration following eye injury and disease. An important contribution to the development of its therapeutic potential will come from the characterization of trkB receptor isoforms and their functional properties.