FUNCTION OF RETINAL TRKB RECEPTOR ISOFORMS

描述(摘自申请者摘要)：长期目标 本研究旨在了解神经营养素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。这个 神经营养因子BDNF支持视网膜和顶盖神经元的存活，因为 以及引导轴突和树突的局部生长以及 以依赖活动的方式调节突触功能。的行为 BDNF主要由TrkB受体介导，该受体广泛表达于 视网膜、顶盖和其他视觉核团。一个关键的悬而未决的问题是 TrkB受体介导对BDNF的这些多效性反应。这个 申请人发现TrkB受体在小鼠脑内的复杂剪接 视觉系统表明，受体结合和信号转导 在受体结构水平上受到严格调控。推进我们的 了解脑源性神经营养因子在视觉系统中的不同作用需要 的功能特性和表达模式的表征 TrkB受体亚型。具体目标主要集中在三个方面 在视觉系统中表达的TrkB剪接变体的主要类别。目标1 将研究细胞外结合结构域中的选择性剪接 (ED基序)调节神经营养素特异性和受体激活。目标 2将确定细胞质插入(JI基序)对 受体激酶活性、信号通路的激活及其下游 细胞反应。AIM 3将确定Kinase缺失的表达 视网膜中的(KD)异构体及其作为血管紧张素转换酶抑制剂的潜在作用 全长(FL)受体在体外和体内发挥作用。BDNF是一种 前景看好的促进视网膜细胞存活和视神经的药物 眼睛受伤和疾病后的再生。对……的重要贡献 其治疗潜力的开发将来自于 TrkB受体亚型的特性及其功能特性。

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.