FUNCTION OF RETINAL TRKB RECEPTOR ISOFORMS

视网膜 TRKB 受体异构体的功能

基本信息

批准号：
2856907
负责人：
RICHARD E ZIGMOND
金额：
$ 17.56万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-01-01 至 2000-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2856907
关键词：
RNA splicing chick embryo embryo /fetus tissue /cell culture enzyme activity gene deletion mutation gene induction /repression growth factor receptors neurotrophic factors protein isoforms protein structure function protein tyrosine kinase receptor binding receptor expression retina

项目摘要

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.

描述（改编自申请人的摘要）：长期目标这项研究旨在了解神经营养素生长因子如何调节脊椎动物视觉系统的正常发育和功能。这神经营养蛋白 BDNF 支持视网膜和顶盖神经元的存活，如以及引导轴突和树突过程的局部生长以活动依赖性方式调节突触功能。的行动 BDNF 主要由 trkB 受体介导，广泛表达于视网膜、顶盖和其他视觉核团。一个尚未解决的关键问题是如何 trkB 受体介导这些对 BDNF 的多效性反应。这申请人发现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。推进我们的了解 BDNF 在视觉系统中的不同作用需要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视觉系统中表达的 trkB 剪接变体的主要类别。目标1 将检查细胞外结合域中的选择性剪接（ED 基序）调节神经营养素特异性和受体激活。目的 2 将确定细胞质插入（JI 基序）对受体激酶活性、信号通路及其下游的激活细胞反应。目标 3 将确定激酶缺失的表达视网膜中的（KD）亚型及其作为抑制剂的潜在作用全长（FL）受体在体外和体内的功能。脑源性神经营养因子 (BDNF) 是有前景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。的重要贡献其治疗潜力的开发将来自于 trkB 受体亚型的表征及其功能特性。