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（根据申请人的摘要改编）：这项研究旨在了解神经营养蛋白生长因子如何调节脊椎动物视觉系统的正常开发和功能。这神经营养蛋白BDNF支持视网膜和构件神经元的存活，AS 以及指导轴突和树突过程的局部增长以及以活动依赖性方式调节突触功能。行动 BDNF主要由TRKB受体介导，在视网膜，Tectum和其他视觉核。一个关键的尚未解决的问题是如何 TRKB受体介导了对BDNF的这些多效性反应。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为在受体结构水平上严格调节。推进我们了解BDNF在视觉系统中的各种作用将需要功能特性和表达模式的表征 TRKB受体同工型。具体目标集中于三个视觉系统中表达的主要类TRKB剪接变体。目标1 将检查细胞外结合结构域中的替代剪接（ED基序）调节神经营养蛋白的特异性和受体激活。目的 2将确定细胞质插入（JI基序）对受体激酶活性，信号通路的激活和下游细胞反应。 AIM 3将确定激酶缺失的表达（KD）视网膜中的同工型及其作为抑制剂的潜在作用全长（FL）受体功能在体外和体内。 bdnf是一个促进视网膜细胞存活和视神经的有希望的药物眼部受伤和疾病后的再生。对其治疗潜力的发展将来自 TRKB受体同工型及其功能特性的表征。