Distinct roles of somatically and dendritically synthesized BDNF in spine morphog

体细胞和树突状合成的 BDNF 在脊柱形态中的不同作用

基本信息

批准号：
8279188
负责人：
BAOJI XU
金额：
$ 33.32万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-15 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8279188
关键词：
3&apos Untranslated Regions Actins Action Potentials Animal Model Binding Brain Brain-Derived Neurotrophic Factor Dendrites Dendritic Spines Development Excitatory Synapse Functional RNA Genes Goals Guanine Nucleotide Exchange Factors Hippocampus (Brain)Human Impaired cognition In Vitro Knock-in Mouse Label Learning Location Mediating Memory Mental Retardation Messenger RNA Mitogen-Activated Protein Kinases Molecular Morphogenesis Morphology Mus NGFR Protein Neurodegenerative Disorders Neurons Pathway interactions Phase Phosphoinositide Pathway Phosphotransferases Physiological Play Process Proteins Rattus Research Project Grants Role Shapes Signal Transduction Signaling Molecule Single Nucleotide Polymorphism Sorting - Cell Movement Stimulus Structure Synapses Synaptic plasticity System Testing Tetrodotoxin Translations Vertebral column Whole-Cell Recordings density gene function immunocytochemistry in vivo inhibitor/antagonist insight knock-down mutant nervous system disorder neuronal cell body novel receptor response small hairpin RNA

项目摘要

DESCRIPTION (provided by applicant): The vast majority of excitatory synapses occur on spines, which are dynamic structures that undergo changes in size, shape, and number during development and in response to physiological stimuli such as neuronal activity and learning. The overall goal of this research project is to elucidate the molecular mechanisms that regulate dendritic spine morphogenesis. Spine development includes formation, maturation, and pruning. Although many proteins have been found to be important for spine formation, the molecular pathway controlling spine formation is not fully understood. Even less is known about the molecular mechanism regulating the later phases of spine development, especially spine pruning, which is an activity-dependent process and likely plays an important role in the refinement of synaptic connections. The gene for brain-derived neurotrophic factor (BDNF) produces two pools of mRNA, with either a short or long 3' untranslated region (3'UTR). Our recent findings show that short 3'UTR Bdnf mRNA is restricted to the soma, whereas long 3'UTR Bdnf mRNA is also transported to dendrites for local translation. This application is aimed at testing the hypothesis that BDNF synthesized in the soma and dendrites regulates formation, maturation, and pruning of spines via distinct signaling cascades and that single nucleotide polymorphisms (SNP) in the human Bdnf 3'UTR may impair localization and translation of Bdnf mRNA in dendrites, leading to spine dysmorphogenesis and cognitive impairments. These hypotheses will be tested in three specific aims. Specific aim 1 proposes to examine the distinct roles of somatically and dendritically synthesized BDNF in spine morphogenesis in cultured rat hippocampal neurons. Specific aim 2 proposes to elucidate the signaling cascades mediating the effects of BDNF on the formation, maturation, and pruning of spines. Specific aim 3 proposes to determine the effects of a human SNP in the long Bdnf 3'UTR on spine morphogenesis and synaptic plasticity. Findings from these studies likely reveal novel mechanisms governing gene function and spine morphogenesis, and provide insights into the functional consequence of SNPs in non-coding sequences.

描述（由申请人提供）：绝大多数兴奋性突触发生在棘上，棘是动态结构，在发育过程中以及响应神经元活动和学习等生理刺激时，会发生大小、形状和数量的变化。该研究项目的总体目标是阐明调节树突棘形态发生的分子机制。脊柱发育包括形成、成熟和修剪。尽管已发现许多蛋白质对于脊柱形成很重要，但控制脊柱形成的分子途径尚未完全了解。关于调节脊柱发育后期的分子机制，尤其是脊柱修剪，我们知之甚少，这是一个依赖于活动的过程，可能在突触连接的细化中发挥着重要作用。脑源性神经营养因子 (BDNF) 基因产生两个 mRNA 库，分别具有短或长的 3' 非翻译区 (3'UTR)。我们最近的研究结果表明，短 3'UTR Bdnf mRNA 仅限于体细胞，而长 3'UTR Bdnf mRNA 也被转运到树突进行局部翻译。本申请旨在测试以下假设：体细胞和树突中合成的 BDNF 通过不同的信号级联调节树突棘的形成、成熟和修剪，并且人类 Bdnf 3'UTR 中的单核苷酸多态性 (SNP) 可能会损害 BDNF 的定位和翻译。树突中的 Bdnf mRNA，导致脊柱畸形发生和认知障碍。这些假设将在三个具体目标中得到检验。具体目标 1 提议检查体细胞和树突状合成的 BDNF 在培养的大鼠海马神经元脊柱形态发生中的不同作用。具体目标 2 提出阐明介导 BDNF 对刺形成、成熟和修剪影响的信号级联。具体目标 3 建议确定长 Bdnf 3'UTR 中的人类 SNP 对脊柱形态发生和突触可塑性的影响。这些研究的结果可能揭示了控制基因功能和脊柱形态发生的新机制，并为非编码序列中 SNP 的功能后果提供了见解。