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都出现在棘突上，它们是动态结构，在发育过程中的大小，形状和数量发生变化，并响应生理刺激，例如神经元活动和学习。该研究项目的总体目标是阐明调节树突状形态发生的分子机制。脊柱发育包括形成，成熟和修剪。尽管已经发现许多蛋白质对于脊柱的形成很重要，但尚未完全了解控制脊柱形成的分子途径。关于调节脊柱发育后期阶段的分子机制，尤其是脊柱修剪，这是一个依赖活性的过程，并且可能在突触连接的完善中起重要作用。脑衍生的神经营养因子（BDNF）的基因产生两个mRNA，其短或长3'未翻译区域（3'UTR）。我们最近的发现表明，短3'UTR BDNF mRNA仅限于SOMA，而长3'UTR BDNF mRNA也被运送到树突上进行局部翻译。 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障碍。这些假设将以三个特定目的进行检验。具体目的1提议检查培养的大鼠海马神经元中脊柱形态发生中体形和树突合成的BDNF的不同作用。具体目的2提议阐明信号传导级联反应介导BDNF对刺的形成，成熟和修剪的影响。具体目标3提出，确定人SNP在长BDNF 3'UTR中对脊柱形态发生和突触可塑性的影响。这些研究的发现可能揭示了有关基因功能和脊柱形态发生的新型机制，并提供了对非编码序列中SNP的功能后果的见解。