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Functional analysis of variant BDNF (Val66Met)

BDNF 变体 (Val66Met) 的功能分析

基本信息

批准号：
7586209
负责人：
Francis Sang Yong Lee
金额：
$ 34.19万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7586209
关键词：
Address Affect Behavioral Binding Biochemical Biological Biological Assay Brain-Derived Neurotrophic Factor Cells Clinical Clinical Pathology Codon Nucleotides Cognitive Defect Disease Epitopes Event Genes Genetic Polymorphism Golgi Apparatus Hippocampus (Brain)Human Impaired cognition Impairment In Vitro Knock-in Mouse Lead Learning Link Mediating Memory Memory impairment Methionine Microscopy Molecular Mus Nervous System Physiology Neuraxis Neurons Pathway interactions Physiological Play Positioning Attribute Predisposition Process Proteins Research Design Research Personnel Research Proposals Role Signal Transduction Single Nucleotide Polymorphism Sorting - Cell Movement Structure Symptoms Tertiary Protein Structure Transgenic Organisms Valine Variant base follow-up in vivo insight nervous system development neuronal survival neuropsychiatry neurotrophic factor novel overexpression polypeptide programs research study response sortilin tool trafficking

项目摘要

DESCRIPTION (provided by applicant): Brain derived neurotrophic factor (BDNF) plays critical roles in vertebrate nervous system development and function. Recently, a single nucleotide polymorphism (Val66Met) in the BDNF gene leading to a prodomain substitution at position 66 from a valine (Val) to methionme (Met) has been shown to lead in humans to hippocampal dependent memory impairments and susceptibility to neuropsychiatric disorders. This BDNF polymorphism represents the first alteration in a neurotrophin that has been linked to clinical pathology. Less is known about the molecular mechanisms underlying altered variant BDNF (BDNFMet) functioning. When overexpressed in hippocampal neurons, BDNFMet has reduced activity dependent secretion, suggesting the presence of a specific signal in the BDNF prodomain that is required for efficient BDNF trafficking to the regulated secretory pathway. Preliminary studies suggest the hypothesis that BDNFMet aberrantly engages the highly specialized biochemical mechanisms that regulate BDNF trafficking to secretory pathways, which are critical determinants of BDNF's biological responses. The proposed studies are designed to identify specific proteins that regulate aberrant BDNFMet trafficking, and to examine the in vivo consequences on hippocampal structure and function. Experiments in this proposal will primarily utilize a novel transgenic knock-in mouse expressing an epitope tagged version of variant BDNF (BDNF 9 e) to enable assessment of BDNFMet trafficking events under endogenously expressed conditions and analysis of in vivo consequences on hippocampal structure and function. The Specific Aims of the proposed studies are to 1) define the trafficking defect and functional consequences in neurons endogenously expressing BDNFMet, 2) identify proteins that are involved in aberrant BDNFMet trafficking, and 3) determine the in vivo consequences of BDNFMet on hippocampal function. These studies will contribute to a fundamental molecular understanding of the mechanisms that underlie aberrant BDNFMet trafficking in neurons, and directly address the physiological relevance of this variant BDNF on hippocampal function.

描述（由申请人提供）：脑源性神经营养因子（BDNF）在脊椎动物神经系统的发育和功能中发挥着关键作用。最近，BDNF 基因中的单核苷酸多态性 (Val66Met) 导致 66 位前结构域从缬氨酸 (Val) 替换为甲硫氨酸 (Met)，已被证明会导致人类海马依赖性记忆障碍和对神经精神疾病的易感性。这种 BDNF 多态性代表了神经营养蛋白中与临床病理学相关的第一个改变。关于 BDNF 变异体 (BDNFMet) 功能改变的分子机制知之甚少。当在海马神经元中过度表达时，BDNFMe 会减少活性依赖性分泌，表明 BDNF 前结构域中存在特定信号，这是有效地将 BDNF 运输到受调节的分泌途径所必需的。初步研究表明，BDNFMet 异常参与高度专业化的生化机制，调节 BDNF 运输到分泌途径，这是 BDNF 生物反应的关键决定因素。拟议的研究旨在识别调节异常 BDNFMet 运输的特定蛋白质，并检查对海马结构和功能的体内影响。本提案中的实验将主要利用表达突变 BDNF (BDNF 9 e) 表位标记版本的新型转基因敲入小鼠，以在内源表达条件下评估 BDNFMet 运输事件，并分析对海马结构和功能的体内影响。拟议研究的具体目标是 1) 定义内源性表达 BDNFMet 的神经元的运输缺陷和功能后果，2) 识别参与异常 BDNFMet 运输的蛋白质，3) 确定 BDNFMet 对海马功能的体内影响。这些研究将有助于从分子角度理解神经元异常 BDNFMe 运输的机制，并直接解决这种变异 BDNF 对海马功能的生理相关性。