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Human VGF Polymorphisms and Depression

人类 VGF 多态性与抑郁症

基本信息

批准号：
7618790
负责人：
STEPHEN R SALTON
金额：
$ 16.95万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7618790
关键词：
3&apos Untranslated Regions 7q22.1 Adult Aging Alder plant Alleles Alzheimer&apos s Disease Amino Acids Antidepressive Agents Anxiety Autistic Disorder Backcrossings Behavior Behavior Disorders Behavioral Brain Brain-Derived Neurotrophic Factor C-terminal CREB1 gene Candidate Disease Gene Chemosensitization Childhood Cloning Code Cognition Cognitive DNA Data Degenerative Disorder Development Electroconvulsive Therapy Endocrine Excision Exercise Exons FLP recombinase Fright Funding Gene Dosage Gene Targeting Generations Genes Genetic Polymorphism Genomics Germ Lines Gills Growth Factor Hippocampus (Brain)Homeostasis Homologous Gene Human Human Genetics Impaired cognition In Vitro Inbreeding Infusion procedures Injection of therapeutic agent Introns Investigation Knock-in Mouse Knock-out Knockout Mice Lead Length Long-Term Potentiation Memory Methods Michigan Molecular Mood Disorders Motor Activity Mus Mutant Strains Mice NTF3 gene Neomycin Nervous System Physiology Nervous system structure Neurons Nonsense Codon Nucleotides Pathway interactions Patients Peptides Performance Phase Phenotype Play Positioning Attribute Process Proteins Public Health Publishing Rattus Regulation Reproductive Behavior Risk Rivers Role Rome Schizophrenia Seizures Signal Transduction Single Nucleotide Polymorphism Single Nucleotide Polymorphism Map Single base substitution Site Slice Sorting - Cell Movement Swimming Synaptic plasticity Tail Suspension Technology Terminator Codon Testing Universities Untranslated Regions VGF protein Variant Yang behavior test blastocyst conditioned fear depressed depression depressive symptoms embryonic stem cell energy balance homologous recombination in vivo insight lateral ventricle mRNA Expression morris water maze mouse model natural Blastocyst Implantation neuron development neurotrophic factor novel particle polypeptide preimplantation premature recombinase research study response synaptogenesis transcription factor

项目摘要

DESCRIPTION (provided by applicant): Growth factors in general, and brain-derived neurotrophic factor (BDNF) in particular, play critical roles in the nervous system to regulate neuronal development and survival, axonal outgrowth, synaptogenesis, and synaptic plasticity. BDNF signaling modifies depressive behavior, and a large number of studies demonstrate additional roles for BDNF/TrkB pathways in contextual fear conditioning and spatial memory, as well as in the regulation of synaptic plasticity and the induction of long term potentiation (LTP). These functions likely depend on genes or gene products that BDNF regulates at the transcriptional, translational or post-translational levels, several via activation of the transcription factor CREB, a critical molecular regulator of memory in a number of different species. However, few candidate genes downstream of neurotrophins and CREB that contribute to memory formation have been identified. Recent studies suggest that VGF, a neuronal secreted protein and peptide precursor that is rapidly induced by the neurotrophins BDNF, NGF and NT3, plays a role in memory formation. VGF-derived peptides are known to regulate synaptic plasticity, reproductive behavior and energy balance. Recent human genetic SNP mapping has identified a VGF polymorphism that results in premature VGF termination after amino acid 524, eliminating several bioactive VGF peptides and an alpha-helical region required for regulated secretion. Preliminary data included in this proposal show that VGF C-terminal peptides have anti-depressant efficacy and also regulate hippocampal neuronal electrical excitability and synaptic plasticity in hippocampal slices, consistent with impaired performance of VGF knockout mice in spatial memory tasks (e.g. Morris water maze) and contextual fear conditioning. In Aim 1 of the R21 phase, we will develop two mouse models that knock human VGF alleles into the mouse Vgf locus, encoding either full length human VGF (amino acids 1-615) or SNP-truncated VGF (amino acids 1-524). In Aim 1 of the R33 phase, we will test expression and function of human VGF in these mouse models, determining whether carriers of this polymorphism could be predisposed to depression and impaired cognition, much as those with aberrant BDNF expression and/or signaling are at risk for memory and behavioral disorders. Performance of VGF knock-in mice will be examined in spatial and contextual fear memory tasks, and in depression and anxiety testing. Overall, the proposed experiments will investigate the roles that VGF, VGF-derived peptides, and a specific polymorphism in the human VGF gene, play in the regulation of hippocampal synaptic plasticity, depression, and hippocampal-dependent memory. Relevance to Public Health: Characterization of the molecules and mechanisms that control cognition and behavior will lead to increased understanding of brain function and memory, both of which are clearly impacted by aging, by degenerative diseases such as Alzheimer's or ALS, and by mood disorders such as depression. to Public Health: Neurotrophic growth factors play critical roles in the nervous system to regulate brain development and function, but few candidate genes have been identified that are induced by neurotrophins and contribute to memory formation and behavior. Characterization of the molecules and mechanisms that control cognition and behavior will lead to increased understanding of brain function and memory, both of which are clearly impacted by aging, by degenerative diseases such as Alzheimer's or ALS, and by mood disorders such as depression.

描述（由申请人提供）：生长因子，特别是脑源性神经营养因子（BDNF），在神经系统中起着调节神经元发育和存活、轴突生长、突触发生和突触可塑性的关键作用。BDNF信号传导改变抑郁行为，大量研究表明BDNF/TrkB通路在情境恐惧条件反射和空间记忆中以及在突触可塑性的调节和长时程增强（LTP）的诱导中具有额外的作用。这些功能可能取决于BDNF在转录、翻译或翻译后水平上调节的基因或基因产物，其中一些是通过激活转录因子CREB来调节的，CREB是许多不同物种中记忆的关键分子调节因子。然而，很少有候选基因下游的神经营养因子和CREB，有助于记忆的形成已被确定。最近的研究表明，VGF是一种神经元分泌的蛋白质和肽前体，由神经营养因子BDNF、NGF和NT 3快速诱导，在记忆形成中起作用。已知VEGF衍生肽调节突触可塑性、生殖行为和能量平衡。最近的人类遗传SNP作图已经鉴定了VGF多态性，其导致VGF在氨基酸524后过早终止，消除了几种生物活性VGF肽和调节分泌所需的α-螺旋区域。本提案中包含的初步数据表明，VGF C-末端肽具有抗抑郁功效，并且还调节海马切片中海马神经元电兴奋性和突触可塑性，这与VGF敲除小鼠在空间记忆任务（例如Morris水迷宫）和情境恐惧条件反射中的受损表现一致。在R21阶段的目标1中，我们将开发两种小鼠模型，其将人VGF等位基因敲入小鼠Vgf基因座，编码全长人VGF（氨基酸1-615）或SNP截短的VGF（氨基酸1-524）。在R33阶段的目标1中，我们将在这些小鼠模型中测试人VGF的表达和功能，确定这种多态性的携带者是否易患抑郁症和认知障碍，就像那些具有异常BDNF表达和/或信号传导的人有记忆和行为障碍的风险一样。将在空间和背景恐惧记忆任务以及抑郁和焦虑测试中检查VGF敲入小鼠的表现。总体而言，拟议的实验将调查的作用，VGF，VGF衍生的肽，和一个特定的多态性在人类VGF基因，在调节海马突触可塑性，抑郁症，和海马依赖性记忆。与公共卫生的相关性：控制认知和行为的分子和机制的表征将导致对大脑功能和记忆的更多理解，这两者都明显受到衰老，退行性疾病如阿尔茨海默氏症或ALS以及情绪障碍如抑郁症的影响。公共卫生：神经营养生长因子在神经系统中起着调节大脑发育和功能的关键作用，但很少有候选基因被确定为由神经营养因子诱导并有助于记忆形成和行为。控制认知和行为的分子和机制的表征将导致对大脑功能和记忆的更多理解，这两者都明显受到衰老，退行性疾病如阿尔茨海默氏症或ALS以及情绪障碍如抑郁症的影响。