Functional analysis of variant BDNF (Val66Met)

BDNF 变体 (Val66Met) 的功能分析

基本信息

批准号：
8914167
负责人：
BARBARA L HEMPSTEAD
金额：
$ 45.95万
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 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8914167
关键词：
Actins Acute Adolescence Adolescent Affect Agonist Animal Model Anxiety Behavior Behavior Therapy Behavioral Biochemical Biological Biological Availability Brain Brain-Derived Neurotrophic Factor Child Childhood Cleaved cell Codon Nucleotides Cognitive Therapy Complex Cues Deformity Dendritic Spines Dense Core Vesicle Disease Event Exhibits Exposure to Extinction (Psychology)Family member Fright Gene Expression Goals Grant Growth Growth Cones Growth Factor Hippocampus (Brain)Human Human Genetics Impairment In Vitro Investigation Knock-in Mouse Knock-out Knockout Mice Label Learning Life Ligands Link Mediating Memory Mental disorders Methionine Microscopy Modeling Morphology Mus NGFR Protein Neuronal Plasticity Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Pathway interactions Patients Phenotype Play Post-Traumatic Stress Disorders Prefrontal Cortex Process Proteolysis Publishing Regulation Reporter Research Design Resolution Risk Role Signal Pathway Signal Transduction Single Nucleotide Polymorphism Site Structure Synaptic plasticity Techniques Testing Time Translating Valine Variant Wild Type Mouse axon growth base brain circuitry classical conditioning clinically significant depolymerization drug discovery evidence base fascin functional disability gain of function insight learning extinction loss of function loss of function mutation meetings mutant neural circuit neuronal survival neurophysiology neuropsychiatry novel public health relevance receptor research study sortilin stress related disorder trafficking transcriptional coactivator p75

项目摘要

DESCRIPTION (provided by applicant): It is now well-accepted that structural and biochemical alterations in brain circuitry during childhood and adolescence can affect learning, memory, and functional circuitry later in life. A common human single nucleotide polymorphism (SNP) in the BDNF prodomain that leads to valise-to-methionine substitution at codon 66 has provided insights into the role of BDNF in altered learning and memory, especially in the realm of fear-related processes. In vitro studies to date have suggested that this SNP acts as a loss of function mutation that impairs BDNF secretion. Thus, the abnormalities found in humans and knock-in mice with this SNP have been attributed to a loss of function model based on decreased bioavailability of mature BDNF. The potential function(s) of the isolated prodomain generated after proteolysis of proBDNF remain cryptic. Here, we provide evidence that the Met prodomain is secreted in an activity-dependent manner, acts as an independent ligand, and elicits antagonistic biological actions to mature BDNF, by activating an alternate set of receptors, p75NTR and SorCS2. Recently, we have made two key findings using the BDNF Met knock-in mouse that suggest that the Met prodomain affects the maturation of a specific brain circuit, leading to functional impairments in fear- based learning that is not evident with BDNF deficiency (BDNF+/- mice). We will directly test the hypothesis that the human Met prodomain of BDNF is a biologically active ligand that induces morphological neuronal remodeling, and explains the significant impact of this SNP on fear circuitry and function. We will identify the mechanisms by which Met prodomain signals through a p75/SorCS2 co-receptor complex to alter neuronal morphology in cultured neurons and affect the developing fear circuitry between the hippocampus and prefrontal cortex. Finally, we will determine the impact of the Met prodomain in fear extinction-related behaviors during a "sensitive period" for fear regulation during the transition into adolescence. Collectively, these studies are designed to investigate an additional potential mechanism by which the BDNF SNP may impact brain function. The hypotheses tested represent a significant reconceptualization of the biological actions of a key brain growth factor.

描述（由适用提供）：现在众所周知，儿童期和青少年期间脑电路的结构和生化改变会影响以后生活中的学习，记忆和功能电路。 BDNF Prodomain中的一种常见的人类单核Otaly多态性（SNP），导致密码子66的valise to-Methionine取代，已为BDNF在改变学习和记忆中的作用提供了见解，尤其是在与恐惧相关过程的领域中。迄今为止，体外研究表明，该SNP充当损害BDNF分泌的功能突变的丧失。这是在人类和使用该SNP的敲门小鼠中发现的异常，这归因于基于成熟BDNF的生物利用度下降的功能模型的丧失。 probdnf的蛋白水解后产生的分离prodomain的潜在功能仍然是密码学。在这里，我们提供的证据表明，MET Prodomain以活性依赖性的方式分泌，充当独立的配体，并通过激活一组替代的受体P75NTR和SORCS2，从而引发拮抗生物学作用来成熟BDNF。最近，我们使用BDNF MET敲入小鼠进行了两个关键发现，这表明MET Prodomain会影响特定的脑电路的成熟，从而导致基于恐惧的学习中的功能障碍，而BDNF缺乏症（BDNF +//-小鼠）并未证明。我们将直接检验以下假设：BDNF的人类MET Prodomain是一种具有生物活性的配体，可诱导形态神经元重塑，并解释了该SNP对恐惧电路和功能的显着影响。我们将通过P75/Sorcs2共受体复合物确定符合Prodomain信号的机制，以改变培养的神经元中的神经元形态，并影响海马和前额叶皮层之间发展的恐惧回路。最后，我们将确定在“敏感时期”期间与恐惧扩展相关的行为中MET Prodomain在过渡到青少年期间的恐惧调节中的影响。总的来说，这些研究旨在研究BDNF SNP可能影响大脑功能的其他潜在机制。所测试的假设代表了关键大脑生长因子的生物学作用的重大重新概念化。