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（由申请人提供）：现在人们普遍认为，童年和青春期大脑回路的结构和生化改变会影响以后的学习、记忆和功能回路，这是一种常见的人类 BDNF 单核苷酸多态性 (SNP)。前结构域导致密码子 66 处验证为甲硫氨酸取代，这为了解 BDNF 在学习和记忆改变中的作用提供了见解，特别是在与恐惧相关的过程领域。迄今为止的体外研究表明，该 SNP 作为功能丧失突变，损害 BDNF 分泌，因此，在具有该 SNP 的人类和敲入小鼠中发现的异常归因于基于生物利用度降低的功能丧失模型。 proBDNF 蛋白水解后产生的分离的前结构域的潜在功能仍然是神秘的，在此，我们提供证据表明 Met 前结构域以活性依赖性方式分泌，充当最近，我们使用 BDNF Met 敲入小鼠获得了两个重要发现，表明 Met 前结构域影响 BDNF 的成熟。特定的大脑回路，导致基于恐惧的学习功能障碍，而 BDNF 缺陷（BDNF+/- 小鼠）并不明显。我们将直接检验 BDNF 的人类 Met 前结构域的假设。是一种生物活性配体，可诱导形态神经元重塑，并解释了该 SNP 对恐惧回路和功能的显着影响。我们将确定 Met 前结构域通过 p75/SorCS2 共受体复合物发出信号以改变培养物中神经元形态的机制。最后，我们将确定 Met 前结构域在恐惧调节的“敏感期”对恐惧消退相关行为的影响。总的来说，这些研究旨在研究 BDNF SNP 可能影响大脑功能的另一种潜在机制。所测试的假设代表了对关键大脑生长因子的生物作用的重大重新概念化。