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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：
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.