Functional analysis of variant BDNF (Val66Met)

BDNF 变体 (Val66Met) 的功能分析

• 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
• 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

 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，儿童期和青春期期间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。 BDNF 前结构域中常见的人类单核苷酸多态性 (SNP) 导致密码子 66 处被蛋氨酸取代，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 作为功能缺失突变，会损害 BDNF 的分泌。因此，在人类和带有该 SNP 的基因敲入小鼠中发现的异常可归因于基于成熟 BDNF 生物利用度降低的功能模型丧失。 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。在这里，我们提供的证据表明，Met 前结构域以活性依赖性方式分泌，作为独立配体，并通过激活另一组受体 p75NTR 和 SorCS2 来引发对成熟 BDNF 的拮抗生物作用。最近，我们使用 BDNF Met 敲入小鼠获得了两项重要发现，表明 Met 前结构域影响特定脑回路的成熟，导致基于恐惧的学习功能受损，而 BDNF 缺陷（BDNF+/- 小鼠）并不明显。我们将直接检验以下假设：BDNF 的人类 Met 前结构域是一种生物活性配体，可诱导形态神经元重塑，并解释该 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神经元中的神经元形态并影响海马体和前额皮质之间正在发育的恐惧回路的机制。最后，我们将确定 Met 前结构域在青春期过渡期间恐惧调节的“敏感期”对恐惧消退相关行为的影响。总的来说，这些研究旨在调查 BDNF SNP 可能影响大脑功能的另一种潜在机制。测试的假设代表了对关键脑生长因子的生物作用的重大重新概念化。