Mechanisms of Neurotrophin and Ephrin Signal Integration

神经营养素和肝配蛋白信号整合的机制

• 批准号: 8733290
• 负责人: CHERYL F DREYFUS
• 金额: $ 40.4万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-03 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8733290
• 关键词: Adaptor Signaling Protein; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Ankyrin Repeat; Autistic Disorder; Behavior; Biochemical; Biological; Biological Assay; Brain-Derived Neurotrophic Factor; Cell Communication; Cells; Complex; Data; Degenerative Disorder; Development; Early treatment; Eph Family Receptors; Ephrins; Event; Growth; Growth Cones; Hippocampus (Brain); Instruction; Integral Membrane Protein; Learning; Ligands; Mediating; Membrane; Memory; Modification; Molecular; Morphology; Nerve Growth Factor Receptors; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Neurons; Outcome; Parkinson Disease; Pattern; Phosphorylation; Play; Proteins; Receptor Signaling; Regulation; Research; Research Personnel; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Protein; Spinal cord injury; Synapses; Synaptic Transmission; Synaptic plasticity; System; Vertebral column; axon growth; axon guidance; density; developmental disease; domain mapping; extracellular; gain of function; loss of function; neurotrophic factor; novel; polypeptide; receptor; relating to nervous system; second messenger; transcriptional coactivator p75

Cell-cell communication represents the combined effects of multiple polypeptide factors. To explain complex effects in the nervous system requires an understanding of how local circuits and signal transduction pathways are integrated. Ephrins and Neurotrophins display both rapid and slower long lasting effects that require receptor signaling to proceed in a linear stop-wise fashion, but also influence each other, either directly or through signaling intermediates. Regulation of Ephrins and Neurotrophins is likely to be determined by the additive effects of their receptors and the duration of second messengers and phosphorylation events. Interactions between Ephrin and Neurotrophin receptors and downstream signaling proteins provide a mechanism for merging the actions of different ligand-receptor systems in order to achieve novel cellular outcomes. This subproject will focus on a set of downstream substrates that are used by both Ephrin and Neurotrophin receptors. The hypothesis is that cooperativity and antagonism between these two different transmembrane protein systems provide additional mechanisms for extracellular signaling. The proposed research is relevant to the understanding and treatment of early developmental disorders, such as autism, and neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases and amyotrophic lateral sclerosis, which depend upon the actions of Ephrins and Neurotrophins for correct developmental patterning and circuit formation.

细胞间通讯是多种多肽因子共同作用的结果。解释复杂 神经系统的影响需要了解局部电路和信号转导 道路是一体化的。肝配蛋白和神经营养蛋白显示快速和缓慢的持久作用， 需要受体信号传导以线性停止方式进行，但也相互影响， 直接或通过信号传导中间体。Ephrin和神经营养因子的调节可能是 由其受体的累加效应和第二信使的持续时间决定， 磷酸化事件。Ephrin和神经营养素受体之间的相互作用及其下游信号传导 蛋白质提供了一种机制，用于合并不同配体-受体系统的作用， 实现新的细胞结果。这个子项目将集中在一套下游基板， 由肝配蛋白和神经营养因子受体共同作用。假设是， 这两种不同的跨膜蛋白系统提供了细胞外 发信号。这项研究有助于理解和治疗早期发育性 自闭症等疾病以及帕金森病和阿尔茨海默病等神经退行性疾病 和肌萎缩侧索硬化症，这取决于行动的肝配蛋白和神经营养因子的正确 发育模式和回路形成。