Mechanisms of Neurotrophin and Ephrin Signal Integration

细胞间通讯是多种多肽因子共同作用的结果。要解释复杂 神经系统中的效应需要了解局部电路和信号转导如何 各条路径都是一体化的。肾上腺素和神经营养素表现出快速和缓慢的长期效应， 需要受体信号以线性停顿的方式进行，但也需要相互影响 直接或通过信号中间体。对肾上腺素和神经营养素的调节可能是 由其受体的相加效应和第二信使的持续时间决定的 磷酸化事件。肾上腺素和神经营养素受体的相互作用及其下游信号转导 蛋白质提供了一种融合不同配体-受体系统的作用的机制，以便 实现新的细胞结果。这个子项目将专注于使用的一组下游底物 由埃弗林和神经营养素受体共同作用。假设是合作和对抗之间的关系 这两个不同的跨膜蛋白系统为细胞外提供了额外的机制 发信号。本研究对早期发育相关疾病的理解和治疗具有重要意义。 障碍，如自闭症，以及神经退行性疾病，如帕金森氏症和阿尔茨海默氏症 和肌萎缩侧索硬化症，这依赖于肾上腺素和神经营养素的作用来纠正 发育图案化和电路形成。 相关性(参见说明)：肾上腺素和神经营养因子是影响 神经系统的许多方面，包括生长锥体引导、轴突生长和更高级别 活动，如突触可塑性。脑源性神经营养因子和肾上腺素参与突触修饰和 海马神经活动。研究神经营养素和肾上腺素的联合作用将有助于 了解它们在发育和退行性疾病中的作用，如阿尔茨海默病和 脊髓损伤。

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 directiy 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. RELEVANCE (See instructions): Ephrins and Neurotrophlns represent major polypeptide factors that influence many aspects ofthe nervous system, including growth cone guidance, axonal growth and higher order activities, such as synaptic plasticity. BDNF and ephrins are involved in synapse modification and hippocampal neural activity. The study of the combined effects of neurotrophins and ephrins will help to understand their roles during development and degenerative diseases, such as Alzheimer's disease and spinal cord injury.