Mechanism of Action For Neural Guidance Factors

神经指导因子的作用机制

• 批准号: 6947911
• 负责人: John G Flanagan
• 金额: $ 36.8万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 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 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6947911
• 关键词: biological signal transduction; ephrins; heparan sulfate; laboratory mouse; laboratory rat; neuronal guidance; nucleic acid sequence; protein binding; protein protein interaction; protein tyrosine phosphatase; proteoglycan; receptor binding; syndecan

The central long-term goal of the project is to understand molecular signaling mechanisms that underly the development of neural connectivity. Many extracellular guidance cues have been identified in the last decade, but the specific molecular pathways involved in their actions are not yet well understood, and are currently an interesting and important area of research. Our main focus is on ephrins and their Eph receptors, which have important functions in axon guidance, dendrite development, and synapse formation. Aim 1 is to investigate downstream signaling mechanisms. A key feature of the ephrins is that they signal bi-directionally, with a 'forward' signal through the receptor, and a 'reverse' signal transduced through the ligand. Reverse signaling pathways have been identified for the transmembrane ephrin-Bs, but signaling by the lipid-anchored ephrin-As is less well understood, and will be a focus of this Aim. Aim 2 is to study upstream regulation of Eph receptors. The focus will be on RNA-based mechanisms that have recently been identified in axons; RNA-based regulation is currently an exciting area of biology generally, and these studies will delineate novel mechanisms in neural development. Aim 3 is to characterize interactions among receptor-like protein tyrosine phosphatases, Eph receptor kinases, and their common theme of regulatory interactions with heparan sulfate proteoglycans. While our primary goal is to elucidate basic molecular mechanisms, the work has broader implications for understanding and treatment of disease. Ephrins and receptor-like protein tyrosine phosphatases have been identified as regulators of CNS axon regeneration. Beyond axonal connectivity, ephrins have important roles in other aspects of biology, including vascular development, cancer, and stem cell biology.

该项目的核心长期目标是了解神经连通性发展的分子信号传导机制。在过去的十年中，已经确定了许多细胞外引导提示，但是涉及其行为所涉及的特定分子途径尚未得到充分了解，目前是一个有趣且重要的研究领域。 我们的主要重点是在轴突引导，树突发展和突触形成中具有重要功能的晶状体及其EPH受体。目的1是研究下游信号传导机制。埃弗林的一个关键特征是它们在双向方向上发出信号，并通过受体的“正向”信号，以及通过配体传递的“反向”信号。已经确定了跨膜ephrin-bs的反向信号通路，但是脂质锚定的ephrin-as的信号传导不太了解，这将是该目标的重点。目的2是研究EPH受体的上游调节。重点将放在基于RNA的 最近在轴突中鉴定出的机制；基于RNA的调节目前是生物学的令人兴奋的领域，这些研究将描述神经发育中的新型机制。目的3是表征受体样蛋白酪氨酸磷酸酶，EPH受体激酶的相互作用及其与乙酰硫酸乙酰肝素蛋白聚糖的调节相互作用的共同主题。尽管我们的主要目标是阐明基本的分子机制，但该工作对理解和治疗疾病具有更广泛的影响。埃弗林和受体样蛋白酪氨酸磷酸酶已被确定为CNS轴突再生的调节剂。除轴突连通性外，埃弗林在生物学的其他方面具有重要作用，包括血管发育，癌症和干细胞生物学。