Mechanism of Action For Neural Guidance Factors

该项目的中心长期目标是了解神经连接发展的分子信号机制。在过去的十年中，已经确定了许多细胞外指导线索，但参与其作用的特定分子途径尚未得到很好的理解，目前是一个有趣且重要的研究领域。 我们的主要重点是ephrin及其Eph受体，它们在轴突导向、树突发育和突触形成中具有重要功能。目的1是研究下游信号传导机制。肝配蛋白的一个关键特征是它们双向信号传导，通过受体传递“正向”信号，通过配体传递“反向”信号。反向信号通路已被确定为跨膜肝配蛋白-Bs，但信号的脂质锚定肝配蛋白-As是不太好理解，这将是一个焦点的目的。目的二是研究Eph受体的上游调控。重点将是基于RNA的 最近在轴突中发现的机制;基于RNA的调节目前是生物学的一个令人兴奋的领域，这些研究将描绘神经发育的新机制。目的3是表征受体样蛋白酪氨酸磷酸酶，Eph受体激酶之间的相互作用，以及它们与硫酸乙酰肝素蛋白聚糖的共同调控作用。虽然我们的主要目标是阐明基本的分子机制，但这项工作对理解和治疗疾病具有更广泛的意义。肝配蛋白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。除了轴突连接，肝配蛋白在生物学的其他方面也有重要作用，包括血管发育、癌症和干细胞生物学。

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.