REGULATION OF AXONAL DEGENERATION BY THE DLK KINASE

描述(由申请人提供)：本提案的长期目标是确定损伤或疾病后促进轴突变性的分子机制。轴突变性是许多神经系统疾病的共同特征。由轴突变性引起的神经病变是糖尿病、青光眼和化疗引起的神经毒性等疾病的特征，轴突丧失是衰弱的神经退行性疾病的早期特征。许多轴突的长度很长，使它们特别容易受到机械损伤，而创伤后的轴突变性是导致残疾的主要原因。最近的研究表明，轴突退变是一个活跃的、高度调控的过程，但促进退变的内在神经机制却知之甚少。这项建议调查了是什么导致轴突退化，以及如何防止这种情况发生。轴突退化是一种活跃的自我毁灭过程，它似乎是自然启动的，并等待触发刺激来激活执行阶段。它是一个循序渐进的过程，从微管失稳开始，然后轴突膜迅速起泡，轴突碎裂，细胞骨架降解，最终被胶质细胞和/或吞噬细胞吞噬。我们现在证明DLK通路在促进损伤后轴突变性的内源性神经元通路中起作用。识别和表征内源性轴突退变途径的组成成分的功能将为深入了解其机制以及许多以轴突退变为特征的神经系统疾病的潜在治疗靶点提供帮助。

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to define the molecular mechanisms that promote axonal degeneration following injury or disease. Axonal degeneration is a common feature of many neurological diseases. Neuropathies due to axonal degeneration are a hallmark of disorders such as diabetes, glaucoma, and chemotherapy-induced neurotoxicity and axonal loss is an early feature of debilitating neurodegenerative diseases. The great length of many axons makes them particularly vulnerable to mechanical injury, and axonal degeneration following trauma is a major cause of disability. Recent studies demonstrate that axonal degeneration is an active and highly regulated process, yet the intrinsic, neuronal mechanism promoting degeneration is poorly understood. This proposal investigates what causes axons to degenerate, and how this can be prevented. Axonal degeneration is an active process of self-destruction that appears to be naturally primed and waiting for a triggering stimulus that activates the execution phase. It proceeds as a stepwise process that begins with microtubule destabilization, followed by rapid blebbing of the axonal membrane, axonal fragmentation, cytoskeletal degradation and eventual engulfment by glial and/or phagocytic cells. We now demonstrate that the DLK pathway functions in the intrinsic neuronal pathway that promotes axonal degeneration following injury. Identifying and characterizing the function of components of the intrinsic axonal degeneration pathway will provide insights into its mechanism as well as potential therapeutic targets for the many neurological diseases characterized by axonal degeneration.