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。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标志，轴突丧失是衰弱性神经退行性疾病的早期特征。许多轴突的大长度使它们特别容易受到机械损伤，创伤后轴突变性是导致残疾的主要原因。近年来的研究表明，轴突变性是一个活跃的、高度调控的过程，但其内在的、促进变性的神经元机制尚不清楚。这一建议调查是什么原因导致轴突退化，以及如何预防这种情况。轴突退化是一种主动的自我毁灭过程，似乎是自然启动的，等待触发刺激激活执行阶段。它是一个循序渐进的过程，从微管不稳定开始，随后是轴突膜的快速起泡，轴突断裂，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在神经元通路中起作用。识别和表征内在轴突变性途径的组成部分的功能将提供对其机制的见解以及许多以轴突变性为特征的神经系统疾病的潜在治疗靶点。

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. PUBLIC HEALTH RELEVANCE: This research is relevant to public health because it will improve our understanding of the mechanism of axonal degeneration following injury and disease. Axonal degeneration is a prominent component of many neurological disorders including neuropathies associated with trauma, diabetes, glaucoma, chemotherapy-induced neurotoxicity, and neurodegenerative diseases. Identifying components of the pathway in axons that promote degeneration will provide insights into the fundamental mechanism underlying axonal degeneration as well as potential therapeutic targets for the many neurological diseases characterized by axonal degeneration.