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。由于轴突变性引起的神经病变是诸如糖尿病、青光眼和化疗诱导的神经毒性的病症的标志，并且轴突损失是使人衰弱的神经变性疾病的早期特征。许多轴突的长度使得它们特别容易受到机械损伤，并且创伤后的轴突变性是残疾的主要原因。最近的研究表明，轴突变性是一个积极的和高度调节的过程，但内在的，神经元的机制，促进变性知之甚少。这项提议调查了是什么原因导致轴突退化，以及如何防止这种情况。 轴突退化是一个自我毁灭的主动过程，似乎是自然引发的，并等待一个触发刺激，激活执行阶段。它作为一个逐步的过程进行，开始与微管不稳定，然后是轴突膜的快速起泡，轴突碎片，细胞骨架降解和最终被神经胶质细胞和/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。识别和表征内源性轴突变性通路的组分的功能将为其机制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提供见解。

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.