Identifying mechanisms that regulate local axon vulnerability to pathological degeneration

识别调节局部轴突易受病理变性影响的机制

• 批准号: 10415770
• 负责人: Daniel Summers
• 金额: $ 37.37万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10415770
• 关键词: Affect; Alzheimer' s Disease; Apoptosis; Attention; Autophagocytosis; Axon; Axonal Transport; Axotomy; Cessation of life; Chemotherapy-induced peripheral neuropathy; Chronic; Clinical; Cytoskeleton; Cytosol; Data; Disease; Distal; Dynein ATPase; Enzymes; Event; Future; Gatekeeping; Genes; Genetic; Genetic Epistasis; Goals; Health; Homeostasis; Human; Human body; Hydrolase; Image; Immune system; Investigation; Knockout Mice; MAP Kinase Gene; Mediating; Membrane; Modeling; Molecular; Nerve Degeneration; Nerve Fibers; Nervous system structure; Neurobiology; Neurodegenerative Disorders; Neurons; Onset of illness; Optic Nerve; Outcome; Parkinson Disease; Pathologic; Pathway interactions; Patients; Peripheral Nervous System; Peripheral Nervous System Diseases; Pharmacology; Predisposition; Recycling; Research; Role; Sensory; Severities; Severity of illness; Signal Transduction; Stress; Therapeutic; Trauma; Traumatic Brain Injury; Work; axon injury; axonal degeneration; immune clearance; improved; in vivo; insight; nerve damage; neuron loss; neuronal cell body; novel; programs; protein aggregation; proteostasis; response; trafficking

Neurodegenerative disorders represent a significant challenge to human health. Many therapeutic strategies revolve around suppressing death of the neuronal cell body. However, neuronal connectivity depends on long projections called axons that use specialized mechanisms to survive in isolation from the soma. The degeneration of axons is a common, sometimes initiating event in a variety of neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, and peripheral neuropathies. Protecting axon health is necessary for sustaining functional connectivity and will have broad relevance to many diseases. Disease onset and severity can vary significantly between patients suggesting there are important, undiscovered factors that influence axon vulnerability to pathological degeneration. The goal of this project is to define novel pathways controlling the fate of a damaged axon. Axon injury stimulates a local self-destruct mechanism that promotes axon dismantling and clearance by the immune system. The enzymes NMNAT2 and SARM1 represent a critical regulatory node in this self-destruction program. Boosting NMNAT2 is neuroprotective and has therapeutic potential. We will define a new mechanism controlling NMNAT2 abundance in axon segments. We will also identify new contributions for autophagy in axon susceptibility and stress signaling. These studies will generate new insight on local mechanisms controlling axon health and reveal new treatment opportunities in neurodegenerative diseases.

神经退行性疾病对人类健康构成重大挑战。许多治疗策略 围绕抑制神经元细胞体的死亡。然而，神经元连接依赖于长 称为轴突的投影使用专门的机制在与躯体隔离的情况下生存。这 轴突变性是多种神经退行性疾病中的常见现象，有时甚至是始发事件 包括阿尔茨海默病、帕金森病和周围神经病。保护轴突健康是 维持功能连接所必需的，并且与许多疾病具有广泛的相关性。疾病 患者之间的发病和严重程度可能存在显着差异，这表明存在重要的、未被发现的因素 影响轴突对病理退化的脆弱性。该项目的目标是定义新颖的 控制受损轴突命运的途径。轴突损伤会刺激局部自毁机制 促进轴突的分解和免疫系统的清除。 NMNAT2 和 SARM1 酶 代表了这个自毁计划中的一个关键监管节点。增强 NMNAT2 具有神经保护作用 具有治疗潜力。我们将定义一种控制轴突片段中 NMNAT2 丰度的新机制。 我们还将确定自噬在轴突易感性和应激信号传导中的新贡献。这些研究 将产生对控制轴突健康的局部机制的新见解并揭示新的治疗机会 在神经退行性疾病中。