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: 10563209
• 负责人: Daniel Summers
• 金额: $ 37.34万
• 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/10563209
• 关键词: Affect; Alzheimer' s Disease; Apoptosis; Attention; Autophagocytosis; Axon; Axonal Transport; Axotomy; Cell Death; 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; 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; neuroprotection; 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.

神经退行性疾病是对人类健康的重大挑战。许多治疗策略 围绕抑制神经元细胞体的死亡。但是，神经元连通性取决于长时间 称为轴突的项目，使用专门的机制与Soma隔离生存。 轴突的变性是在多种神经退行性疾病中常见的，有时是启动的事件 包括阿尔茨海默氏病，帕金森氏病和周围神经病。保护轴突健康是 维持功能连通性所必需的，并将广泛释放到许多疾病中。疾病 患者之间的发作和严重程度可能会有很大差异，表明存在重要的，未发现的因素 这会影响轴突对病理变性的脆弱性。该项目的目的是定义小说 控制受损轴突的命运的途径。轴突损伤刺激了局部自我毁灭机制，该机制 通过免疫系统促进轴突拆卸和清除。酶NMNAT2和SARM1 在此自我毁灭计划中代表关键的监管节点。增强NMNAT2是神经保护性的， 具有治疗潜力。我们将定义一种控制轴突段中NMNAT2抽象的新机制。 我们还将确定自噬在轴突敏感性和应力信号传导中的新贡献。这些研究 将对控制轴突健康的本地机制产生新的见解，并揭示新的治疗机会 在神经退行性疾病中。