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

基本信息

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
项目类别：
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&apos 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

项目摘要

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提出了重大挑战。围绕抑制神经细胞体的死亡然而，神经连接依赖于长期。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。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。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、未被发现的因素该项目的目标是定义新颖的。控制受损轴突命运的通路会刺激局部自毁机制。促进免疫系统酶 NMNAT2 和 SARM1 的轴突分解和清除。增强 NMNAT2 具有神经保护作用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。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。