The Function and Mechanisms of Autophagy in Spinal Cord Injury

自噬在脊髓损伤中的功能和机制

• 批准号: 10439021
• 负责人: MARTA M LIPINSKI
• 金额: $ 223.18万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10439021
• 关键词: Administrative Supplement; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Animals; Autophagocytosis; Behavior; Biochemical; Brain; Brain Injuries; Brain Pathology; Cell Death; Cells; Chronic; Cognitive; Data; Defect; Dementia; Development; Early Intervention; Elderly; Encephalitis; Flow Cytometry; Functional disorder; Goals; Grant; Healthcare; Homeostasis; Hyperesthesia; Impaired cognition; Impairment; Inflammasome; Inflammation; Inflammatory Response; Injury; Innate Immune Response; Interferons; Knock-in Mouse; Life Expectancy; Link; Lipids; Long-Term Effects; Lysosomal Function Inhibition; Mass Spectrum Analysis; Mediating; Mental Depression; Microglia; Microscopy; Mus; Mutant Strains Mice; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Organelles; Outcome; Pathologic; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Phenotype; Pilot Projects; Population; Population Study; Proteins; Quality Control; Rattus; Recovery; Research; Risk; Risk Factors; Role; Senile Plaques; Site; Spinal cord injury; Testing; Therapeutic Effect; Therapeutic Intervention; Trehalose; Work; age related; aged; aging brain; axon injury; base; cell injury; dementia risk; design; falls; functional outcomes; high risk; improved; inhibition of autophagy; injured; innovation; lipid metabolism; lipidomics; neuroinflammation; neuron loss; novel; population based; progressive neurodegeneration; protein aggregation; proteostasis; tau-1; traumatic event; young adult

Project Summary With recent advances in treatment and healthcare, life expectancy for persons following spinal cord injury (SCI) has increased substantially for several decades after their traumatic event. Moreover, given increased falls in the elderly, the risk of SCI has been increasing in that population. Although aging is a key risk factor for cognitive decline and incident Alzheimer’s Disease and Related Dementia (AD/ADRD), recent large-scale longitudinal population-based studies indicate that patients with SCI are at a high risk of dementia associated with substantial cognitive decline. This represents an unmet health-care challenge. However, there is a lack of information in the brain pertaining to the natural brain aging and brain aging trajectories of AD/ADRD following SCI. Such information is needed for the design of targeted, early interventions aimed at reducing the risk of cognitive decline after SCI. The autophagy-lysosomal pathway is essential for intracellular lipid, protein, and organelle degradation and quality control. Impaired autophagy is strongly implicated in accumulation of pathological protein aggregates such as phospho-tau tangles and amyloid β plaques and consequent neuronal cell damage and death in neurodegenerative diseases. Recent data indicate that age related decline in autophagy and lysosomal function in the brain was exacerbated by SCI. This was accompanied by increased brain inflammation and neurodegeneration, suggesting that perturbation of autophagy may provide a mechanistic link between SCI and AD/ADRD. Moreover, disruption of lipid homeostasis in the aged brain may contribute to autophagy defects. We hypothesize that SCI accelerates inhibition of autophagy-lysosomal function in the ageing brain through perturbation of lysosomal lipid homeostasis, ultimately aggravating long- term pathological and functional outcomes and increasing posttraumatic dementia risk. We will use young adult and aged animals with autophagy hypomorph or heperactivation to delineate the roles of autophagy-lysosomal pathway as a key regulator of brain pathology in SCI. HILIC-MS/MS based lipidomics, flow cytometry, complementary microscopy and biochemical approaches will be used in AIM 1 to determine if lipid accumulation causes lysosomal dysfunction and inhibition of autophagy in the ageing brain after SCI. AIM 2 will determine if inhibition of precision autophagy in the ageing brain after SCI leads to exacerbated inflammation and neurodegeneration increasing dementia risk. Using becn1 mutant mice with autophagy heperactivation or a naturally occurring autophagy inducer trehalose in aged mice or mice aging after SCI, AIM 3 will evaluate long-term effects of increased autophagy on proteostasis, neuroinflammation, neurodegeneration and cognitive outcomes relevant to AD/ADRD after SCI. The information gained from these highly significant and innovative studies will have an important positive impact through identifying autophagy-lysosomal function in the link between SCI and AD/dementia and through the development of novel potential therapeutic interventions.

项目摘要 随着治疗和医疗保健的最新进展，脊髓损伤（SCI）患者的预期寿命 在他们的创伤事件发生后的几十年里，此外，鉴于增加的福尔斯， 在老年人中，SCI的风险一直在增加。虽然衰老是一个关键的风险因素， 认知能力下降和阿尔茨海默病及相关痴呆（AD/ADRD）事件，最近大规模 基于人群的纵向研究表明，SCI患者患痴呆的风险很高， 认知能力严重下降这是一个尚未解决的保健挑战。然而，缺乏 脑中与AD/ADRD的自然脑老化和脑老化轨迹有关的信息， SCI.需要这些信息来设计有针对性的早期干预措施， SCI后认知功能下降自噬-溶酶体途径对于细胞内脂质、蛋白质和 细胞器降解和质量控制。受损的自噬强烈地暗示着 病理性蛋白质聚集体，例如磷酸化-tau缠结和淀粉样蛋白β斑块，以及随后的神经元 神经退行性疾病中的细胞损伤和死亡。最近的数据表明， 自噬和溶酶体功能在脑中被SCI加重。与此同时， 脑炎症和神经变性，这表明自噬的扰动可能提供了一个 SCI和AD/ADRD之间的机制联系。此外，老年大脑中脂质稳态的破坏可能 导致自噬缺陷我们假设SCI加速了对自噬-溶酶体的抑制， 通过扰乱溶酶体脂质体内平衡，最终加重长- 长期病理和功能结果以及增加的创伤后痴呆风险。 我们将使用年轻的成年和老年动物与自噬低态或肝激活，以描绘 自噬-溶酶体途径在SCI脑病理中的作用。基于HILIC-MS/MS 脂质组学、流式细胞术、互补显微镜和生物化学方法将用于AIM 1， 确定脂质积累是否会导致溶酶体功能障碍和衰老大脑中自噬的抑制 SCI之后AIM 2将确定SCI后衰老大脑中精确自噬的抑制是否会导致 炎症和神经退行性变加剧，增加痴呆风险。使用Becn 1突变小鼠， 自噬过度活化或天然存在的自噬诱导剂海藻糖在老年小鼠或小鼠衰老中的作用 SCI后，AIM 3将评估增加的自噬对蛋白质稳态，神经炎症， 与SCI后AD/ADRD相关的神经变性和认知结果。 从这些非常重要和创新的研究中获得的信息将具有重要意义。 通过确定SCI和AD/痴呆之间联系中的自噬-溶酶体功能产生积极影响， 通过开发新的潜在治疗干预措施。