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.

项目概要 随着治疗和医疗保健的最新进展，脊髓损伤 (SCI) 患者的预期寿命有所延长 此外，由于跌倒次数的增加，他们的创伤性事件发生后的几十年里，这一数字大幅增加。 尽管老龄化是一个关键的危险因素，但老年人群中 SCI 的风险一直在增加。 认知能力下降和阿尔茨海默氏病和相关痴呆（AD/ADRD）事件，最近大规模 基于人群的纵向研究表明 SCI 患者患痴呆症的风险很高 认知能力显着下降，这是一个未得到满足的医疗保健挑战。 大脑中有关 AD/ADRD 的自然大脑衰老和大脑衰老轨迹的信息 SCI 需要此类信息来设计旨在降低风险的有针对性的早期干预措施。 SCI 后认知能力下降。自噬-溶酶体途径对于细胞内脂质、蛋白质和蛋白质至关重要。 细胞器降解和质量控制受损与自噬的积累密切相关。 病理性蛋白质聚集体，例如磷酸 tau 缠结和 β 淀粉样蛋白斑块以及随后的神经元 最近的数据表明，神经退行性疾病中的细胞损伤和死亡与年龄相关。 SCI 会加剧大脑中的自噬和溶酶体功能。 脑炎症和神经退行性变，表明自噬的扰动可能提供 此外，老年大脑脂质稳态的破坏可能与 SCI 和 AD/ADRD 之间存在机制联系。 我们勇敢地承认 SCI 加速了自噬溶酶体的抑制。 通过扰动溶酶体脂质稳态来影响衰老大脑的功能，最终加剧长期 足月病理和功能结果以及增加创伤后痴呆风险。 我们将使用具有自噬亚型或超激活的年轻人和老年动物来描绘 自噬-溶酶体途径作为基于 HILIC-MS/MS 的脑病理学关键调节因子的作用。 AIM 1 将使用脂质组学、流式细胞术、互补显微镜和生化方法来 确定脂质积累是否会导致衰老大脑中的溶酶体功能障碍和自噬抑制 SCI 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 使用becn1突变小鼠会加重炎症和神经退行性变，增加痴呆风险。 衰老小鼠中的自噬过度激活或天然存在的自噬诱导剂海藻糖 SCI 后，AIM 3 将评估自噬增加对蛋白质稳态、神经炎症、 SCI 后与 AD/ADRD 相关的神经退行性变和认知结果。 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 通过识别自噬-溶酶体功能在 SCI 和 AD/痴呆之间的联系产生积极影响 通过开发新颖的潜在治疗干预措施。