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.

项目总结