Exploring autophagy as a target for Alzheimer's Disease

探索自噬作为阿尔茨海默病的靶标

• 批准号: 10194214
• 负责人: Michael Block Lazarus
• 金额: $ 16.94万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194214
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; American; Attention; Autophagocytosis; Autophagosome; Biochemical; Bioinformatics; Biological Assay; Biological Models; Biology; Brain Diseases; CRISPR screen; Cause of Death; Cell model; Cells; Chemicals; Clinical; Complex; Crystallization; DNA Damage; Data; Development; Disease; Disease Marker; Disease Progression; Enzyme Inhibitor Drugs; Functional disorder; Genes; Genetic; Genetic Transcription; Goals; Grant; Interdisciplinary Study; Intervention; Lead; Mammals; Mentorship; Modeling; Nerve Degeneration; Neurons; Neurosciences; Organelles; Pathogenesis; Pathway Analysis; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Pilot Projects; Prevalence; Process; Proteins; Recycling; Regulator Genes; Role; Science; Structure; System; Testing; Therapeutic; United States; Work; base; experience; high throughput screening; improved; induced pluripotent stem cell; inhibitor/antagonist; lipid metabolism; misfolded protein; neurotoxic; neurotoxicity; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; prevent; protein aggregation; small molecule; tau Proteins; therapeutic target; tool; transcriptome sequencing

Project Abstract Alzheimer’s disease (AD) is a degenerative brain disease that affects more than 5 million Americans and is the 6th leading cause of death in the United States. There are no known drugs that slow its progression and given its increasing prevalence, the development of new therapeutic options represents an enormous unmet clinical need. The discovery of new therapeutic targets and new drugs that can prevent the neurodegeneration and buildup of neurotoxic protein aggregates, which are the hallmark of AD, are desperately needed. One emerging pathway that has recently garnered attention is autophagy, a highly conserved catabolic pathway that is responsible for the degradation and recycling of cellular components ranging from proteins to whole organelles. There is emerging evidence that autophagic dysfunction is involved in the pathogenesis of AD. Indeed, buildup of autophagic vesicular structures in neurons is also a hallmark in the progression of the disease. It is thought that autophagy is responsible for clearing misfolded protein aggregates, and when it is dysfunctional or can no longer clear the aggregates efficiently enough, neurotoxicity can occur. However, no good drugs exist that increase autophagy to test this hypothesis and serve as potential new drugs. We are proposing to develop small molecules to selectively increase the autophagic rate as a novel therapeutic strategy for slowing the progression of AD. Because protein aggregation is the key phenomenon at the center of AD, we believe that activating the pathway that clears large protein aggregates could provide a novel therapeutic strategy for this disease.

项目摘要 阿尔茨海默病（AD）是一种退行性脑部疾病，影响超过500万美国人， 是美国第六大死因没有已知的药物可以减缓其进展， 鉴于其日益流行，新的治疗选择的发展代表了一个巨大的未满足 临床需要发现新的治疗靶点和新的药物，可以防止神经退行性变 和神经毒性蛋白聚集体的积累，这是AD的标志，是迫切需要的。一 最近引起关注的新兴途径是自噬，一种高度保守的分解代谢途径， 负责从蛋白质到整体的细胞成分的降解和回收 细胞器有证据表明自噬功能障碍参与了AD的发病机制。 事实上，神经元中自噬囊泡结构的积累也是疾病进展的标志。 人们认为，自噬是负责清除错误折叠的蛋白质聚集体，当它功能失调时， 或不能再足够有效地清除聚集体，则可能发生神经毒性。然而，没有好的药物存在 来验证这一假设，并作为潜在的新药。我们建议发展 小分子选择性增加自噬率作为一种新的治疗策略， AD的进展。由于蛋白质聚集是AD中心的关键现象，我们认为， 激活清除大蛋白聚集体的途径可以为此提供一种新的治疗策略， 疾病