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: 10380139
• 负责人: Michael Block Lazarus
• 金额: $ 16.9万
• 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/10380139
• 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; Role; Science; Structure; System; Testing; Therapeutic; United States; Work; base; experience; gene regulatory network; high throughput screening; improved; induced pluripotent stem cell; inhibitor; 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，影响着500多万美国人和 是美国第六大死因。目前还没有已知的药物可以减缓它的进展 鉴于其日益流行，新的治疗方法的发展是一个巨大的未得到满足的问题 临床需要。可预防神经变性的新治疗靶点和新药的发现 而神经毒性蛋白聚集体的积累是AD的标志，这是迫切需要的。一 最近引起注意的新途径是自噬，这是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。越来越多的证据表明，自噬功能障碍参与了AD的发病机制。 事实上，神经元中自噬泡泡结构的积聚也是疾病进展的一个标志。 人们认为，自噬负责清除错误折叠的蛋白质聚集体，当它功能失调时 或者不能再足够有效地清除聚集体，就可能发生神经毒性。然而，没有好的药物存在。 这增加了自噬来检验这一假说，并成为潜在的新药。我们正在提议开发 小分子选择性提高自噬速度作为延缓自噬的新治疗策略 AD的进展。因为蛋白质聚集是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这一疾病提供一种新的治疗策略 疾病。