Exploring autophagy as a target for Alzheimer's Disease

探索自噬作为阿尔茨海默病的靶标

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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氏病（AD）是一种退化性脑疾病，会影响超过500万美国人和是美国第六大死亡原因。鉴于其越来越流行，新的治疗方法的发展代表了一个巨大的未定临床需要。迫切需要的是AD的标志的神经毒性蛋白聚集体的积累。最近获得Attension的新兴途径是自噬，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窖藏成分的降解和回收细胞器。实际上，神经元中自噬囊泡结构的积累也是该疾病进展的标志。自噬是对清除错误折叠蛋白聚集体的响应，何时功能失调或者不能再有效地清除聚集体，但是可以发生神经毒性。这增加了自噬来检验这一假设并作为潜在的新药。小分子有选择地提高自噬速率，这是一种没有新颖的治疗性，使得 AD的进展，因为蛋白质聚集是AD的关键现象激活清除大型蛋白质聚集体的途径可以为此提供新的治疗策略疾病。