Role of selective autophagy in aging and neurodegeneration: a small molecule approach

选择性自噬在衰老和神经退行性变中的作用：一种小分子方法

• 批准号: 10573102
• 负责人: Ee Phie Tan
• 金额: $ 12.63万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573102
• 关键词: 3-Dimensional; Acid Lipase; Address; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Astrocytes; Autophagocytosis; Autophagosome; Autopsy; Binding; Binding Proteins; Brain; Caenorhabditis elegans; Candidate Disease Gene; Cell model; Cell physiology; Cells; Ceramides; Characteristics; Chronic Disease; Deposition; Deterioration; Disease; Disease Progression; Exhibits; Failure; Future; Genes; Genetic; Health; Homeostasis; Human; Individual; Intervention; Knowledge; Link; Lipids; Longevity; Lysosomes; Maintenance; Membrane; Methods; Modeling; Molecular; Molecular Profiling; Nematoda; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Organoids; Pathogenicity; Pathway interactions; Phenotype; Play; Process; Proteins; Proteomics; Recycling; Research; Role; Therapeutic; Tissues; Vesicle; age related; cell injury; combat; design; efficacy evaluation; familial Alzheimer disease; fitness; functional restoration; healthspan; high throughput screening; human disease; improved; insight; knock-down; molecular phenotype; nervous system disorder; novel; pharmacologic; preservation; protein aggregation; receptor; receptor function; recruit; screening; small molecule; tool

PROJECT SUMMARY/ABSTRACT A hypothesis of aging is that the accumulation of cellular damage can lead to tissue malfunction and organismal deterioration. A key mechanism for maintaining cellular homeostasis and preserving cell function is autophagy, a hydrolytic cellular recycling process whereby cytosolic materials, referred to as cargo, including lipid droplets (LDs) and damaged proteins, are degraded in the lysosome. In turn, aberrations in autophagy can result in the accumulation of different toxic cytosolic contents, which is a molecular signature of many age-related disorders, including neurodegeneration. While there is a prominent functional link between autophagy, aging and diseases, the molecular mechanisms that cause the age-dependent decreases in autophagy remain unclear. Notably, autophagy can also selectively recruit one type of molecule for degradation. Recent studies support the hypothesis that selective autophagy plays a crucial role in combating chronic diseases. Several human brain post-mortem studies have uncovered lipid species that accumulate in brains affected by Alzheimer’s disease (AD), possibly impeding neuronal function and thereby contributing to neurodegeneration. Therefore, discovering different interventions that can be used to affect lipophagy (LD turnover) selectively may be ideal for tackling lipidotoxicity-linked AD. However, such pharmacological or genetic tools are currently unavailable. Furthermore, selective cellular factors that can facilitate LD recruitment for lipophagy remain unknown. In this proposal, I aim to address these greater needs in understanding the regulatory mechanisms of lipophagy and its function relevant to aging and neurodegenerative disorders. Our lab recently performed a cellular LD clearance high-throughput screen to identify small molecules and pathways that induce selective lipid clearing autophagy for slowing age-related diseases. Among these, we identified compound A20 that clears lipids in an autophagy-dependent manner in the nematode C. elegans to promote healthspan and lifespan. Emerging evidence suggests that A20 may act via lipophagy to clear lipids. I hypothesize that uncovering the lipophagy mechanism utilized by A20 will help us identify novel lipophagy regulators. Furthermore, since lipid accumulation is now linked to AD, I will employ a novel human AD patient- derived organoid model (3D neuronal culture with astrocytes) to determine whether A20 normalizes the lipid- linked pathogenic signature and normalizes pathogenic molecular phenotypes. Finally, I will characterize the functional changes in lipophagy and lipid homeostasis during AD using these human-derived organoid models. My studies are significant, as they will help us generate new mechanistic insights towards lipophagy activation during aging linked to AD. Such knowledge is vital to further our understanding of diseases exhibiting a lipophagy deregulation component. Furthermore, completion of these studies may potentially reveal strategies that could be used to combat neurodegenerative diseases.

项目概要/摘要 衰老的一个假设是细胞损伤的积累会导致组织功能障碍和生物功能障碍。 维持细胞稳态和保护细胞功能的关键机制是自噬， 水解细胞回收过程，其中细胞质物质（称为货物）包括脂滴 （LD）和受损的蛋白质在溶酶体中被降解，自噬的异常可能导致。 不同有毒胞质内容物的积累，这是许多与年龄相关的疾病的分子特征， 虽然自噬、衰老和疾病之间存在显着的功能联系， 导致年龄依赖性自噬减少的分子机制仍不清楚。 值得注意的是，自噬还可以选择性地招募一种类型的分子进行降解。最近的研究支持这一点。 选择性自噬在对抗多种人类大脑疾病中发挥着至关重要作用的假设。 尸检研究发现，受阿尔茨海默病影响的大脑中会积聚脂质物质 （AD），可能会阻碍神经功能，从而导致神经退行性变。 可用于选择性影响脂肪吞噬（LD 周转）的不同干预措施可能是谈判的理想选择 然而，目前尚无此类药理学或遗传工具。 可以促进 LD 招募以进行脂肪吞噬的选择性细胞因子仍然未知。在本提案中，我的目标是。 满足了解脂肪吞噬的调节机制及其功能的更大需求 与衰老和神经退行性疾病有关。 我们的实验室最近进行了细胞 LD 清除高通量筛选，以识别小分子和 其中，我们通过诱导选择性脂质清除自噬来减缓与年龄相关的疾病。 鉴定出化合物 A20 可以在线虫秀丽隐杆线虫中以自噬依赖性方式清除脂质 促进健康和寿命 新证据表明 A20 可能通过脂肪吞噬作用清除脂质 I。 揭示 A20 所利用的脂肪自噬机制将有助于我们识别新型脂肪自噬 此外，由于脂质积累现在与 AD 相关，我将采用一种新型人类 AD 患者—— 衍生类器官模型（星形胶质细胞的 3D 神经元培养物）以确定 A20 是否使脂质正常化 最后，我将描述相关的致病特征并将致病分子表型标准化。 使用这些人源类器官模型研究 AD 期间脂肪吞噬和脂质稳态的功能变化。 我的研究很重要，因为它们将帮助我们对脂肪吞噬激活产生新的机制见解 这些知识对于进一步了解与 AD 相关的疾病至关重要。 此外，完成这些研究可能会揭示一些策略。 可用于对抗神经退行性疾病。