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.

项目摘要/摘要 衰老的一个假说是细胞损伤的积累会导致组织功能障碍和生物体功能障碍。 恶化维持细胞稳态和保护细胞功能的关键机制是自噬， 一种水解细胞回收过程，其中胞质物质（称为货物，包括脂滴） (LDs)和受损的蛋白质在溶酶体中被降解。反过来，自噬中的畸变可以导致 不同毒性细胞溶质内容物的积累，这是许多与年龄相关的疾病的分子特征， 包括神经退化虽然自噬、衰老和疾病之间存在显著的功能联系， 导致自噬的年龄依赖性降低的分子机制仍不清楚。 值得注意的是，自噬也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 选择性自噬在对抗慢性疾病中起关键作用的假设。几个人脑 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)可能阻碍神经元功能，从而导致神经变性。因此，发现 不同的干预措施，可以用来影响脂肪吞噬（LD营业额）选择性可能是理想的解决 神经毒性相关的AD。然而，目前还没有这种药理学或遗传学工具。此外，委员会认为， 可促进LD募集用于脂肪吞噬的选择性细胞因子仍然未知。在这份提案中，我的目标是 为了解决这些更大的需求，了解脂肪吞噬的调节机制及其功能， 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，以鉴定小分子和 诱导选择性脂质清除自噬以减缓年龄相关疾病的途径。其中，我们 鉴定了在线虫C中以自噬依赖性方式清除脂质的化合物A20。优雅地 促进健康和寿命。新出现的证据表明，A20可能通过噬脂作用清除脂质。我 假设揭示A20所利用噬脂机制将帮助我们鉴定新的噬脂作用 监管部门此外，由于脂质积累现在与AD有关，我将使用一种新的人类AD患者- 衍生的类器官模型（含星形胶质细胞的3D神经元培养），以确定A20是否使脂质正常化 关联的病原体特征并使病原体分子表型正常化。最后，我将描述 使用这些人源性类器官模型研究AD期间脂肪吞噬和脂质稳态的功能变化。 我的研究是重要的，因为它们将帮助我们产生对脂肪吞噬激活的新的机制见解 与AD相关的衰老过程中这些知识对于我们进一步了解表现出嗜脂性的疾病至关重要 放松管制的组成部分。此外，这些研究的完成可能会揭示一些策略， 用于治疗神经退行性疾病。