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 衰老的一个假设是，细胞损伤的积累会导致组织故障和生物体 恶化。维持细胞稳态和保留细胞功能的关键机制是自噬的， 水解细胞回收过程，胞质材料称为货物，包括脂质液滴 （LDS）和受损的蛋白质在溶酶体中降解。反过来，自噬的畸变会导致 不同毒性胞质含量的积累，这是许多与年龄有关疾病的分子特征， 包括神经变性。虽然自噬，衰老和疾病之间存在着突出的功能联系，但 导致年龄依赖性下降的自噬下降的分子机制尚不清楚。 值得注意的是，自噬还可以选择性地募集一种类型的分子降解。最近的研究支持 选择性自噬在对抗慢性疾病中起着至关重要的作用的假设。几个人的大脑 验尸研究发现了在受阿尔茨海默氏病影响的大脑中积累的脂质物种 （AD），可能阻碍神经元功能，从而导致神经变性。因此，发现 可用于影响脂肪的不同干预措施，有选择地影响脂肪症（LD营业额） 脂质毒性连接的AD。但是，目前无法使用这种药物或遗传工具。此外， 可以促进LD募集脂肪的选择性细胞因子仍然未知。在这个建议中，我的目标 解决这些更大的需求，以理解寄生虫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一个细胞LD清除高通量屏幕，以识别小分子和 影响选择性脂质清除自噬的途径，以减缓与年龄有关的疾病。其中，我们 确定的化合物A20以秀丽隐杆线虫中的自噬依赖性方式清除脂质 促进HealthSpan和寿命。新兴的证据表明，A20可以通过寄生虫起作用以清除脂质。我 假设发现A20使用的脂肪机制将有助于我们识别新型的脂肪 监管机构。此外，由于脂质积累现在与AD有关，我将采用新型的人类AD患者 - 衍生的器官模型（带星形胶质细胞的3D神经元培养），以确定A20是否归一化脂质 连接的致病性特征并使致病分子表型归一化。最后，我将表征 使用这些人类衍生的类器官模型，在AD期间，寄生虫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产生新的机械洞察力，以实现脂流质激活 在与AD相关的老化期间。这种知识对于进一步的理解是至关重要的 放松调节组件。此外，这些研究的完成可能会揭示可能的策略 用于打击神经退行性疾病。