Tubular lysosomes in health and disease

管状溶酶体在健康和疾病中的作用

• 批准号: 10456328
• 负责人: Alyssa Johnson
• 金额: $ 35.49万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10456328
• 关键词: Alzheimer' s Disease; Animals; Autophagocytosis; Back; Biological; Biological Models; Biology; Cells; Cues; Cytoplasm; Defect; Degenerative Disorder; Dependence; Disease; Epidemic; Functional disorder; Genes; Health; Homeostasis; Human; Impairment; Knowledge; Link; Lysosomes; Maintenance; Mammals; Metabolic Diseases; Metabolism; Molecular; Molecular Disease; Mutation; Neurons; Nutrient; Organelles; Parkinson Disease; Pathology; Proteins; Recycling; Research; Starvation; Stimulus; System; Therapeutic; Tissues; Tubular formation; Work; age related; fly; improved; novel; protein aggregation; proteostasis; repaired

Abstract Age-dependent degenerative diseases, such as ALS, Alzheimer’s and Parkinson’s disease, are reaching epidemic proportions and no viable treatment options exist to halt or reverse the course of the disease. The lack of disease-modifying treatments is in large part due to our lack of knowledge about the molecular disease pathology. An early hallmark of most degenerative diseases is an accumulation of protein aggregates and damaged organelles, implying that proteostasis defects are an underlying molecular cause of degeneration. Lysosomes are digestive organelles that clear damaged proteins and are also critical regulators of cellular metabolism. Thus, it is not surprising that lysosome impairment is linked to a broad spectrum of degenerative and metabolic diseases. Revealing novel ways to improve or maintain lysosome function in various biological contexts could open promising therapeutic avenues to treat a wide range of metabolic and degenerative diseases. We recently discovered a unique class of degradative tubular lysosomes (TLs) that are conserved in flies, worms and mammals. Significantly, mutation of two genes required for TL maintenance are linked with human degenerative diseases, underscoring the potential biomedical relevance of TLs. Our recent work has demonstrated that TLs are exceptionally digestive, tissue specific and in some cases even stimulus dependent. For example, TLs are stimulated in gut cells during starvation, a major cue that stimulates the autophagy- lysosome system to increase nutrient recycling. We hypothesize that TLs might be deployed under certain conditions when autophagic demand is high. This context dependency also suggests that TLs have the capacity to be stimulated and opens the possibility that TLs could be induced in other tissues where they do not exist naturally, such as neurons. Using worm and fly model systems, we aim to understand fundamental aspects of TL biology in health animals and their connection to human degenerative diseases. Three major research questions we are tackling in my lab include: (1) what are the control mechanisms for starvation- induced TLs in the gut? (2) are TLs functionally distinct from vesicular lysosomes? and (3) is TL dysfunction an underlying cause for age-dependent degenerative diseases? We anticipate that these studies will reveal novel aspects of lysosome biology and might inform strategies to co-opt these mechanisms to boost lysosome function in healthy animals or repair lysosomes in disease states.

摘要 与年龄相关的退行性疾病，如肌萎缩侧索硬化症、阿尔茨海默氏症和帕金森氏症，正在 流行比例大，没有可行的治疗选择来阻止或逆转疾病的进程。这个 缺乏改善疾病的治疗方法在很大程度上是由于我们对分子疾病缺乏了解。 病理学。大多数退行性疾病的早期特征是蛋白质聚集体和 细胞器受损，这意味着蛋白质平衡缺陷是导致退化的潜在分子原因。 溶酶体是清除受损蛋白质的消化细胞器，也是细胞的关键调节器。 新陈代谢。因此，溶酶体损伤与广泛的退行性疾病有关也就不足为奇了。 和代谢性疾病。揭示了在各种生物中改善或维持溶酶体功能的新方法 环境可以为治疗广泛的代谢和退行性疾病开辟有希望的治疗途径 疾病。我们最近发现了一类独特的降解性管状溶酶体(TL)，它们在 苍蝇、蠕虫和哺乳动物。值得注意的是，TL维持所需的两个基因突变与 人类退行性疾病，强调了TL的潜在生物医学相关性。我们最近的工作是 证明TL具有特殊的消化性、组织特异性，在某些情况下甚至依赖于刺激。 例如，TL在饥饿期间在肠道细胞中被刺激，这是刺激自噬的一个主要线索- 溶酶体系统，以增加营养循环。我们假设TL可能在某些情况下部署 自噬需求高的情况。这种上下文依赖关系还表明TL具有 刺激的能力，并打开了在其他组织中诱导TL的可能性 不是自然存在的，比如神经元。使用蠕虫和苍蝇模型系统，我们的目标是了解基本 健康动物的TL生物学方面及其与人类退行性疾病的联系。三大 我们在实验室中解决的研究问题包括：(1)饥饿的控制机制是什么- 肠道中诱导的TL？(2)TL与囊泡溶酶体在功能上有区别吗？(3)TL功能障碍是一种 年龄相关性退行性疾病的根本原因是什么？我们预计这些研究将揭示出新奇的 溶酶体生物学的方方面面，并可能为利用这些机制来促进溶酶体的策略提供参考 在健康动物中发挥功能或在疾病状态下修复溶酶体。