Tubular lysosomes in health and disease
管状溶酶体在健康和疾病中的作用
基本信息
- 批准号:10218223
- 负责人:
- 金额:$ 35.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Alzheimer&aposs DiseaseAnimalsAutophagocytosisBackBiologicalBiological ModelsBiologyCellsCuesCytoplasmDefectDegenerative DisorderDependenceDiseaseEpidemicFunctional disorderGenesHealthHomeostasisHumanImpairmentKnowledgeLinkLysosomesMaintenanceMammalsMetabolic DiseasesMetabolismMolecularMolecular DiseaseMutationNeuronsNutrientOrganellesParkinson DiseasePathologyProteinsRecyclingResearchStarvationStimulusSystemTherapeuticTissuesTubular formationWorkage relatedflyimprovednovelprotein aggregationproteostasisrepaired
项目摘要
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
肌萎缩侧索硬化症、阿尔茨海默氏症和帕金森氏症等神经系统依赖性退行性疾病正在达到
目前还没有可行的治疗方案来阻止或扭转这种疾病的进程。的
缺乏改善疾病的治疗方法在很大程度上是由于我们缺乏对分子疾病的了解
病理大多数退行性疾病的早期标志是蛋白质聚集体的积累,
细胞器受损,这意味着蛋白质稳态缺陷是退化的潜在分子原因。
溶酶体是消化细胞器,其清除受损的蛋白质,并且也是细胞增殖的关键调节剂。
新陈代谢.因此,溶酶体损伤与广泛的退行性疾病有关并不奇怪。
和代谢性疾病。揭示了在各种生物学中改善或维持溶酶体功能的新方法
背景下可以打开有前途的治疗途径,以治疗广泛的代谢和退行性疾病,
疾病我们最近发现了一类独特的降解性管状溶酶体(TL),它们在细胞中是保守的。
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的突变与
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
表明TL是异常消化的、组织特异性的,并且在某些情况下甚至依赖于刺激。
例如,在饥饿期间,肠细胞中的TL被刺激,这是刺激自噬的主要线索。
溶酶体系统,以增加营养循环。我们假设TL可以在某些情况下部署,
当自噬需求很高时。这种上下文依赖性也表明TL具有
这可能会刺激细胞的生长,并开启了在其他组织中诱导TL的可能性,
不存在于自然界,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的
TL生物学在健康动物及其与人类退行性疾病的联系方面。三大
在我的实验室里,我们正在解决的研究问题包括:(1)饥饿的控制机制是什么?
在肠道内诱发了TL (2)TL在功能上与囊泡溶酶体不同吗?(3)TL功能障碍,
年龄依赖性退行性疾病的根本原因我们预计,这些研究将揭示新的
溶酶体生物学方面,并可能告知策略,以增选这些机制,以促进溶酶体
在健康动物中起作用或在疾病状态下修复溶酶体。
项目成果
期刊论文数量(0)
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Alyssa Johnson其他文献
Alyssa Johnson的其他文献
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