Mechanisms Of Er-To-Golgi Transport Of Lysosomal Enzymes
溶酶体酶从 Er 到高尔基体的转运机制
基本信息
- 批准号:10094001
- 负责人:
- 金额:$ 31.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-02-01 至 2023-01-31
- 项目状态:已结题
- 来源:
- 关键词:AcidsAgingAmino Acid MotifsBiogenesisCLN6 geneCLN8 geneCOP-Coated VesiclesCarbohydratesCell DeathCellsCellular biologyClientCommunitiesComplementDataDefectDegenerative DisorderDiseaseEndoplasmic ReticulumEngineeringEnzymesFutureGoalsGolgi ApparatusGrowthHealthHomeostasisHomoHumanHydrolaseImmune System DiseasesImpairmentIntegral Membrane ProteinInvestigationKnock-inKnockout MiceLysosomesMalignant NeoplasmsMammalian CellMapsMediatingMetabolismMethodsMissense MutationModelingMolecularMolecular BiologyMusMutateMutationOrganOrganellesPathogenesisPathogenicityPathway interactionsProteinsProteomicsResearchRoleSignal TransductionSignaling ProteinSorting - Cell MovementSpielmeyer-Vogt DiseaseStructural ModelsSurfaceSystemTertiary Protein StructureTestingTherapeuticTissuesTransportationWorkbasebiochemical toolscancer typecohortdisease-causing mutationhuman diseasein vivointerdisciplinary approachmacromoleculemolecular modelingmutantoverexpressionreceptorrecruittherapy designtraffickingvesicle transport
项目摘要
PROJECT SUMMARY/ABSTRACT
Lysosomes control a substantial part of cellular metabolism by acting as the main catabolic hub of the cell and
serving as a platform for the integration of numerous signals that modulate cell death, growth and proliferation.
Most lysosomal functions rely on a set of more than 50 acid hydrolases that degrade a wide variety of
macromolecules. Lysosomal enzymes are trafficked to the lysosome in two stages: transport of the newly
synthesized proteins from the endoplasmic reticulum (ER) to the Golgi complex, and their subsequent
receptor-assisted transfer from the Golgi to endolysosomal compartments. How lysosomal enzymes are
transported from the ER to the Golgi complex is unknown and, to our knowledge, the simple model of a bulk,
unregulated transportation has never been questioned. We have identified two candidate ER receptors, CLN6
and CLN8, whose deficiency results in altered maturation of lysosomal enzymes and lysosomal storage
disorder-like diseases. We propose to study how CLN6 and CLN8 function in the pathway of maturation of
lysosomal enzymes. First, we will test the hypothesis that CLN6 and CLN8 directly interact with lysosomal
enzymes and that such interaction is disrupted by disease-associated mutations on either CLN6/CLN8 or on
the surface of lysosomal enzymes (Aim 1). Second, we will examine the trafficking and maturation of newly
synthesized lysosomal enzymes to identify the exact step that is disrupted by CLN6 and CLN8 deficiency. We
will also define CLN6 and CLN8 functions in vivo by carrying out detailed tissue-specific analyses of lysosomal
composition in CLN6- and CLN8-deficient mouse lines by LC-MS/MS-based proteomics. To this aim, we have
generated a knock-in Lamp1FLAG mouse line to efficiently isolate lysosomes from the desired tissues (Aim 2).
Third, we will identify the protein domains and motifs that are involved in CLN6/CLN8 interaction and that direct
their sorting across the compartments of the early secretory pathway via COP-coated vesicles (Aim 3). We will
accomplish our goals with a multi-disciplinary approach that uses the tools of biochemistry, molecular biology,
cell biology and mouse engineering and we will also develop a new method of in vivo lysosome isolation from
mouse tissues. Our results are likely to have important consequences for our understanding of the
mechanisms governing lysosomal biogenesis and of the molecular pathogenesis of numerous human
diseases. Some of the regulatory mechanisms we uncover may serve in the future as targets for modulating
lysosomal biogenesis in diseases resulting from impaired lysosomal function or in conditions, such as certain
types of cancer, that are characterized by aberrant or unrestricted lysosomal activation.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Marco Sardiello其他文献
Marco Sardiello的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Marco Sardiello', 18)}}的其他基金
TFEB-mediated lysosome-to-nucleus signaling in aging and lifespan regulation
TFEB 介导的溶酶体到细胞核信号传导在衰老和寿命调节中的作用
- 批准号:
10172235 - 财政年份:2021
- 资助金额:
$ 31.5万 - 项目类别:
TFEB-mediated lysosome-to-nucleus signaling in aging and lifespan regulation
TFEB 介导的溶酶体到细胞核信号传导在衰老和寿命调节中的作用
- 批准号:
10413974 - 财政年份:2021
- 资助金额:
$ 31.5万 - 项目类别:
TFEB-mediated lysosome-to-nucleus signaling in aging and lifespan regulation
TFEB 介导的溶酶体到细胞核信号传导在衰老和寿命调节中的作用
- 批准号:
10583543 - 财政年份:2021
- 资助金额:
$ 31.5万 - 项目类别:
Mechanisms Of Er-To-Golgi Transport Of Lysosomal Enzymes
溶酶体酶从 Er 到高尔基体的转运机制
- 批准号:
10345430 - 财政年份:2019
- 资助金额:
$ 31.5万 - 项目类别:
Mechanisms Of Er-To-Golgi Transport Of Lysosomal Enzymes
溶酶体酶从 Er 到高尔基体的转运机制
- 批准号:
10376728 - 财政年份:2019
- 资助金额:
$ 31.5万 - 项目类别:
Modulation of lysosomal function for the treatment of neuronal ceroid lipofuscino
调节溶酶体功能治疗神经元蜡样脂褐质
- 批准号:
9103210 - 财政年份:2012
- 资助金额:
$ 31.5万 - 项目类别:
Modulation of lysosomal function for the treatment of Batten disease
调节溶酶体功能治疗巴顿病
- 批准号:
10317363 - 财政年份:2012
- 资助金额:
$ 31.5万 - 项目类别:
Modulation of lysosomal function for the treatment of Batten disease
调节溶酶体功能治疗巴顿病
- 批准号:
10247068 - 财政年份:2012
- 资助金额:
$ 31.5万 - 项目类别:
Modulation of lysosomal function for the treatment of neuronal ceroid lipofuscino
调节溶酶体功能治疗神经元蜡样脂褐质
- 批准号:
8660355 - 财政年份:2012
- 资助金额:
$ 31.5万 - 项目类别:
Modulation of lysosomal function for the treatment of neuronal ceroid lipofuscino
调节溶酶体功能治疗神经元蜡样脂褐质
- 批准号:
8843982 - 财政年份:2012
- 资助金额:
$ 31.5万 - 项目类别:
相似海外基金
Interplay between Aging and Tubulin Posttranslational Modifications
衰老与微管蛋白翻译后修饰之间的相互作用
- 批准号:
24K18114 - 财政年份:2024
- 资助金额:
$ 31.5万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
The Canadian Brain Health and Cognitive Impairment in Aging Knowledge Mobilization Hub: Sharing Stories of Research
加拿大大脑健康和老龄化认知障碍知识动员中心:分享研究故事
- 批准号:
498288 - 财政年份:2024
- 资助金额:
$ 31.5万 - 项目类别:
Operating Grants
EMNANDI: Advanced Characterisation and Aging of Compostable Bioplastics for Automotive Applications
EMNANDI:汽车应用可堆肥生物塑料的高级表征和老化
- 批准号:
10089306 - 财政年份:2024
- 资助金额:
$ 31.5万 - 项目类别:
Collaborative R&D
Baycrest Academy for Research and Education Summer Program in Aging (SPA): Strengthening research competencies, cultivating empathy, building interprofessional networks and skills, and fostering innovation among the next generation of healthcare workers t
Baycrest Academy for Research and Education Summer Program in Aging (SPA):加强研究能力,培养同理心,建立跨专业网络和技能,并促进下一代医疗保健工作者的创新
- 批准号:
498310 - 财政年份:2024
- 资助金额:
$ 31.5万 - 项目类别:
Operating Grants
関節リウマチ患者のSuccessful Agingに向けたフレイル予防対策の構築
类风湿性关节炎患者成功老龄化的衰弱预防措施的建立
- 批准号:
23K20339 - 财政年份:2024
- 资助金额:
$ 31.5万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Life course pathways in healthy aging and wellbeing
健康老龄化和福祉的生命历程路径
- 批准号:
2740736 - 财政年份:2024
- 资助金额:
$ 31.5万 - 项目类别:
Studentship
I-Corps: Aging in Place with Artificial Intelligence-Powered Augmented Reality
I-Corps:利用人工智能驱动的增强现实实现原地老龄化
- 批准号:
2406592 - 财政年份:2024
- 资助金额:
$ 31.5万 - 项目类别:
Standard Grant
NSF PRFB FY 2023: Connecting physiological and cellular aging to individual quality in a long-lived free-living mammal.
NSF PRFB 2023 财年:将生理和细胞衰老与长寿自由生活哺乳动物的个体质量联系起来。
- 批准号:
2305890 - 财政年份:2024
- 资助金额:
$ 31.5万 - 项目类别:
Fellowship Award
虚弱高齢者のSuccessful Agingを支える地域課題分析指標と手法の確立
建立区域问题分析指标和方法,支持体弱老年人成功老龄化
- 批准号:
23K20355 - 财政年份:2024
- 资助金额:
$ 31.5万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
「ケア期間」に着目したbiological aging指標の開発
开发聚焦“护理期”的生物衰老指数
- 批准号:
23K24782 - 财政年份:2024
- 资助金额:
$ 31.5万 - 项目类别:
Grant-in-Aid for Scientific Research (B)