Uncovering kinase cascade mechanisms that target organelles for destruction by selective autophagy
揭示通过选择性自噬破坏靶向细胞器的激酶级联机制
基本信息
- 批准号:9215087
- 负责人:
- 金额:$ 32.87万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-04-01 至 2021-01-31
- 项目状态:已结题
- 来源:
- 关键词:ATP phosphohydrolaseAddressAnimal ModelAutophagocytosisAutophagosomeBindingBiochemicalBiogenesisBiologicalBiological AssayCRISPR interferenceCandidate Disease GeneCase StudyCell ExtractsCellsComplexCytoplasmDecision MakingDefectDrug TargetingEncapsulatedEngineeringEukaryotic CellFluorescenceFluorescence MicroscopyGene ExpressionGenesGeneticGenetic ScreeningGenetic studyGoalsGrantGuide RNAHealthHumanHypoxiaIntegral Membrane ProteinK562 CellsLysosomesMammalian CellMeasuresMedicalMembraneModelingNerve DegenerationOrganellesPathway interactionsPatientsPhosphorylationPhosphotransferasesProcessProtein KinaseProteinsPublishingRNA libraryRegulationReporterRoleSaccharomyces cerevisiaeSaccharomycetalesScaffolding ProteinSignal TransductionStarvationStructureSubstrate SpecificityTestingTimeVesicleVesicle Transport PathwayViralWorkYeastscasein kinase Ichemical geneticscomparativefluorescence imagingfollow-upgenetic analysisgenetic approachhigh throughput screeninghuman diseaseimprovedin vitro Assayinsightmutantnovelperoxisomeperoxisome membraneprotein aggregatepublic health relevancereceptorreceptor bindingreceptor functionscaffold
项目摘要
PROJECT SUMMARY/ABSTRACT
Macroautophagy (hereafter autophagy) is an umbrella term for vesicle transport pathways that target
cytoplasmic components to the lysosome for destruction. There are two classes of autophagy: nonselective
and selective. During nonselective autophagy, bulk cytoplasm gets packaged into specialized vesicles, called
autophagosomes, which fuse with the lysosome to degrade their encapsulated contents. By contrast, during
selective autophagy, specific toxic structures – such as ubiquitinated protein aggregates – are recognized by
autophagy receptors, which also interact with the nascent autophagosome membrane to enable vesicle
engulfment of the receptor-target complex.
In a recently published work, we discovered that autophagy receptors also have an unanticipated regulatory
role as activators of the dedicated kinase that controls initiation of autophagosome formation. This work fits
nicely with other studies showing that receptor activity is not constitutive but rather directly controlled by
general kinases. To gain further insights into receptor function, we have hypothesized that receptors enable
transduction of selective autophagy signals down kinase cascades – from general kinases to the dedicated
autophagy kinase – to make decisions about the destruction of selective autophagy targets – which specific
target should be destroyed and when? This proposal uses selective autophagy of peroxisomes (pexophagy) to
build a case study for the kinase signal cascade hypothesis. The bulk of the proposed work will be performed
using budding yeast because this model organism has facile genetics, is tractable biochemically, and
accessible cell biologically to imaging by fluorescence microscopy. The remainder of the work comprises
pioneering genetic screens in mammalian cells for pexophagy mutants. Our strong track record in doing follow-
up mechanistic work on the GET pathway components, which were identified originally by yeast high-
throughput screens, will help guide us from screen hits towards new mammalian pexophagy components and
mechanistic insights that are missing from the current picture. This latter work also has direct medical
relevance because in certain Zellweger Spectrum patients, peroxisomes can form normally, but are degraded
by autophagy.
项目总结/摘要
巨自噬(以下简称自噬)是一个总括性术语,囊泡转运途径,靶向
细胞质成分到达溶酶体进行破坏。自噬有两种类型:非选择性自噬
而且有选择性。在非选择性自噬过程中,大量的细胞质被包装成专门的小泡,称为
自噬体,其与溶酶体融合以降解其包封的内容物。相比之下,
在选择性自噬中,特异性毒性结构-如泛素化蛋白质聚集体-被
自噬受体,也与新生的自噬体膜相互作用,使囊泡
吞噬受体-靶复合物。
在最近发表的一项研究中,我们发现自噬受体也有一种意想不到的调节作用,
作为控制自噬体形成起始的专用激酶的激活剂的作用。这项工作符合
与其他研究表明受体活性不是组成性的,而是直接受
一般激酶为了进一步了解受体功能,我们假设受体能够
选择性自噬信号的转导激酶级联-从一般激酶到专用激酶
自噬激酶-决定选择性自噬靶点的破坏-哪些特定的
目标应该在何时被摧毁该提案使用过氧化物酶体的选择性自噬(pexophagy),
为激酶信号级联假说建立一个案例研究。大部分拟议的工作将在
使用芽殖酵母,因为这种模式生物具有简单的遗传学,在生物化学上易于处理,
生物学上可接近的细胞通过荧光显微镜成像。其余工作包括
在哺乳动物细胞中进行食粪突变体的遗传筛选的先驱。我们在跟踪方面的良好记录-
在GET途径组分上进行了机械工作,这些组分最初由酵母高-
通量筛选,将有助于指导我们从筛选命中到新的哺乳动物pexophagy组件,
机械的洞察力,这是从目前的图片失踪。这后一项工作也有直接的医疗
相关性,因为在某些Zellweger Spectrum患者中,过氧化物酶体可以正常形成,但被降解
通过自噬。
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 }}
Vladimir Denic其他文献
Vladimir Denic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('Vladimir Denic', 18)}}的其他基金
Mechanistic dissection of eukaryotic protein biogenesis and degradation pathways
真核蛋白质生物发生和降解途径的机制剖析
- 批准号:
10623737 - 财政年份:2018
- 资助金额:
$ 32.87万 - 项目类别:
Defining the Essential Function of Heat Shock Factor and the Consequences of its Age-Associated Decline
定义热休克因子的基本功能及其与年龄相关的下降的后果
- 批准号:
8869633 - 财政年份:2015
- 资助金额:
$ 32.87万 - 项目类别:
Defining the Essential Function of Heat Shock Factor and the Consequences of its Age-Associated Decline
定义热休克因子的基本功能及其与年龄相关的下降的后果
- 批准号:
9050618 - 财政年份:2015
- 资助金额:
$ 32.87万 - 项目类别:
Mechanistic analysis of post-translation membrane protein insertion into the ER.
翻译后膜蛋白插入内质网的机制分析。
- 批准号:
8450736 - 财政年份:2012
- 资助金额:
$ 32.87万 - 项目类别:
Mechanistic analysis of post-translation membrane protein insertion into the ER.
翻译后膜蛋白插入内质网的机制分析。
- 批准号:
8219332 - 财政年份:2012
- 资助金额:
$ 32.87万 - 项目类别:
Mechanistic analysis of post-translation membrane protein insertion into the ER.
翻译后膜蛋白插入内质网的机制分析。
- 批准号:
8635374 - 财政年份:2012
- 资助金额:
$ 32.87万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 32.87万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 32.87万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 32.87万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 32.87万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 32.87万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 32.87万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 32.87万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 32.87万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 32.87万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 32.87万 - 项目类别:
Research Grant