Control of vesicular trafficking in the hepatocyte.
控制肝细胞中的囊泡运输。
基本信息
- 批准号:8838778
- 负责人:
- 金额:$ 30万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-04-01 至 2015-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAnimalsAutophagocytosisBiochemicalBiological AssayCell LineCellsCellular biologyCholesterolCommunicable DiseasesComplexCultured CellsDevelopmentDiabetes MellitusDiseaseEndocytic VesicleEndocytosisEndocytosis PathwayEndosomesEventFailureFluorescence MicroscopyFunctional disorderGoalsGuanosine Triphosphate PhosphohydrolasesHealthHeat-Shock ResponseHepatitisHepatocyteHomeostasisHybridsImmune System DiseasesIn VitroKineticsKnowledgeLipidsLiverLiver diseasesLysosomesMalignant NeoplasmsMediatingMembraneMembrane LipidsMetabolic DiseasesMicrotubulesMolecularMolecular ChaperonesMotorMusNamesObesityOxidative StressPathogenesisPathologyPathway interactionsPhysiologicalPopulationProceduresProcessProtein C InhibitorProteinsProteolysisProteomicsRattusRecruitment ActivityRelative (related person)StarvationStimulusSystemTechnologyTestingTherapeuticVacuoleVesiclebasecell motilitycell typechemical geneticsfunctional declinegenetic manipulationhuman diseaseknock-downlate endosomeliver functionnew therapeutic targetnovelprotein complexprotein degradationreceptor mediated endocytosisreconstitutionresponsetooltrafficking
项目摘要
DESCRIPTION (provided by applicant): Endocytosis and autophagy represent fundamental processes that are essential to the health of many cell types, including hepatocytes. Previous studies from our groups and others have identified cross-talk between endocytosis and autophagy: 1) specific compartments are shared between them; 2) both contribute to cellular proteolysis and 3) both pathways require regulated trafficking of vesicles that interact in a dynamic manner, undergoing fission and fusion as part of their maturation process. Based on prior findings, we propose that dysfunction of the endocytic or autophagic trafficking pathways can have deleterious effects on normal liver function and contribute to the pathogenesis of hepatic disorders. The overall goal of this proposal is to characterize at the molecular level the functional interaction between the endocytic and the autophagic pathways and their contribution to cellular homeostasis. To this end we will: 1) mechanistically define vesicle- associated protein
complexes that regulate motor recruitment and activity required for endocytic/autophagic vesicle processing by fission and fusion; 2) determine the consequences of changes in membrane lipid composition on the interactions between endocytic and autophagic pathways and 3) characterize quantitatively the functional interplay between endocytosis and autophagy. We will use chemical and genetic manipulations in cultured hepatocyte cell lines and in rat and mouse liver combined with biochemical and morphological approaches to answer these questions. The complementary expertise of the two co-PIs, Dr. Allan Wolkoff (endocytosis and liver pathophysiology) and Dr. Ana Maria Cuervo (autophagy and cell biology) greatly enhances their ability to discover interactions between the endocytic and the autophagic pathways in liver and to study the consequences that failure in one of these pathways has on the other. The major significance of the proposed studies resides in the fact that alterations in endocytosis and autophagy have been observed in human diseases that include protein conformational disorders (e.g. alpha1-antitrypsin deficiency), cancer, metabolic disorders (e.g. diabetes, obesity) and infectious and immune diseases. However, incomplete knowledge regarding details of endocytosis and autophagy limits development of mechanism-based therapeutics. Successful completion of these studies will ultimately provide the tools needed to identify novel therapeutic targets to restore normal liver function or perhaps slow the functional decline associated with common liver disorders resulting from dysfunction of the endosome/lysosome system.
描述(由申请人提供):内吞作用和自噬是对包括肝细胞在内的许多细胞类型的健康至关重要的基本过程。我们的研究小组和其他人之前的研究已经确定了内吞作用和自噬之间的串扰:1)它们之间共享特定的隔室;2)两者都有助于细胞蛋白水解;3)这两种途径都需要调节囊泡的运输,这些囊泡以动态的方式相互作用,在其成熟过程中经历裂变和融合。基于先前的研究结果,我们提出内吞或自噬运输途径的功能障碍可能对正常肝功能产生有害影响,并参与肝脏疾病的发病机制。本建议的总体目标是在分子水平上表征内吞和自噬途径之间的功能相互作用及其对细胞稳态的贡献。为此,我们将:1)从机制上定义囊泡相关蛋白
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)
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ANA MARIA CUERVO其他文献
ANA MARIA CUERVO的其他文献
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{{ truncateString('ANA MARIA CUERVO', 18)}}的其他基金
Molecular and Cellular Mechanisms of the Lysosomal Storage Disease Cystinosis
溶酶体贮积病胱氨酸中毒的分子和细胞机制
- 批准号:
10434057 - 财政年份:2017
- 资助金额:
$ 30万 - 项目类别:
Molecular and Cellular Mechanisms of the Lysosomal Storage Disease Cystinosis
溶酶体贮积病胱氨酸中毒的分子和细胞机制
- 批准号:
10683169 - 财政年份:2017
- 资助金额:
$ 30万 - 项目类别:
Project 3: Autophagy dysfunction and neuronal activity in FTD
项目 3:FTD 中的自噬功能障碍和神经元活动
- 批准号:
9292170 - 财政年份:2016
- 资助金额:
$ 30万 - 项目类别:
Understanding Alzheimer's Disease in the Context of the Aging Brain
在大脑老化的背景下了解阿尔茨海默病
- 批准号:
9856238 - 财政年份:2016
- 资助金额:
$ 30万 - 项目类别:
Project 3: Autophagy dysfunction and neuronal activity in FTD
项目 3:FTD 中的自噬功能障碍和神经元活动
- 批准号:
10011929 - 财政年份:2016
- 资助金额:
$ 30万 - 项目类别:
Functional Consequences of Impaired Autophagy in Aging
衰老过程中自噬受损的功能后果
- 批准号:
8792022 - 财政年份:2014
- 资助金额:
$ 30万 - 项目类别:
Control of vesicular trafficking in the hepatocyte.
控制肝细胞中的囊泡运输。
- 批准号:
8633455 - 财政年份:2013
- 资助金额:
$ 30万 - 项目类别:
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