Downregulation of Rab3D: Critical Role in Golgi Disorganization and the Pathogenesis of Alcoholic Liver Disease
Rab3D 下调:在高尔基体紊乱和酒精性肝病发病机制中的关键作用
基本信息
- 批准号:10455408
- 负责人:
- 金额:--
- 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:2020-04-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:Admission activityAffectAlcohol abuseAlcoholic HepatitisAlcoholic Liver CirrhosisAlcoholic Liver DiseasesAlcoholic liver damageAlcoholsAnimal ModelAutophagocytosisAutophagosomeBiochemicalBiologyCell surfaceCellsChronicCirrhosisCoat Protein Complex ICountryCultured CellsDataDefectDestinationsDevelopmentDisease ProgressionDown-RegulationEndocytosisEthanolExocytosisFaceFamilyFatty acid glycerol estersFoundationsFunctional disorderGeneral PopulationGlutaminaseGoalsGolgi ApparatusGuanosine Triphosphate PhosphohydrolasesHealthcareHeavy DrinkingHepatocyteHepatomegalyHepatotoxicityHypertrophyImpairmentIn VitroIncidenceInjuryInvestigationKnockout MiceLaboratoriesLeadLinkLiverMediatingMedicalMedical centerMembraneMilitary PersonnelMonomeric GTP-Binding ProteinsMorphologyMotorNonmuscle Myosin Type IIANonmuscle Myosin Type IIBOrganOrganellesPancreasPathogenesisPathway interactionsPatientsPharmacologyPhysiologicalPlayPrevalencePrincipal InvestigatorProcessProtein IsoformsProtein SecretionProteinsRecoveryRecyclingResearch PersonnelRoleSeveritiesSmall Interfering RNAStructureTherapeuticToxic effectVacuoleVesicleVeteransWorkalcohol effectalcohol exposurebaseexperiencehuman subjectimprovedin vivoinnovationinsightknock-downknockout genelipid metabolismlipid transportliver injurymilitary veteranmouse modelnon-muscle myosinnovelnovel strategiesnovel therapeutic interventionprotein metabolismprotein transportreceptorreconstitutionrestorationsuccesstherapeutic developmenttherapeutic targettrafficking
项目摘要
The goal of this VA Merit is to examine how ethanol exposure results in impaired function of the Golgi apparatus.
The Golgi apparatus (also called the Golgi body or Golgi complex) packages proteins into membrane bound
vesicles inside the cell before the vesicles are sent to their destination. As such, this organelle resides at the
intersection of the secretory, lysosomal, and endocytic pathways; it is known to be of particular importance in
processing proteins for secretion. Previous work from our laboratory has identified multiple defects in
endocytosis, protein trafficking, and secretion, after alcohol administration, but we have not until now, examined
a role for altered Golgi function in these processes. Because the incidence of alcoholic liver disease (ALD) is
greater in the Veteran population and more than half of all medical admissions in VA Medical Centers across the
country are linked to alcohol abuse, we are focusing efforts towards the identification of potential targets to
intervene during the progressive injury which occurs after chronic alcohol administration, and perhaps the Golgi
will prove to be such a target. Of central importance to our study is the role of a small GTPase, Rab3D, which
is involved in exocytosis, secretion and vesicle trafficking. We have shown that Rab3D protein content was
significantly decreased after alcohol administration, and recently we have obtained exciting new preliminary data
that ethanol-impaired Rab3D function plays an important role in Golgi disorganization and fragmentation. The
studies proposed in this application will extend our ongoing investigation of how ethanol alters hepatocyte
biology, specifically in protein processing, to an examination of its role in transport through the Golgi. We provide
a concept as to how alcohol-induced remodeling of Golgi morphology is a significant impairment of post-Golgi
trafficking, and this leads to utilization of trans-Golgi membranes for the formation of autophagosomes. These
recent and novel findings provide an excellent foundation for this proposal and support our central hypothesis
that EtOH-induced down-regulation of Rab3D disrupts the assembly and function of Golgi apparatus leading to
impaired protein trafficking and metabolism, contributing to liver injury. To examine this hypothesis, we have
proposed three specific aims; in Aim 1 we will determine how the function of Rab3D regulates the integrity of the
Golgi, in Aim 2 we will examine how autophagy is linked to EtOH-induced Golgi disorganization, and in Aim 3
we will explore recent preliminary data examining recovery of compact Golgi and reconstitution of trans-Golgi
membranes. Altogether, successful completion of these aims will characterize the effect of EtOH on Golgi
disorganization, and establish a role for altered Rab3D during this process. We will be able to correlate
mechanisms of alcohol-mediated liver cell trafficking impairments with impaired Golgi function and provide key
information that could lead to therapeutic strategies aimed at reducing or eliminating liver injury. Dr. Casey is
the principal investigator, and she is joined by three outstanding co-investigators (Drs. Petrosyan, Thomes and
Rasineni). The investigators have complementary strengths which are essential for the success of the project.
All four are experienced with alcoholic liver injury, and Dr. Casey has specific expertise in protein trafficking and
endocytosis, while Dr. Rasineni is currently examining Rab3D function in another organ, the pancreas. Dr.
Petrosyan is an expert in Golgi morphology, and Dr. Thomes brings years of experience in autophagy for the
project. Together with this expertise and our exciting and innovative approach, we anticipate that we will be
successful in these studies and will be able to contribute to improved healthcare for Veteran patients by the
identification of mechanisms involved in the alcoholic liver injury.
这个VA优点的目标是检查乙醇暴露如何导致高尔基体功能受损。
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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Carol A. Casey其他文献
Su1011 Chronic Ethanol Administration Reduces Hepatocyte-Mediated Elimination of Activated T Lymphocytes
- DOI:
10.1016/s0016-5085(13)63686-0 - 发表时间:
2013-05-01 - 期刊:
- 影响因子:
- 作者:
Erin C. Bundren;Dean Tuma;Carol A. Casey;Benita L. McVicker - 通讯作者:
Benita L. McVicker
Carol A. Casey的其他文献
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{{ truncateString('Carol A. Casey', 18)}}的其他基金
Alcohol Center Of Research -- Nebraska (ACORN)
内布拉斯加州酒精研究中心 (ACORN)
- 批准号:
10526252 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Downregulation of Rab3D: Critical Role in Golgi Disorganization and the Pathogenesis of Alcoholic Liver Disease
Rab3D 下调:在高尔基体紊乱和酒精性肝病发病机制中的关键作用
- 批准号:
9885965 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Downregulation of Rab3D: Critical Role in Golgi Disorganization and the Pathogenesis of Alcoholic Liver Disease
Rab3D 下调:在高尔基体紊乱和酒精性肝病发病机制中的关键作用
- 批准号:
10115517 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Downregulation of Rab3D: Critical Role in Golgi Disorganization and the Pathogenesis of Alcoholic Liver Disease
Rab3D 下调:在高尔基体紊乱和酒精性肝病发病机制中的关键作用
- 批准号:
10619594 - 财政年份:2020
- 资助金额:
-- - 项目类别:
ShEEP Request for a SpectraMax M Series Multi-Mode Microplate Reader
ShEEP 请求 SpectraMax M 系列多功能酶标仪
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10177680 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Alcohol-altered CEA processing: Role in liver metastases in colorectal cancer
酒精改变 CEA 加工:在结直肠癌肝转移中的作用
- 批准号:
8744678 - 财政年份:2013
- 资助金额:
-- - 项目类别:
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