Endocytic Control of Autophagosome Formation in Lupus T cells
狼疮 T 细胞中自噬体形成的内吞控制
基本信息
- 批准号:9221987
- 负责人:
- 金额:$ 40.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-02-15 至 2021-01-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdverse effectsAffectAgeAmino AcidsAppearanceAutoimmune DiseasesAutoimmunityAutophagocytosisAutophagosomeBackBiogenesisBiological Response ModifiersCD4 Positive T LymphocytesCell Differentiation processCell SurvivalCellsClinicalComplexDataDegradation PathwayDependenceDevelopmentDiseaseEndosomesEtiologyExhibitsFOXP3 geneFRAP1 geneFamilyFeedbackFemale of child bearing ageFlareFunctional disorderGenerationsGenesGenetic PolymorphismGoalsGuanosine Triphosphate PhosphohydrolasesHydroxychloroquineImmune responseImmune systemIn VitroInbred MRL lpr MiceInflammatoryKnock-in MouseKnowledgeLIGHT proteinLightLinkLongitudinal StudiesLupusLysosomesMediatingMedicalMicrotubule-Associated ProteinsModelingMonomeric GTP-Binding ProteinsMusNephritisOnset of illnessOrganellesPathogenesisPathway interactionsPatientsPharmacologyPlayPopulationPreventionProductionPublic HealthRecyclingRegulatory T-LymphocyteResearchRoleSecondary toSirolimusSiteSplenocyteSurfaceSystemic Lupus ErythematosusT-Cell ActivationT-Cell DevelopmentT-LymphocyteTFRC geneTestingTherapeuticWorkadaptive immune responsebasechronic autoimmune diseaseclinical efficacycohorteffective therapyexperimental studygene therapyin vivoinhibitor/antagonistinnovationlupus prone micemembermortalitynovel therapeuticsoverexpressionprotein degradationpublic health relevancerab GTP-Binding Proteinsthymocytetransdifferentiation
项目摘要
DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology. The pathogenesis is at least partly attributed to T-cell dysfunction. Therefore, the proposed studies will focus on a critical gap in knowledge - how autophagy pathways that regulate normal T-cell development cause pro-inflammatory population skewing and dysfunction in SLE. The central hypothesis of this project has been based on recent evidence for the contribution of endosomes to the formation of autophagosomes and the role of Rab4A in increased autophagy in lupus T cells. Rab4A is a small GTPase that regulates endosome recycling. It is markedly overexpressed in SLE patients and, even prior to disease onset, in lupus-prone mice. Although autophagy genes, in particular ATG5, have been genetically linked to SLE, their role in pathogenesis is undefined. Notably, ATG5 is transported by CD71+ endosomes which are recycled by Rab4A. Newly developed mice carrying constitutively active Rab4AQ72L show increased expression of CD71 and depletion of ATG5. Splenocytes and thymocytes of these mice show activation of mTORC1 and depletion of FoxP3. While mTORC1 is generally regarded as an inhibitor of autophagy, it is activated on the surface of lysosomes. Thus, based on compelling preliminary data, the Specific Aims will test the working hypothesis that Rab4A overexpression is responsible for accelerated autophagy and, through promoting the traffic of mTORC1 to lysosomes, for abnormal T-cell development in SLE. Given that the GTPase inhibitor 3-PEHPC inactivates Rab4A in vitro and blocks lupus pathogenesis in vivo, the proposed experiments will determine whether 1) Rab4A promotes CD71/ATG5-dependent autophagosome formation in SLE patients; 2) mTORC1 activation and FoxP3 depletion occur through endocytic traffic to lysosomes; and 3) inactivation of Rab4A blocks pathogenesis in lupus-prone mice. Under Aim 1, Rab4A overexpression will be assessed in longitudinal studies of SLE patients as the cause of enhanced autophagosome biogenesis via the retention of CD71. Under Aim 2, Rab4A-initiated traffic of mTOR from inhibitory Rab5+ endosomes to Rheb+ lysosomes will be evaluated as the mechanism underlying mTORC1 activation and the resultant Treg→Th17 trans-differentiation in SLE patients. Under Aim 3, the role of Rab4A-driven autophagy in lupus will be modeled by the impact of constitutively active Rab4AQ72L on development of autoimmunity and the dependence of pathogenesis on Rab4A, ATG5 and ATG7 and downstream activation of mTORC1 and inhibition of mTORC2. The proposed research is significant because it will advance our basic understanding of autophagosome biogenesis and its impact on T-cell development and plasticity with broad translational relevance for the pathogenesis and treatment of lupus. The approach is innovative as it will employ genetically defined checkpoints of endosomal traffic to influence lupus pathogenesis. The results will bring new perspectives to our understanding of endosome traffic, how it controls autophagosome formation and its role in disease pathogenesis, and will identify new mechanistic targets for treatment of SLE.
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)
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Andras Perl其他文献
Andras Perl的其他文献
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{{ truncateString('Andras Perl', 18)}}的其他基金
Endocytic Control of Autophagosome Formation in Lupus T cells
狼疮 T 细胞中自噬体形成的内吞控制
- 批准号:
9019238 - 财政年份:2016
- 资助金额:
$ 40.5万 - 项目类别:
Pathogenesis and Treatment of Liver Disease in Transaldolase Deficiency
转醛醇酶缺乏性肝病的发病机制和治疗
- 批准号:
8501433 - 财政年份:2010
- 资助金额:
$ 40.5万 - 项目类别:
Pathogenesis and Treatment of Liver Disease in Transaldolase Deficiency
转醛醇酶缺乏性肝病的发病机制和治疗
- 批准号:
8078182 - 财政年份:2010
- 资助金额:
$ 40.5万 - 项目类别:
Pathogenesis and Treatment of Liver Disease in Transaldolase Deficiency
转醛醇酶缺乏性肝病的发病机制和治疗
- 批准号:
7893483 - 财政年份:2010
- 资助金额:
$ 40.5万 - 项目类别:
Pathogenesis and Treatment of Liver Disease in Transaldolase Deficiency
转醛醇酶缺乏性肝病的发病机制和治疗
- 批准号:
8286307 - 财政年份:2010
- 资助金额:
$ 40.5万 - 项目类别:
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