权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
Andras Perl
金额：
$ 40.5万
依托单位：
UPSTATE MEDICAL UNIVERSITY
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：
https://reporter.nih.gov/project-details/9221987
关键词：
Address Adverse effects Affect Age Amino Acids Appearance Autoimmune Diseases Autoimmunity Autophagocytosis Autophagosome Back Biogenesis Biological Response Modifiers CD4 Positive T Lymphocytes Cell Differentiation process Cell Survival Cells Clinical Complex Data Degradation Pathway Dependence Development Disease Endosomes Etiology Exhibits FOXP3 gene FRAP1 gene Family Feedback Female of child bearing age Flare Functional disorder Generations Genes Genetic Polymorphism Goals Guanosine Triphosphate Phosphohydrolases Hydroxychloroquine Immune response Immune system In Vitro Inbred MRL lpr Mice Inflammatory Knock-in Mouse Knowledge LIGHT protein Light Link Longitudinal Studies Lupus Lysosomes Mediating Medical Microtubule-Associated Proteins Modeling Monomeric GTP-Binding Proteins Mus Nephritis Onset of illness Organelles Pathogenesis Pathway interactions Patients Pharmacology Play Population Prevention Production Public Health Recycling Regulatory T-Lymphocyte Research Role Secondary to Sirolimus Site Splenocyte Surface Systemic Lupus Erythematosus T-Cell Activation T-Cell Development T-Lymphocyte TFRC gene Testing Therapeutic Work adaptive immune response base chronic autoimmune disease clinical efficacy cohort effective therapy experimental study gene therapy in vivo inhibitor/antagonist innovation lupus prone mice member mortality novel therapeutics overexpression protein degradation public health relevance rab GTP-Binding Proteins thymocyte transdifferentiation

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.