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

The contribution of GPCRs to thymocyte medullary entry and central tolerance

GPCR 对胸腺细胞髓质进入和中枢耐受的贡献

基本信息

批准号：
9230336
负责人：
Lauren Ilyse Richie EHRLICH
金额：
$ 37.32万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-15 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9230336
关键词：
Affect Affinity Antigen Receptors Apoptosis Atypical lymphocyte Autoantigens Autoimmune Diseases Autoimmune Process Autoimmunity Automobile Driving CD8B1 gene Candidate Disease Gene Cells Defect Dendritic Cells Disease model Ensure Epithelial Cells Etiology Expression Library Flow Cytometry G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Gene Rearrangement Genes Genetic Genetic Recombination Genetic Transcription Goals Human Image Immunologics Impairment Individual Knockout Mice Life Location Maintenance Major Histocompatibility Complex Microscopy Modeling Molecular Molecular Profiling Mouse Strains Mus Nature Open Reading Frames Patients Peripheral Process Production Proteins Receptor Cell Role Self Tolerance Slice Stromal Cells Structure of thymic medulla Syndrome T-Cell Antigen Receptor Specificity T-Cell Development T-Cell Receptor T-Lymphocyte Testing Thymic epithelial cell Thymus Gland Transgenic Organisms adaptive immune response autoreactive T cell autoreactivity base cell motility central tolerance combinatorial defined contribution gain of function imaging approach imaging study migration mouse model novel novel therapeutics pathogen prevent public health relevance receptor thymocyte two-photon

项目摘要

DESCRIPTION (provided by applicant): In this project we propose to determine the role of candidate G protein-coupled receptors (GPCRs) in enforcing deletion of developing auto-reactive T cells in the thymus. In order for T cells to recognize and respond to the wide array of pathogens encountered throughout life, each cell expresses a unique antigen receptor, the T cell receptor (TCR), that is capable of recognizing and responding to individual pathogens. These vastly diverse receptors are generated by random and imprecise rearrangements of gene segments encoding the TCR. Unfortunately, this random recombination process also yields autoreactive TCRs that could induce autoimmune diseases. To prevent overt autoimmunity, developing T cells are educated in the thymus through interactions with thymic stromal cells: thymocytes expressing overtly autoreactive TCRs are induced to undergo apoptosis. This process of thymic self-tolerance induction is referred to as central tolerance. Central tolerance i imposed largely within the interior, medullary region of the thymus, where thymocytes encounter a wide array of self-antigens expressed on stromal cells, namely dendritic cells and/or medullary thymic epithelial cells. It is critical that developing thymocytes enter the medulla and interact with stromal cells therein to eliminate autoreactive cells. From studies of Autoimmune Polyglandular Syndrome-I patients along with mouse models of this disorder, we know that if central tolerance induction in the medulla is impaired, multi-organ autoimmunity ensues. Based on our previous studies, GPCR signaling is required for thymocyte medullary entry. In this proposal, the role of candidate GPCRs in promoting medullary entry and self-tolerance will be evaluated. Using 2-photon microscopy, live thymocytes deficient for candidate GPCRs will be imaged to determine whether their ability to enter the medulla or to interact with medullary stromal cells is impaired. In a complementary set of traditional immunological approaches, murine models deficient for candidate GPCRs will be tested for overt autoimmunity, as well as for an inability to induce central tolerance to model medullary self- antigens. Finally, unbiased gain-of-function screens will identify additional molecular candidates that promote thymocyte medullary entry and self-tolerance. These studies will illuminate molecular mechanisms that promote thymocyte migration into the medulla and interactions with medullary stromal cells to promote central tolerance, thus broadening our understanding of the etiology of autoimmune diseases.

描述（由申请人提供）：在这个项目中，我们提议确定候选G蛋白偶联受体（gpcr）在强制删除胸腺中正在发育的自身反应性T细胞中的作用。为了使T细胞能够识别和响应生命中遇到的各种各样的病原体，每个细胞都表达一种独特的抗原受体，即T细胞受体（TCR），它能够识别和响应单个病原体。这些种类繁多的受体是由编码TCR的基因片段随机和不精确的重排产生的。不幸的是，这种随机重组过程也会产生可诱导自身免疫性疾病的自身反应性tcr。为了防止明显的自身免疫，发育中的T细胞通过与胸腺基质细胞的相互作用在胸腺中被教育：表达明显的自身反应性tcr的胸腺细胞被诱导进行凋亡。这种胸腺自我耐受诱导的过程称为中枢耐受。中枢耐受主要发生在胸腺的内部髓质区域，在那里胸腺细胞会遇到大量表达于基质细胞（即树突状细胞和/或胸腺髓质上皮细胞）上的自身抗原。发育中的胸腺细胞进入髓质并与基质细胞相互作用以消除自身反应性细胞是至关重要的。从自身免疫性多腺综合征- i患者以及该疾病的小鼠模型的研究中，我们知道，如果髓质的中枢耐受性诱导受损，则会发生多器官自身免疫。根据我们之前的研究，胸腺细胞进入髓质需要GPCR信号。在本提案中，候选gpcr在促进髓质进入和自我耐受中的作用将被评估。使用双光子显微镜，将对候选gpcr缺失的活胸腺细胞进行成像，以确定它们进入髓质或与髓质基质细胞相互作用的能力是否受损。在一套补充的传统免疫学方法中，将测试候选gpcr缺失的小鼠模型是否存在显性自身免疫，以及是否无法诱导对模型髓质自身抗原的中枢耐受。最后，无偏倚的功能获得筛选将确定促进胸腺细胞髓质进入和自我耐受的其他候选分子。这些研究将阐明促进胸腺细胞向髓质迁移以及与髓质基质细胞相互作用以促进中枢耐受性的分子机制，从而拓宽我们对自身免疫性疾病病因学的理解。