Control of development and tolerogenic properties of thymic epithelial cells by micro RNAs

髓质和皮质胸腺上皮细胞（cTECs和mTECs）支持阳性选择和耐受诱导的不同方面。例如，终末分化的mTEC“混杂地”表达组织特异性自身抗原，并且这种现象对于自身耐受性是必需的。迄今为止，发展线索和遗传控制机制，编排TEC的发展和耐受性的性质只是不完全理解。我们计划解决一个尚未探索的层在TEC的遗传控制，即微（mi）RNA的作用。基于我们实验室最近建立的不同TEC亚群的miRNA表达谱，我们将应用功能获得和丧失策略来检验以下假设：（a）下调的miRNA可能参与“混杂基因表达”，因为它们的缺失可能建立异位基因表达的“松弛沉默”的容许状态，和（B）mTEC中上调的miRNA可能是其致耐受性特性的关键调节剂。该项目的长期前景是获得一个综合的理解如何在TECs基因调控网络影响T细胞的命运决定。

Medullary and cortical thymic epithelial cells (cTECs and mTECs) support distinct aspects of positive selection and tolerance induction. For example, terminally differentiated mTECs “promiscuously” express tissue-specific self-antigens and this phenomenon is essential for self-tolerance. To date, the developmental cues and the genetic control mechanisms that orchestrate TEC development and their tolerogenic properties are only incompletely understood. We plan to address an as yet unexplored layer of genetic control in TECs, that is, the role of micro (mi)RNAs. Based upon miRNA expression profiles of different TEC subsets that have recently been established in our lab, we will apply gain and loss of function strategies to test the hypotheses that (a) down-regulated miRNAs may be involved in “promiscuous gene expression”, as their absence may establish a permissive state of “relaxed silencing” of ectopic gene expression, and (b) that up-regulated miRNAs in mTECs may be critical regulators of their tolerogenic properties. The long-term perspective of this project is to obtain an integrated understanding of how gene regulatory networks in TECs impinge on T cell fate decisions.