The role of NF-kB transcription factors in regulating T cell transcription networks

T细胞是适应性免疫反应的关键因素，有助于区分自我和非自我。因此，不适当的T细胞反应可导致自身免疫和慢性炎症性疾病。当T细胞被免疫信号激活时，它们会启动一系列蛋白质的生产，这些蛋白质既控制T细胞的功能，也控制免疫系统的其他部分。编码这些蛋白质的基因拥有响应免疫信号的分子开关（启动子和增强子）。这些分子开关结合被称为转录因子的蛋白质组。在T细胞功能中起关键作用的转录因子家族是NF-kB家族，由五个不同的成员组成，其中三个在T细胞功能中起重要作用。异常的NF-kB功能或表达与自身免疫、慢性炎症和癌症有关。此外，NF-kB蛋白是移植排斥反应的关键成分。使用NF-kB通路作为这些病理的治疗靶点具有巨大的兴趣。通过对缺乏特定家族成员的小鼠的研究，我们目前对这些因素的生物学有了详细的了解。虽然我们知道NF-kB蛋白开启的一些基因，但我们目前缺乏NF-kB调节基因的足够详细的知识，以便将分子功能与生物学结果联系起来。为了了解NF-kB功能的分子机制并将其与生物学结果联系起来，我们需要对NF-kB在细胞中的作用有一个全面的了解。本研究采用实验和计算两种方法来破译T细胞中NF-kB蛋白控制的基因表达程序。NF-kB蛋白参与的T细胞转录网络也将被研究。这些实验产生的知识将为设计基于NF-kB通路的治疗方法提供坚实的基础。

T cells are a key element of the adaptive immune response and help to distinguish between self and non-self. Hence, an inappropriate T cell response can lead to autoimmunity and chronic inflammatory disease. When T cells are activated by an immune signal they switch on the production of an array of proteins that control both T cell function and other arms of the immune system. The genes encoding these proteins possess molecular switches (promoters and enhancers) that respond to immune signals. These molecular switches bind groups of proteins known as transcription factors. One family of transcription factors that plays a key role in T cell function is the NF-kB family consisting of five different members, three of which are important in T cell function. Aberrant NF-kB function or expression has been associated with autoimmunity, chronic inflammation and cancer. In addition, NF-kB proteins are key components of transplant rejection. There is enormous interest in using the NF-kB pathway as a therapeutic target for these pathologies. We currently have a detailed knowledge of the biology of these factors through studies of mice lacking specific family members. While we know some of the genes that are switched on by the NF-kB proteins, we currently lack a sufficiently detailed knowledge of NF-kB-regulated genes in order to link the molecular function with the biological outcomes. In order to understand the molecular mechanism of NF-kB function and relate this to the biological outcomes, we need a global view of NF-kB action in the cell. This proposal uses both experimental and computational approaches to decipher the gene expression program controlled by NF-kB proteins in T cells. The T cell transcription networks in which NF-kB proteins participate will also be investigated. The knowledge generated by these experiments will provide a solid basis for designing therapeutic approaches based on the NF-kB pathway.