A functional proteomics approach to the study of inducible gene transcription in a chromatin context.

免疫系统的细胞检测对身体的攻击，如感染、炎症或引起过敏的因素。通过一组复杂的信号通路，细胞将这些信息转化为这些细胞中表达基因模式的变化。基因表达的这些变化发生得很快，而且通常是暂时的。基因表达模式的改变会导致细胞功能的改变，而细胞功能的改变又是免疫反应下游事件的关键。在T细胞(一种重要的免疫细胞类型)中，有一组基因会对免疫刺激做出快速而短暂的反应，那就是编码被称为细胞因子的蛋白质的基因。这些细胞因子的功能是在细胞之间传递信息，从而激活免疫反应的下游事件。因此，了解这些基因如何开启和关闭的机制对于理解免疫反应和开发基于基因转录的潜在新疗法至关重要。基因以一种称为染色质的复杂结构存在于细胞的细胞核中。因此，这些基因的RNA转录过程是在这种复杂结构的背景下进行的。虽然已经有许多研究确定了控制细胞因子基因表达的分子机制，但很少有人注意到染色质在该基因转录的诱导性和暂时性中所起的作用。这一建议解决了可诱导细胞因子基因转录发生在染色质背景下的分子机制。我们将使用体外和体内的方法来探索覆盖在这些基因上的染色质结构，以及这种结构被改变以允许基因表达的机制。

Cells of the immune system detect assaults on the body such as infection, inflammatory or allergy-causing agents. Using a complex set of signaling pathways, the cells translate this information into a change in the pattern of expressed genes in those cells. These changes in gene expression occur rapidly and are generally transient. The changes that occur in gene expression pattern leads to functional changes in the cell that in turn are critical for the downstream events of the immune response. One set of genes that is rapidly and transiently switched on in response to immune stimuli in T cells (one important immune cell type) are those that encode proteins known as cytokines. These cytokines function to send messages between cells thus activating downstream events of the immune response. Thus understanding the mechanism of how these genes are switched on and off is critical in understanding an immune response and in developing potential novel therapeutics based on gene transcription. Genes exist in the nucleus of the cell in the context of a complex structure known as chromatin. The process of RNA transcription from these genes, therefore, takes place in the context of this complex structure. While there have been many studies defining the molecular mechanisms that control the expression of cytokine genes, little attention has been paid to the role of chromatin in the inducible and transient nature of this gene transcription. This proposal addresses the molecular mechanisms by which inducible cytokine gene transcription occurs in a chromatin context. We will use both in vitro and in vivo approaches to probe the structure of chromatin that overlies these genes and the mechanism by which this structure is altered to allow the genes to be expressed.