RUI: Elucidating the Mechanisms Governing Differential Expression of the Lat Gene

哺乳动物的lat基因编码一种适配器蛋白（lat），这种蛋白仅在有限的细胞类型中表达，包括T细胞、肥大细胞、自然杀伤细胞和血小板。LAT蛋白在受体参与后酪氨酸磷酸化导致其与多种下游信号分子相互作用，这是正常细胞功能所必需的事件。除了其细胞类型受限的表达模式外，在T细胞被激活以引发免疫反应的过程中，lat mRNA的水平也发生了改变。有趣的是，似乎T细胞中的某些信号转导通路刺激晚期基因表达，而其他信号转导通路具有抑制作用。本研究的目的是对lat基因差异表达的各种分子过程进行全面的研究。这一目标将通过以下方式实现：(1)鉴定构成近端晚启动子的DNA元件；(2)表征与这些定义的DNA元件相互作用的蛋白质，并确定它们在控制晚期基因表达中的功能相关性；(3)研究近端晚启动子在T细胞活化过程中基因的细胞型特异性表达及其差异表达中的作用；(4)研究RNA稳定性和远端控制区对后期基因表达调控的作用。对lat基因调控的研究不仅可以提供控制其表达的分子机制的重要信息，而且有助于建立适用于各种生物体中其他基因的基因调控的一般原理。这项研究将由首席研究员和阿格尼斯·斯科特学院的本科生合作进行，这是一所四年制女子文理学院。

The mammalian lat gene encodes an adaptor protein (LAT) that is expressed in only a limited number of cell types, including T cells, mast cells, natural killer cells, and platelets. Tyrosine phosphorylation of the LAT protein following receptor engagement results in its interaction with a variety of downstream signaling molecules, an event essential for proper cellular function. In addition to its cell-type restricted expression pattern, the level of lat mRNA is altered during the process by which T cells are activated to elicit an immune response. Interestingly, it appears that certain signal transduction pathways in T cells stimulate lat gene expression whereas others have an inhibitory effect. The objective of this research is to initiate a comprehensive study into the various molecular processes responsible for differential expression of the lat gene. This objective will be accomplished by the following means: (1) identification of the DNA elements comprising the proximal lat promoter; (2) characterization of the proteins that interact with these defined DNA elements and a determination of their functional relevance in controlling lat gene expression; (3) investigation into the role of the proximal lat promoter in the genes' cell-type specific expression and its differential expression during T cell activation; and (4) examination of the contribution of RNA stability and the role of distal control regions to the regulation of lat gene expression. Studies of the regulation of the lat gene will not only provide important information concerning the molecular mechanisms controlling its expression but in addition will contribute to the establishment of general principles of gene regulation which will be applicable to other genes in a variety of living organisms. This research will be conducted as a collaboration between the principal investigator and undergraduate students at Agnes Scott College, a four-year liberal arts institution for women.