The role of the RasGRP protein family in lymphocyte development

T细胞是一群白细胞，它们在体内巡逻，寻找入侵的微生物。T细胞在一个叫做胸腺的器官中发育，经过一系列定义明确且易于监控的阶段成熟，最终进入血液循环。由于T细胞发育的途径是众所周知的，它经常被用作一个模型系统，用来理解各种信号通路的功能和调控，这些信号通路对许多生物反应至关重要，包括生长、分化、生存和死亡。这个研究项目的重点是了解一个至关重要的信号通路Ras/MAPK通路的调节，通过一个蛋白质家族，统称为RasGRP家族，使用早期T细胞发育作为模型系统。在T细胞和许多其他血细胞中，有两个蛋白家族被认为可以激活Ras/MAPK通路；RasGRP和Sos家族。虽然已知Ras/MAPK通路在早期T细胞发育过程中被激活，但RasGRP蛋白和Sos蛋白对Ras激活的贡献尚不清楚。我们将利用含有各种抑制剂的细胞培养和缺乏RasGRP蛋白的小鼠，确定RasGRP和Sos在T细胞发育的不同阶段之间的相互作用。此外，我们将通过在基因缺乏RasGRP的细胞中表达突变的RasGRP蛋白来研究RasGRP蛋白的调控机制。总的来说，这些研究将揭示RasGRP和Sos蛋白在T细胞中对Ras的调控，并可应用于其他细胞类型和生物反应。

T cells are a population of white blood cells that patrol the body in search of invading microorganisms. During their development in an organ called the thymus, T cells mature through a well-defined and easily monitored series of stages culminating with their entry into the circulation. Because the pathway of T cell development is well-known, it is often used as a model system with which to understand the function and regulation of various signaling pathways that are crucial to many biological responses including growth, differentiation, survival and death. This research program focuses on understanding the regulation of a critically important signaling pathway called the Ras/MAPK pathway by a family of proteins, collectively called the RasGRP family, using early T cell development as a model system. In T cells and many other blood cells, two families of proteins are thought to activate the Ras/MAPK pathway; the RasGRP and the Sos families. While it is known that the Ras/MAPK pathway is activated during early T cell development, the contribution of RasGRP proteins and Sos proteins to Ras activation is unclear. Using cell culture with various inhibitors and mice deficient in RasGRP proteins, we will determine the interplay between RasGRPs and Sos at various stages of T cell development. Furthermore, we will examine the mechanisms by which the RasGRP proteins are regulated by expressing mutant RasGRP proteins in cells that are genetically deficient for RasGRPs. Collectively, these studies will shed light on to the regulation of Ras by RasGRP and Sos proteins in T cells that can be applied to other cell types and biological responses.