The role of the RasGRP protein family in lymphocyte development

T细胞是一群白色血细胞，它们在体内巡逻，寻找入侵的微生物。在它们在一个称为胸腺的器官中发育期间，T细胞通过一系列明确且易于监测的阶段成熟，最终进入循环。由于T细胞发育的途径是众所周知的，因此它通常被用作模型系统，用于理解对许多生物反应（包括生长、分化、存活和死亡）至关重要的各种信号传导途径的功能和调节。该研究计划的重点是了解一个非常重要的信号通路称为Ras/MAPK通路的蛋白质家族，统称为RasGRP家族的调节，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，两个蛋白质家族被认为激活Ras/MAPK通路; RasGRP和Sos家族。虽然已知Ras/MAPK途径在早期T细胞发育期间被激活，但RasGRP蛋白和Sos蛋白对Ras激活的贡献尚不清楚。使用细胞培养与各种抑制剂和小鼠缺乏RasGRP蛋白，我们将确定RasGRP和Sos之间的相互作用在T细胞发育的各个阶段。此外，我们将研究RasGRP蛋白通过在RasGRP基因缺陷的细胞中表达突变型RasGRP蛋白来调节的机制。总的来说，这些研究将阐明T细胞中RasGRP和Sos蛋白对Ras的调节，这些蛋白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.