Signals that control thymocyte migration

描述（由申请人提供）：在过去的几年中，成像方法的进步已经使得有可能跟踪三维组织内的细胞运动，从而在理解细胞迁移的体内控制方面开辟了新的前沿。小鼠胸腺是探索这一问题的理想实验系统，因为发育中的T细胞具有高度运动性，并经历与其发育程序紧密相关的长距离迁移。我们的总体方法包括三个阶段。1)我们将使用双光子成像来观察和定量胸腺细胞在胸腺深处的迁移，并形成关于胸腺细胞运动是如何调节的初步假设。2)我们将使用随机计算机模拟来完善我们的假设，以评估吸引/排斥分子，粘附蛋白，固有运动性和细胞包装等因素如何影响胸腺细胞迁移。3)然后，我们将通过实验改变这些因素，并检查这些改变对胸腺细胞迁移和TCR库选择的影响来验证我们的假设。这一关于未成熟胸腺前体产生成熟功能性T细胞的过程的基本信息，将提高我们操纵对疾病的免疫反应和改善人类健康的能力。

DESCRIPTION (provided by applicant): In the past few years, advances in imaging methods have made it possible to track cell movement within 3 dimensional tissues, opening up a new frontier in understanding the in vivo control of cell migration. The thymus of the mouse is an ideal experimental system to explore this problem, since developing T cells are highly motile and undergo long range migrations that are tightly linked to their developmental program. Our general approach consists of three phases. 1) We will use 2-photon imaging to observe and quantitate thymocyte migration deep within the thymus and to form initial hypotheses about how thymocyte motility is regulated. 2) We will refine our hypotheses using stochastic computer simulations to assess how factors such as attractive/repulsive molecules, adhesion proteins, inherent motility and cell packing could effect thymocyte migration. 3) We will then test our hypotheses by experimentally altering these factors and examining the effect of these alterations on thymocyte migration and TCR repertoire selection. This fundamental information about the process whereby immature thymic precursors give rise to mature, functional T cells, will improve our ability to manipulate the immune response to disease and to improve human health.