Signals that control thymocyte migration

描述(申请人提供)：在过去的几年里，成像方法的进步使追踪三维组织内的细胞运动成为可能，开辟了理解体内控制细胞迁移的新前沿。小鼠的胸腺是探索这一问题的理想实验系统，因为发育中的T细胞具有高度的运动性，并经历与其发育程序密切相关的长距离迁移。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，并形成胸腺细胞运动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、黏附蛋白、固有的运动性和细胞包装等因素如何影响胸腺细胞的迁移。3)然后，我们将通过实验改变这些因素来检验我们的假设，并检查这些改变对胸腺细胞迁移和TCR谱系选择的影响。这些关于未成熟胸腺前体细胞产生成熟的、功能正常的T细胞过程的基本信息，将提高我们操纵疾病免疫反应的能力，并改善人类健康。

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.