The role of c-Abl in T cell activation

摘要 实际上，T细胞功能的每一个方面都依赖于肌动蛋白动力学的调节变化。我最近有过 表明Abelson激酶c-Abl在T细胞活化和适当的肌动蛋白反应中是必需的 迁移。与此一致的是，来自c-Abl缺陷小鼠的研究和对患者的临床研究的证据 Abl抑制剂伊马替尼治疗表明有效的T细胞介导的Abl激酶功能是必需的 豁免权。然而，人们对c-Abl在T细胞中的正常作用知之甚少。我的长期职业目标是 建立我自己的研究利基，建立一个围绕理解c-abl功能的研究计划。 免疫系统。我的直接目标是测试c-Abl通过以下方式调节T细胞激活的假设 调节肌动蛋白相关蛋白HS1和WAVE2的功能。为了检验这一假设，我将进行 三个具体目标：1)由于本地化是调节c-abl功能的关键机制，我将 C-Abl在免疫突触(IS)的募集和激活，并分析调节c-Abl的结构域。 ABL在T细胞中的定位。2)为了了解c-Abl是如何调节HS1活性的，我将确定c-Abl ABL使HS1磷酸化，并评估这种磷酸化的功能后果。另外，我会 分析活体T细胞中c-Abl和HS1的空间和功能相互作用。3)了解c-abl如何 与WAVE2相互作用，我会问c-Abl是否磷酸化WAVE2或WAVE复杂成分，并分析 C-Abl对活T细胞WAVE2定位的调节作用这些研究将在Janis博士身上进行 伯克哈特的实验室，并将利用她的实验室和儿童中心出色的研究环境 费城医院和宾夕法尼亚大学。我期望通过实施这个项目，我将获得 在研究原发T细胞反应方面的宝贵经验。特别是，我计划结合使用 先进的成像和蛋白质分析工具，在蛋白质水平上解决T细胞信号问题 动力学和信号复合体的形成。这将帮助我进入重要的和未被研究的领域 T细胞信号，并将形成我的独立研究计划的基础。

ABSTRACT Virtually every aspect of T cell function depends on regulated changes in actin dynamics. I have recently shown that the Abelson kinase c-Abl is required for appropriate actin responses in T cell activation and migration. In keeping with this, evidence from studies using c-Abl-deficient mice and clinical studies of patients treated with the Abl inhibitor imatinib indicate that Abl kinase function is required for effective T cell-mediated immunity. However, little is known about the normal role of c-Abl in T cells. My long-term career goal is to establish my own research niche, with a research program revolving around understanding c-Abl function in the immune system. My immediate goal is to test the hypothesis that c-Abl regulates T cell activation by regulating the function of the actin-associated proteins HS1 and WAVE2. To test this hypothesis, I will conduct three specific aims: 1) Since localization is a key mechanism by which c-Abl function is regulated, I will image c-Abl recruitment and activation at the immunological synapse (IS), and analyze the domains that regulate c- Abl localization in T cells. 2) To understand how c-Abl regulates HS1 activity, I will identify the sites where c- Abl phosphorylates HS1, and assess the functional consequences of this phosphorylation. In addition, I will analyze the spatial and functional interaction of c-Abl and HS1 in living T cells. 3) To understand how c-Abl interacts with WAVE2, I will ask if c-Abl phosphorylates WAVE2 or WAVE complex components, and analyze the regulatory role of c-Abl on WAVE2 localization in living T cells. These studies will be conducted in Dr. Janis Burkhardt's lab, and will draw upon the outstanding research environment in her lab and at the Children's Hospital of Philadelphia and University of Pennsylvania. I anticipate that by carrying out this project, I will gain valuable experience in studying primary T cell responses. In particular, I plan to use a combination of advanced imaging and protein analytical tools to address the problem of T cell signaling at the level of protein dynamics and signaling complex formation. This will help me to move into important and understudied areas of T cell signaling, and will form the foundation for my independent research program.