The role of c-Abl in T cell activation

c-Abl 在 T 细胞激活中的作用

• 批准号: 8242647
• 负责人: Yanping Huang
• 金额: $ 12.22万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242647
• 关键词: ABL1 gene; Actins; Address; Adverse effects; Affect; Antibodies; Area; Autoimmunity; Biosensor; Cell physiology; Cells; Cellular Immunity; Clinical Research; Complex; Cytoskeleton; Disease; Environment; Event; Family; Fluorescence Microscopy; Foundations; Gastrointestinal Neoplasms; Goals; Image; Imatinib; Immune system; Immunologic Deficiency Syndromes; Inflammatory; Life; Maps; Mass Spectrum Analysis; Molecular; Movement; Mus; Mutate; Patients; Pediatric Hospitals; Pennsylvania; Philadelphia; Phosphorylation; Phosphorylation Site; Phosphotransferases; Protein Dynamics; Proteins; Research; Resistance; Role; Signal Transduction; Signaling Molecule; Site; Structure; T cell differentiation; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Tyrosine Phosphorylation; Universities; analytical tool; base; c-abl Proto-Oncogenes; career; cell motility; cell type; chemokine; experience; genetic regulatory protein; human YWHAQ protein; immunological synapse; immunological synapse formation; in vivo; inhibitor/antagonist; kinase inhibitor; leukemia/lymphoma; migration; mutant; polymerization; programs; protein function; research study; response; tool

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.

摘要 事实上，T细胞功能的每个方面都依赖于肌动蛋白动力学的调节变化。我最近 显示Abelson激酶c-Abl是T细胞活化中适当肌动蛋白反应所需的， 迁移与此一致，来自使用c-Abl缺陷小鼠的研究和患者的临床研究的证据 用Abl抑制剂伊马替尼治疗表明，Abl激酶功能是T细胞介导的有效免疫应答所必需的。 免疫力然而，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，研究计划围绕理解c-Abl功能， 免疫系统.我的近期目标是检验c-Abl通过以下方式调节T细胞活化的假设： 调节肌动蛋白相关蛋白HS 1和WAVE 2的功能。为了验证这个假设，我将进行 三个具体目标：1）由于定位是调节c-Abl功能的关键机制，我将想象 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。 T细胞中Abl定位。2)为了了解c-Abl如何调节HS 1活性，我将确定c-Abl在HS 1中的作用位点。 Abl磷酸化HS 1，并评估这种磷酸化的功能后果。此外，我将 分析c-Abl和HS 1在活T细胞中的空间和功能相互作用。3)为了了解c-Abl 与WAVE 2相互作用，我将询问c-Abl是否磷酸化WAVE 2或WAVE复合物组分，并分析 c-Abl对WAVE 2在活T细胞中定位的调节作用。这些研究将在Dr. Janis Burkhardt的实验室，并将利用她的实验室和儿童实验室的优秀研究环境， 费城医院和宾夕法尼亚大学。我期望通过实施这个项目， 研究原发性T细胞反应的宝贵经验。特别是，我计划使用 先进的成像和蛋白质分析工具，以解决蛋白质水平的T细胞信号传导问题 动力学和信号复合物的形成。这将有助于我进入重要和未充分研究的领域， T细胞信号，并将形成我的独立研究计划的基础。