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.

抽象的 事实上，T 细胞功能的每个方面都取决于肌动蛋白动力学的调节变化。我最近有 表明 Abelson 激酶 c-Abl 是 T 细胞激活中适当肌动蛋白反应所必需的， 迁移。与此相一致的是，来自使用 c-Abl 缺陷小鼠的研究和患者临床研究的证据 用 Abl 抑制剂伊马替尼治疗表明 Abl 激酶功能是有效 T 细胞介导的 免疫。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 建立我自己的研究领域，研究项目围绕理解 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) 处募集和激活，并分析调节 c-的结构域 T 细胞中的 Abl 定位。 2) 为了了解 c-Abl 如何调节 HS1 活性，我将确定 c- Abl 磷酸化 HS1，并评估这种磷酸化的功能后果。另外，我会 分析活 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 细胞中 WAVE2 定位的调节作用。这些研究将在 Janis 博士中进行 Burkhardt 的实验室，并将利用她的实验室和儿童医院出色的研究环境 费城医院和宾夕法尼亚大学。我预计通过实施这个项目，我将获得 研究原代T细胞反应的宝贵经验。特别是，我计划结合使用 先进的成像和蛋白质分析工具可解决蛋白质水平上的 T 细胞信号传导问题 动力学和信号复合物的形成。这将帮助我进入重要且未被充分研究的领域 T 细胞信号传导，并将构成我的独立研究计划的基础。