The role of c-Abl in T cell activation

c-Abl 在 T 细胞激活中的作用

基本信息

批准号：
8034240
负责人：
Yanping Huang
金额：
$ 11.92万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
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/8034240
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

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：实际上 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。我最近证明，T 细胞激活和迁移中适当的肌动蛋白反应需要 Abelson 激酶 c-Abl。与此相一致的是，使用 c-Abl 缺陷小鼠的研究和使用 Abl 抑制剂伊马替尼治疗的患者的临床研究的证据表明，Abl 激酶功能是有效的 T 细胞介导的免疫所必需的。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自己的研究领域，研究项目围绕了解免疫系统中的 c-Abl 功能。我的近期目标是检验 c-Abl 通过调节肌动蛋白相关蛋白 HS1 和 WAVE2 的功能来调节 T 细胞活化的假设。为了检验这个假设，我将实现三个具体目标：1）由于定位是调节 c-Abl 功能的关键机制，我将对免疫突触 (IS) 处的 c-Abl 募集和激活进行成像，并分析这些域调节 T 细胞中的 c-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的位点，并评估这种磷酸化的功能后果。此外，我将分析活 T 细胞中 c-Abl 和 HS1 的空间和功能相互作用。 3）为了了解c-Abl如何与WAVE2相互作用，我将询问c-Abl是否磷酸化WAVE2或WAVE复杂成分，并分析c-Abl对活体T细胞中WAVE2定位的调节作用。这些研究将在 Janis Burkhardt 博士的实验室进行，并将利用她的实验室以及费城儿童医院和宾夕法尼亚大学的出色研究环境。我预计通过开展这个项目，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来解决蛋白质动力学和信号复合物形成水平上的 T 细胞信号传导问题。这将帮助我进入 T 细胞信号传导的重要且未被充分研究的领域，并将为我的独立研究项目奠定基础。