Investigating a novel role of DRAK2 in T cell migration and synapse formation

研究 DRAK2 在 T 细胞迁移和突触形成中的新作用

基本信息

批准号：
10680274
负责人：
Benjamin Andrew Wilander
金额：
$ 4.37万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10680274
关键词：
Actins Address Affect Affinity American Antigen-Presenting Cells Area Autoantigens Autoimmune Diseases Autoimmunity CCL19 gene Cell Adhesion Molecules Cell Survival Cell physiology Cellular biology Central Nervous System Chemotactic Factors Cytoskeletal Modeling Data Development Disease Disease Resistance Event Failure Frequencies Genes Health Homeostasis Image Analysis Immune Immune response Immune system Immunity Immunology Immunosuppression Impairment Infection Inflammatory Insulin-Dependent Diabetes Mellitus Kinetics Knowledge Lymphocyte Lymphoid Cell Malignant Neoplasms Measures Mediating Mentorship Microscopy Modeling Molecular Morphology Multiple Sclerosis Mus Organ Pathway interactions Patients Peptides Peripheral Persons Polymers Process Protein-Serine-Threonine Kinases Public Health Regulation Resistance Resources Risk Role Saint Jude Children&apos s Research Hospital Serine Signal Pathway Signal Transduction Stimulus Stromal Cells Surface Synapses T cell response T cell therapy T-Cell Activation T-Lymphocyte Techniques Testing Therapeutic United States Wild Type Mouse autoreactive T cell autoreactivity cell motility chemokine chemokine receptor differential expression experience experimental study genetic regulatory protein immunological synapse immunological synapse formation improved in vivo insight migration mouse model new therapeutic target novel pathogen polymerization response synaptogenesis training opportunity tumor

项目摘要

Project Summary Autoimmune disease is a rising threat that affects over 24 million Americans. Many of the current therapies for the over 80 distinct autoimmune diseases seek to broadly suppress the immune system. However, this leads to many deleterious effects and leaves patients at risk for development of infection and cancer. There is an urgent need to develop therapeutics that selectively inhibit the autoreactive immune response without compromising immunity to pathogens and tumors. However, we lack a complete understanding of molecular pathways that differentially impact autoreactive and pathogen-specific T cells. DRAK2 is a serine/threonine kinase expressed highly in lymphocytes. Drak2-/- mice are resistant to disease in mouse models of type 1 diabetes and multiple sclerosis. Resistance to these autoimmune diseases is partly due to reduced accumulation of T cells in the target organs of Drak2-/- mice compared to wildtype mice. However, Drak2-/- mice maintain the ability to effectively clear tumors and pathogens similar to wildtype mice, and Drak2-/- T cells are able to enter peripheral organs in response to pathogens. Thus, DRAK2 functions in a signaling pathway that differentially impacts autoreactive and pathogen-specific T cells. However, the distinct roles of DRAK2 on T cell activation, migration, and function remain unclear. A further understanding of how DRAK2 impacts T cell function will provide essential insight into molecular pathways distinctly affecting autoreactive and pathogen-specific T cells, which is critical in order to develop improved therapies for autoimmune diseases. To fill this gap in knowledge, I will evaluate the role of DRAK2 in critical aspects of T cell migration and synapse formation, which are essential for optimal T cell activation. My preliminary data demonstrate that genes associated with migration, synapse formation, and actin regulation are differentially expressed in T cells in the absence of Drak2. Additionally, Drak2-/- T cells display decreased migration to the chemokine, CCL19 and abnormal synapse morphology compared to wildtype T cells. Thus, I hypothesize that DRAK2 regulates T cell synapse formation and migration, which impairs optimal T cell activation. To address this hypothesis, in Aim 1, I will assess T cell migration in the absence of Drak2 by evaluating chemokine receptor surface expression, migration to chemokines, actin protrusion formation, and in vivo migration. In Aim 2, I will determine if synapses formed between Drak2-/- T cells and antigen presenting cells differ in size, kinetics, or organization compared to wildtype T cells. Together, these studies will investigate how DRAK2 alters the critical T cell functions of migration and synapse formation. Further insight into the role of DRAK2 in T cell activation and function will reveal pathways that differentially impact autoreactive and pathogen- specific T cells, which will provide important information for developing novel therapeutic targets to treat autoimmune disease.

项目摘要自身免疫性疾病是一种不断增长的威胁，影响了超过2400万美国人。许多目前的疗法超过80种不同的自身免疫性疾病试图广泛抑制免疫系统。但是，这导致了许多有害影响，并使患者有感染和癌症发展的风险。有紧急需要开发有选择地抑制自动反应反应而不会损害的治疗剂对病原体和肿瘤的免疫力。但是，我们对分子途径的完全了解差异影响自动反应性和病原体特异性T细胞。 Drak2是一种丝氨酸/苏氨酸激酶高度在淋巴细胞中。 Drak2 - / - 小鼠在1型糖尿病的小鼠模型中对疾病具有抗性和多种硬化。对这些自身免疫性疾病的抗性部分是由于T细胞在靶标的中积累降低与野生型小鼠相比，drak2 - / - 小鼠的器官。但是，drak2 - / - 小鼠保持有效清除的能力肿瘤和病原体类似于野生型小鼠，Drak2 - / - T细胞能够进入外围器官对病原体的反应。因此，drak2在信号通路中起作用，从而差异影响自动反应和病原体特异性T细胞。但是，drak2在T细胞激活，迁移和功能中的不同作用保持不清楚。对DRAK2如何影响T细胞功能的进一步理解将为您提供基本洞察力分子途径明显影响自动反应性和病原体特异性T细胞，这对于至关重要开发改进的自身免疫性疾病的疗法。为了填补知识的差距，我将评估 Drak2在T细胞迁移和突触形成的临界方面，对于最佳T细胞至关重要激活。我的初步数据表明，与迁移，突触形成和肌动蛋白相关的基因在没有Drak2的情况下，调节在T细胞中差异表达。此外，Drak2 - / - T细胞显示与野生型T细胞相比，向趋化因子，CCL19和异常突触形态的迁移减少。因此，我假设Drak2调节T细胞突触的形成和迁移，这会损害最佳的T细胞激活。为了解决这一假设，在AIM 1中，我将在没有Drak2的情况下评估T细胞迁移评估趋化因子受体表面表达，迁移至趋化因子，肌动蛋白突出形成，并在体内迁移。在AIM 2中，我将确定是否在Drak2 - / - T细胞和抗原呈递细胞之间形成突触与野生型T细胞相比，大小，动力学或组织不同。这些研究将共同研究 Drak2改变了迁移和突触形成的关键T细胞功能。进一步了解 T细胞活化和功能中的Drak2将揭示差异影响自动反应和病原体的途径特定的T细胞将为开发新的治疗靶标提供重要信息自身免疫性疾病。