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

• 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
• 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' 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

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日益严重的威胁，影响着2400多万美国人。目前的许多治疗方法 超过80种不同的自身免疫性疾病试图广泛地抑制免疫系统。但这导致 许多有害的影响，并使患者处于感染和癌症发展的风险中。目前迫切 需要开发选择性抑制自身反应性免疫反应而不损害 对病原体和肿瘤的免疫力然而，我们缺乏对分子途径的完整理解， 差异影响自身反应性和病原体特异性T细胞。DRAK 2是一种丝氨酸/苏氨酸激酶， 在淋巴细胞中的比例很高。Drak 2-/-小鼠在1型糖尿病和多发病小鼠模型中对疾病具有抵抗力 硬化症对这些自身免疫性疾病的抵抗力部分是由于靶细胞中T细胞的积累减少 Drak 2-/-小鼠与野生型小鼠相比的器官。然而，Drak 2-/-小鼠保持了有效清除 肿瘤和病原体与野生型小鼠相似，Drak 2-/- T细胞能够进入外周器官， 对病原体的反应。因此，DRAK 2在信号通路中发挥作用，该信号通路差异性地影响自身反应性 和病原体特异性T细胞。然而，DRAK 2对T细胞活化、迁移和功能的不同作用， 仍然不清楚。对DRAK 2如何影响T细胞功能的进一步了解将为以下方面提供必要的见解： 分子途径明显影响自身反应性和病原体特异性T细胞，这对于 开发出治疗自身免疫性疾病的改良疗法。为了填补这一知识空白，我将评估 DRAK 2在T细胞迁移和突触形成的关键方面，这对于最佳T细胞 activation.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， 在缺乏Drak 2的情况下，T细胞中的调节差异表达。此外，Drak 2-/- T细胞显示 与野生型T细胞相比，趋化因子、CCL 19和异常突触形态的迁移减少。 因此，我假设DRAK 2调节T细胞突触的形成和迁移，这损害了最佳的T细胞功能。 activation.为了解决这一假设，在目标1中，我将通过以下方式评估在缺乏Drak 2的情况下的T细胞迁移： 评估趋化因子受体表面表达、向趋化因子的迁移、肌动蛋白突起形成，以及 体内迁移。在目标2中，我将确定Drak 2-/- T细胞和抗原呈递细胞之间是否形成突触 与野生型T细胞相比，它们在大小、动力学或组织上不同。总之，这些研究将调查如何 DRAK 2改变T细胞迁移和突触形成的关键功能。进一步深入了解 DRAK 2在T细胞活化和功能中的作用将揭示不同影响自身反应性和病原体的途径。 特异性T细胞，这将为开发新的治疗靶点提供重要信息， 自身免疫性疾病