Modulation of T lymphocyte Activation by ß2-Adrenergic Receptor Signalling Pathways

α2-肾上腺素能受体信号通路对 T 淋巴细胞激活的调节

• 批准号: RGPIN-2019-06980
• 负责人: Darlington, Peter
• 金额: $ 2.33万
• 依托单位: Concordia University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=753413
• 关键词: Modulation; lymphocyte; Activation; Adrenergic; Receptor

Background: My research program is focused on studying the regulation of helper T cells in the adaptive immune system. Helper T cells detect infections and coordinate the immune system response against infections. T cells have to be regulated by the body, otherwise they can accidentally attack self-tissue leading to autoimmunity, or, if they fail to function properly, opportunistic infections could occur. My laboratory studies the basic question of how adrenaline hormones regulate helper T cells. Adrenaline is constantly rising and falling in the body, but we do not yet understand how this affects the adaptive immune system. In the proposed research we will expand the basic knowledge of how helper T cells respond to adrenaline receptors. In objective (1) we will characterize how stimulating the adrenaline receptor affects helper T cell signalling pathways, and determine how this alters the function of helper T cells. In objective (2) we will develop a new protocol to measure changes in gene expression, and use this to determine how the adrenaline receptors alter the function of helper T cells. In objective (3) we will test a novel idea about how adrenaline receptors alter the way helper T cells use carbohydrates for energy. Methods: For the proposed research, we will get helper T cells from healthy human volunteers who donate a small amount of blood. The cells are then kept alive in the laboratory where we will create an immune response and test the effects of various chemicals that stimulate adrenaline receptors. We will measure signalling pathways, genes and proteins, and carbohydrates using a variety of cytometry, microscopy, and molecular biology techniques. Relevance: We have discovered that some chemicals boost helper T cells, while other chemicals inhibit helper T cells. Understanding more about how this works will help immunologists improve their models describing the immune system. Another way to apply the fundamental knowledge that we create is in the understanding of how behaviour alters the immune system. For example, stress is known to suppress immunity against viruses, but stress can also cause flare-ups in autoimmunity. We speculate that if an autoimmune patient gets stressed their adrenaline goes up, which may boost helper T cells making their symptoms worse. Pharmaceutical and biotechnology companies will be interested in this knowledge to develop new drugs to treat autoimmune diseases, and patients may better understand their symptoms. Future directions: Our long term objectives are to study these novel signalling pathways in helper T cells, which can be quite diverse and mediate many cellular responses. Another long term goal is to test our theories by stimulating natural adrenaline responses in humans and measuring their immune responses. We will also collaborate with other research groups in order to apply our basic knowledge to help discover better ways to treat people with autoimmunity or immune-deficiencies.

背景：我的研究项目主要集中在研究辅助性T细胞在适应性免疫系统中的调节。辅助T细胞检测感染并协调免疫系统对感染的反应。T细胞必须受到身体的调节，否则它们可能会意外地攻击自身组织，导致自身免疫，或者，如果它们不能正常发挥作用，可能会发生机会性感染。我的实验室研究肾上腺素激素如何调节辅助性T细胞的基本问题。肾上腺素在体内不断上升和下降，但我们还不知道它如何影响适应性免疫系统。在拟议的研究中，我们将扩展辅助T细胞如何响应肾上腺素受体的基本知识。在目标（1）中，我们将描述刺激肾上腺素受体如何影响辅助性T细胞信号通路，并确定这如何改变辅助性T细胞的功能。在目标（2）中，我们将开发一种新的方案来测量基因表达的变化，并使用它来确定肾上腺素受体如何改变辅助T细胞的功能。在目标（3）中，我们将测试一个关于肾上腺素受体如何改变辅助T细胞使用碳水化合物作为能量的方式的新想法。方法：对于拟议的研究，我们将从捐献少量血液的健康人类志愿者中获得辅助性T细胞。然后，这些细胞在实验室中保持活力，我们将在那里产生免疫反应，并测试刺激肾上腺素受体的各种化学物质的影响。我们将测量信号通路，基因和蛋白质，碳水化合物使用各种细胞计数，显微镜和分子生物学技术。 相关性：我们发现，一些化学物质促进辅助性T细胞，而其他化学物质抑制辅助性T细胞。了解更多关于这是如何工作的，将有助于免疫学家改进他们描述免疫系统的模型。应用我们创造的基础知识的另一种方式是理解行为如何改变免疫系统。例如，众所周知，压力会抑制对病毒的免疫力，但压力也会导致自身免疫的爆发。我们推测，如果一个自身免疫病患者感到压力，他们的肾上腺素就会上升，这可能会增加辅助性T细胞，使他们的症状恶化。制药和生物技术公司将对这些知识感兴趣，以开发治疗自身免疫性疾病的新药，患者可能会更好地了解他们的症状。 未来方向：我们的长期目标是研究辅助性T细胞中的这些新的信号通路，这些信号通路可以是相当多样化的，并介导许多细胞反应。另一个长期目标是通过刺激人体的天然肾上腺素反应并测量其免疫反应来测试我们的理论。我们还将与其他研究小组合作，以应用我们的基本知识，帮助发现更好的方法来治疗自身免疫或免疫缺陷的人。