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

背景：我的研究重点是研究获得性免疫系统中辅助T细胞的调节。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如何调节辅助性T细胞这一基本问题。肾上腺素在体内不断上升和下降，但我们还不知道这是如何影响适应性免疫系统的。在这项拟议的研究中，我们将扩展辅助性T细胞如何对肾上腺素受体做出反应的基本知识。在目标(1)中，我们将描述刺激肾上腺素受体如何影响辅助T细胞信号通路，并确定这如何改变辅助T细胞的功能。在目标(2)中，我们将开发一种新的方法来测量基因表达的变化，并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性T细胞利用碳水化合物作为能量的方式的新想法。 方法：在拟议的研究中，我们将从捐献少量血液的健康人类志愿者中获取辅助T细胞。然后，这些细胞在实验室中保持存活，在那里我们将产生免疫反应，并测试刺激肾上腺素受体的各种化学物质的效果。我们将使用各种细胞学、显微镜和分子生物学技术来测量信号通路、基因和蛋白质以及碳水化合物。 相关性：我们已经发现，一些化学物质促进辅助T细胞，而其他化学物质抑制辅助T细胞。更多地了解这一机制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力的爆发。我们推测，如果自身免疫患者受到压力，他们的肾上腺素会上升，这可能会增加辅助T细胞，使他们的症状恶化。制药和生物技术公司将对这一知识感兴趣，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T细胞中的这些新的信号通路，这些信号通路可以相当多样化，并介导许多细胞反应。另一个长期目标是通过刺激人类的自然肾上腺素反应和测量他们的免疫反应来检验我们的理论。我们还将与其他研究小组合作，以应用我们的基本知识来帮助发现治疗自身免疫或免疫缺陷患者的更好方法。

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.