Mobility, organization and signalling of immune cell surface receptors

免疫细胞表面受体的移动性、组织和信号传导

• 批准号: RGPIN-2015-04611
• 负责人: Coombs, Daniel
• 金额: $ 3.79万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=648041
• 关键词: Mobility; organization; signalling; immune; cell

B cells are an essential part of the adaptive immune response. In vivo, B cells can become activated (leading to proliferation and secretion of antibodies that bind to and neutralize invading pathogens) after binding specific antigens with their B cell receptors (BCR). B cell surface receptors are known to spatially organize themselves during antigenic signal detection. Therefore, in order to obtain a proper understanding of B cell activation, we need to study the motion of surface molecules such as BCR and relate their motion to the biochemical reactions within the cell that lead to cell activation. ******This proposal focuses on the use of cutting-edge single particle tracking and super-resolution microscopy as tools to probe the nanometer-scale spatial dynamics of B cell surface receptors and the impact of those dynamics on cellular activation. To perform the experiments, we will label individual receptors with fluorescent tags and track the motion and spatial distribution of individual molecules using microscopy. These experiments will allow us to clearly understand the strengths and limitations of single particle tracking and super-resolution microscopy in this context. A second major part of this proposal is to develop new mathematical and statistical models that will help us to synthesize the experimental data into a coherent, quantitatively accurate picture.******The information from these experiments will advance our basic understanding of B cell activation. This is important in understanding autoimmune diseases and the immune response to pathogens, for instance. Certain classes of drugs for treatment of autoimmune disorders and cancers work in a way that mimics part of the immune system, and understanding the physical parameters that govern this complex system will allow us to understand the mechanism of existing drugs and potentially propose new therapies. Developing our expertise in advanced microscopy will lead to new collaborative work with cell biologists and immunologists around the world. A final important impact of the work will be the ongoing training of researchers who are conversant with experimental and theoretical/computational techniques in immunology and cell biology.

B细胞是自适应免疫反应的重要组成部分。在体内，B细胞可以被激活（导致与其B细胞受体（BCR）结合特异性抗原后，与结合并中和入侵病原体结合并中和入侵病原体的抗体的扩增和分泌。 B细胞表面受体在抗原信号检测过程中在空间上组织自身。因此，为了获得对B细胞活化的正确了解，我们需要研究表面分子（例如BCR）的运动，并将其运动与细胞内导致细胞活化的生化反应相关联。 *****该提案的重点是使用尖端的单个粒子跟踪和超分辨率显微镜作为探测B细胞表面受体的纳米尺度空间动力学的工具，以及这些动力学对细胞激活的影响。为了执行实验，我们将使用显微镜标记具有荧光标签的单个受体，并使用显微镜跟踪单个分子的运动和空间分布。这些实验将使我们能够清楚地了解在这种情况下单个粒子跟踪和超分辨率显微镜的优势和局限性。该提案的第二个主要部分是开发新的数学和统计模型，这些模型将帮助我们将实验数据综合为连贯的，定量准确的图片。******这些实验中的信息将提高我们对B细胞激活的基本理解。例如，这对于理解自身免疫性疾病和对病原体的免疫反应很重要。某些治疗自身免疫性疾病和癌症治疗的药物以模仿免疫系统的一部分的方式起作用，并且了解控制这种复杂系统的物理参数将使我们能够了解现有药物的机制，并可能提出新的疗法。开发我们的高级显微镜专业知识将导致与世界各地的细胞生物学家和免疫学家进行新的合作工作。这项工作的最终重要影响将是对研究人员的持续培训，这些研究人员熟悉了免疫学和细胞生物学方面的实验和理论/计算技术。