Mobility, organization and signalling of immune cell surface receptors

B细胞是适应性免疫反应的重要组成部分。在体内，B细胞在与其B细胞受体(BCR)结合特定抗原后可被激活(导致结合并中和入侵病原体的抗体的增殖和分泌)。众所周知，B细胞表面受体在抗原信号检测过程中会在空间上自我组织。因此，为了正确理解B细胞的激活，我们需要研究BCR等表面分子的运动，并将它们的运动与导致细胞激活的细胞内的生化反应联系起来。*这项建议侧重于使用尖端的单粒子跟踪和超分辨率显微镜作为工具来探索B细胞表面受体的纳米尺度空间动力学以及这些动力学对细胞激活的影响。为了进行实验，我们将用荧光标签标记单个受体，并使用显微镜跟踪单个分子的运动和空间分布。这些实验将使我们清楚地了解单粒子跟踪和超分辨率显微镜在这方面的优势和局限性。这项建议的第二个主要部分是开发新的数学和统计模型，帮助我们将实验数据合成一个连贯的、定量准确的图像。这些实验提供的信息将促进我们对B细胞激活的基本理解。例如，这对于了解自身免疫性疾病和对病原体的免疫反应很重要。治疗自身免疫性疾病和癌症的某些药物的工作方式模仿了免疫系统的一部分，了解控制这一复杂系统的物理参数将使我们能够了解现有药物的机制，并有可能提出新的治疗方法。发展我们在先进显微镜方面的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。这项工作的最后一个重要影响将是对熟悉免疫学和细胞生物学实验和理论/计算技术的研究人员进行持续培训。

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.