Functional roles of lipid domains in B cell signaling

脂质结构域在 B 细胞信号传导中的功能作用

基本信息

批准号：
10393588
负责人：
Sarah L Veatch
金额：
$ 28.31万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10393588
关键词：
Actins Adaptive Immune System Adaptor Signaling Protein Affinity Aging Amino Acid Motifs Antigens Apoptosis Autoimmunity B cell differentiation B-Cell Activation B-Cell Antigen Receptor B-Cell Development B-Lymphocytes Biochemical Biosensor Cell Surface Proteins Cell Surface Receptors Cell membrane Cell surface Cells Cellular biology Characteristics Chemicals Coupling Cytoskeleton Data Decision Making Defect Development Disease Drug Targeting Elements Event Exposure to Fluorescence Funding Future Goals Health Heterogeneity Human Image Immune System Diseases Immune response Immune system Immunodeficiency and Cancer Immunologic Deficiency Syndromes Immunotherapeutic agent Knowledge Lateral Lead Ligands Light Lipids Literature Lymphoma MAP Kinase Gene Mediating Membrane Membrane Proteins Methodology Microscopy Mission Modeling Outcome Pathway interactions Peripheral Pharmaceutical Preparations Phase Phosphoric Monoester Hydrolases Phosphotransferases Play Receptor Activation Receptor Signaling Regulation Reporting Research Resolution Role Signal Transduction Spatial Distribution Structure Techniques Technology Testing Tyrosine Phosphorylation United States National Institutes of Health Vesicle Work cancer cell crosslink effective intervention experimental study extracellular human disease immune function immunoregulation innovation membrane model novel strategies optogenetics physical model predictive modeling preference prevent receptor receptor function reconstitution release of sequestered calcium ion into cytoplasm response scaffold src-Family Kinases tool tyrosine receptor

项目摘要

PROJECT SUMMARY B cells sense and manipulate the lateral organization of numerous cell surface receptors in order to facilitate their functional roles within the immune system. Receptor clustering as a physical mode of signal initiation is ubiquitous in B cells, yet the corresponding general mechanisms by which clustering is sensed and controlled by intracellular components are unknown. A mechanistic understanding of clustering-mediated B cell signaling events is essential because they play important roles in immune function, defects lead to diseases such as cancer and immunodeficiency, and widely used immunotherapeutic drugs exploit these mechanisms. The goal of this work is to develop a framework that describes how receptor organization is tied to receptor functions for the class of B cell surface receptors that partition with ordered membrane domains. The working hypothesis is that ordered domain stabilization provides a fundamental paradigm for the initiation and regulation of diverse B cell signaling responses. The proposed research is guided by a predictive model of B cell receptor (BCR) signaling developed in the previous funding cycle and experimentally tests predictions of this model extended beyond BCR signaling alone. Guided by extensive preliminary data, three specific aims will be pursued: 1) Establish a generalized mechanism of signaling activated by clustering B cell surface proteins, 2) Modulate B cell membrane organization and signaling through optogenetic control of scaffolding elements, and 3) Identify immunomodulatory roles facilitated by membrane domains in BCR signaling. The first aim will establish a general sensing mechanism that describes signals initiated via clustering of more than 15 distinct B cell surface proteins that are reported in the literature to partition with ordered domains. The second aim will define how scaffolding elements template functional membrane organization that spans plasma membrane leaflets and the contribution of this effect to ligand-independent signaling. The third aim will identify and isolate the roles that phase-like membrane domains play in downstream cellular decision-making by modulating signals initiated through the BCR. All aims use quantitative super-resolution fluorescence localization microscopy techniques with the sensitivity to detect subtle domain-mediated interactions in chemically fixed and live cells. The proposed work is innovative because it applies predictive models of membrane organization and exploits recent advances in super-resolution imaging, biosensor technology, and optogenetics. A broadly applicable mechanistic model for B cell signaling will drive future advances in basic B cell biology, elucidate the mechanisms underlying the efficacy of several widely used B cell-targeted drugs, and provide new approaches for the treatment of immune diseases.

项目摘要 B细胞感知并操纵众多细胞表面受体的横向组织以促进它们在免疫系统中的功能作用。作为信号启动的物理模式的受体聚类是在B细胞中无处不在，但是感测和控制聚类的相应一般机制细胞内组件是未知的。对聚类介导的B细胞信号的机械理解事件是必不可少的，因为它们在免疫功能中起重要作用，缺陷导致疾病，例如癌症和免疫缺陷，并广泛使用免疫治疗药物来利用这些机制。目标这项工作的是开发一个框架，描述受体组织如何与受体功能相关联与有序膜结构域分配的B细胞表面受体的类别。工作假设是该有序的域稳定为启动和调节b提供了基本范式细胞信号反应。拟议的研究以B细胞受体（BCR）的预测模型为指导在先前的资金周期中开发的信号传导，并通过实验测试该模型扩展的预测仅超越BCR信号。在广泛的初步数据的指导下，将追求三个具体目标：1）建立通过聚类B细胞表面蛋白激活的信号传导的通用机制，2）调节B 细胞膜组织和通过对脚手架元件的光遗传学控制的信号传导，3）确定膜域在BCR信号传导中促进的免疫调节作用。第一个目标将建立一般传感机制描述了通过超过15个不同的B细胞表面蛋白聚类引发的信号在文献中报道了与有序域分配的。第二个目标将定义脚手架元素模板功能膜组织跨越质膜传单和贡献这对不依赖配体的信号传导的影响。第三个目标将识别和隔离相似的角色膜域通过调节通过 BCR。所有目标都使用定量超分辨率荧光定位显微镜技术与检测化学固定和活细胞中微妙的结构域介导的相互作用的敏感性。拟议的工作是创新，因为它应用了膜组织的预测模型，并利用了最新进展超分辨率成像，生物传感器技术和光遗传学。广泛适用的机械模型 B细胞信号传导将推动基本B细胞生物学的未来进步，阐明几种广泛使用B细胞靶向药物的功效，并提供了治疗免疫的新方法疾病。