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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.

项目概要 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。受体聚类作为信号起始的物理模式是在 B 细胞中普遍存在，但感知和控制聚类的相应一般机制细胞内成分的作用尚不清楚。对聚类介导的 B 细胞信号转导的机制理解事件至关重要，因为它们在免疫功能中发挥着重要作用，缺陷会导致疾病，例如癌症和免疫缺陷以及广泛使用的免疫治疗药物都利用了这些机制。目标这项工作的重点是开发一个框架，描述受体组织如何与受体功能联系起来一类以有序膜域分隔的 B 细胞表面受体。工作假设是有序域稳定化为多种 B 的启动和调节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上一个融资周期中开发的信号并通过实验测试了该模型的预测扩展不仅仅是 BCR 信号传导。在大量初步数据的指导下，将实现三个具体目标：1) 建立通过聚集 B 细胞表面蛋白激活信号传导的通用机制，2) 调节 B 通过支架元件的光遗传学控制进行细胞膜组织和信号传导，以及 3) 识别 BCR 信号转导中膜结构域促进的免疫调节作用。第一个目标是建立一个总体传感机制，描述通过超过 15 种不同 B 细胞表面蛋白聚集引发的信号文献中报道了用有序域进行分区。第二个目标将定义脚手架如何元素模板跨越质膜小叶的功能性膜组织及其贡献这种效应对配体依赖性信号传导的影响。第三个目标将识别并隔离类似阶段的角色膜结构域通过调节通过细胞膜发起的信号在下游细胞决策中发挥作用 BCR。所有目标均使用定量超分辨率荧光定位显微镜技术检测化学固定细胞和活细胞中微妙的域介导的相互作用的灵敏度。拟议的工作是创新性在于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础 B 细胞生物学的未来进步，阐明 B 细胞信号传导背后的机制多种广泛使用的B细胞靶向药物的疗效，为免疫性疾病的治疗提供新途径疾病。