Cell decision underlying B-cell immune responses

B 细胞免疫反应的细胞决策

基本信息

批准号：
10094180
负责人：
Alexander Hoffmann
金额：
$ 42.7万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10094180
关键词：
Address Adjuvant Affinity Antibodies Antibody Affinity Antibody Diversity Antibody Response Antigens B Cell Proliferation B cell differentiation B-Lymphocytes Cell Cycle Cell Differentiation process Cell Size Cell Survival Cells Cessation of life Chromatin Computer Models Computer Simulation Data Decision Making Down-Regulation Effectiveness Equilibrium Event Failure Family member Feedback Funding Generations Genomics Goals Growth Heterogeneity Humoral Immunities Immune Immune response Immunoglobulin Somatic Hypermutation Individual Interferometry Literature Lymphoma Mediating Memory B-Lymphocyte Microscopy Modeling Molecular Mouse Strains Mus Phase Physiological Plasma Plasma Cells Population Population Dynamics Process Proliferating Race Reaction Reporter Repression Signal Transduction Software Tools Stimulus Structure Structure of germinal center of lymph node System Systems Biology Technology Testing Trees Vaccination Vaccine Antigen Venus c-myc Genes dimer genetic pedigree improved in vivo live cell microscopy mathematical model multi-scale modeling mutant novel plasma cell differentiation programs response simulation tool

项目摘要

Project Summary/Abstract A hallmark of the humoral immune response is a two phased antibody response, the first being rapid and providing for low affinity antibodies, and the second occurring with a week delay but providing high affinity antibodies. An appropriate balance of both phases of the response is critical for an effective immune response. The two phased humoral immune response is governed by B-cell population dynamics that represent the composite of the decisions made by individual cells whether to enter a growth phase and the cell cycle that results in division, whether to survive or die, and whether to differentiate into antibody secreting plasma cells and/or memory B-cells. At any given timepoint there is a great variety of B-cell fates, and prior studies assumed that this is due to stochastic fate decisions by individual cells at each generation. Instead, our recently established long-term microscopy workflow revealed that cells make highly deterministic fate decisions, and that the cell-to-cell variability within the population is largely due to heterogeneity in the founder cells. This renders humoral immunity substantially more predictable, so long as we have a mechanistic understanding of how molecular networks control B-cell decision making in proliferation and differentiation. The overarching goal of the proposed project is to develop quantitative understanding and multi-scale model of how the multi-dimeric NFκB system controls B-cell decision making to effect cell survival, proliferation, and differentiation. The overarching hypothesis of the proposed studies is that the coordinated dynamics of NFκB family members RelA and cRel control the phasing of B-cell proliferation and differentiation and thus the affinity, abundance and diversity of antibodies and hence efficacy of the humoral immune response. We will address this hypothesis with an iterative systems biology approach structured into following three Specific Aims: 1. Delineate how NFκB system dynamics control the lineages of proliferating B-cells 2. Delineate how NFκB system dynamics control plasma B-cell differentiation 3. NFκB system control of humoral immunity in vivo: phasing low and high affinity antibody responses Each Aim involves novel multiscale mathematical modeling and quantitative experimentation, including unprecedented long term microscopy, novel fluorescent reporter mouse strains, and single cell genomic technologies.

项目摘要/摘要体液免疫响应的标志是两种分阶段抗体反应，第一种抗体迅速且提供低亲和力抗体，第二次出现在一周的延迟中，但提供了高亲和力抗体。反应的两个阶段的适当平衡对于有效的免疫至关重要回复。两种分阶段的体液免疫响应由B细胞种群动力学控制，代表单个细胞做出的决定是否进入生长阶段和细胞周期的综合导致分裂，无论是生存还是死亡，以及是否分化为分泌浆细胞的抗体和/或内存B细胞。在任何给定的时间点上都有多种B细胞命运和先前的研究假设这是由于每一代单个细胞的随机命运决定。相反，我们的最近建立的长期显微镜工作流程表明，细胞成为高度确定性的命运决策，并且人群内的细胞间变异性很大程度上是由于创始人的异质性细胞。只要我们有机械了解分子网络如何控制B细胞决策在增殖和分化中。拟议项目的总体目标是建立定量理解和多尺度模型多维NFκB系统如何控制B细胞决策以实现细胞存活，增殖和分化。拟议研究的总体假设是NFκB家族成员的协调动力学 Rela和Crel控制B细胞增殖和分化的分量，因此具有抽象性抗体的多样性以及体液免疫响应的效率。我们将通过迭代系统生物学方法来解决这一假设具体目的： 1。描述NFκB系统动力学如何控制增殖B细胞的谱系 2。描述NFκB系统动力学如何控制等离子体B细胞分化 3。体内体内免疫组织性的NFκB系统控制：低和高亲和力抗体反应每个目标都涉及新颖的多尺度数学建模和定量实验，包括前所未有的长期显微镜，新型荧光报告基因菌株和单细胞基因组技术。