Role of the BCR in B lymphocyte survival and development

BCR 在 B 淋巴细胞存活和发育中的作用

• 批准号: 6511409
• 负责人: John G Monroe
• 金额: $ 8.92万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6511409
• 关键词: B cell receptor; B lymphocyte; biological signal transduction; cell membrane; genetically modified animals; immunoglobulins; laboratory mouse; ligands; lymphopoiesis; protein structure function; receptor binding; receptor expression

DESCRIPTION (provided by applicant): The division between normal cellular homeostasis and malignant transformation is maintained by regulation of the balance between cell death and survival, proliferation and differentiation. Cell surface receptors, whose signals affect the balance between these cell fates, often do so in a manner that depends upon the differentiation and activation state of the cell and the strength of the signal generated. The B cell antigen receptor (BCR) can generate signals that lead to a variety of outcomes depending upon the developmental stage of the B cell and the degree and persistence of receptor aggregation. Genetic and biochemical studies have shown that various forms of the BCR are expressed at defined stages of B cell development. Although expression of these receptors is required for development of B cells, we currently have little understanding of how signals are generated at these developmental checkpoints. We hypothesize that these different receptor structures exist to chaperone the BCR-associated signaling molecules Iga and IgB to the plasma membrane. At the plasma membrane, Iga and IgB generate signals in a ligand-independent manner. This hypothesis maintains that the BCR and BCR-like structures on developing B cells are capable of ligand-dependent (in the case of the mature BCR) as well as ligand-independent functions (all stages of BCR expression). The existence, regulation, and biological relevance of these ligand-independent "tonic" signals represent the broad goals of the proposed studies. Specifically, in Aim 1 we propose to establish the existence of ligand-independent signals through the BCR within the context of normal physiological control and to define to what extent it differs biochemically from aggregation-dependent signaling. In Aim 2 we will determine the biological relevance of ligand-independent tonic signaling and to what extent targeting Iga/IgB complexes to the plasma membrane defines the minimal requirement for positive selection at defined, checkpoints in B cell development. Finally, in studies planned for Aim 3, we expect to define the structural requirements for BCR tonic signaling in the context of positive selection during B cell development and survival in the periphery. Based upon preliminary data that strongly support the central hypothesis of these studies, accomplishing these specific aims will provide a new understanding of the role of the B cell antigen receptor in regulating development and survival of developing and mature B cells.

描述（由申请人提供）：正常细胞之间的分裂 通过调节，稳态和恶性转变可以保持 细胞死亡与生存，增殖和分化之间的平衡。 细胞表面受体，其信号会影响这些细胞之间的平衡 命运，通常以取决于差异化和 细胞的激活状态和产生的信号的强度。 b 细胞抗原受体（BCR）可以产生导致各种各样的信号 结果取决于B细胞的发育阶段和程度 和受体聚集的持久性。遗传学和生化研究具有 表明在B细胞的定义阶段表达了各种形式的BCR 发展。尽管这些受体的表达需要发育 在B单元中，我们目前对信号的产生方式几乎没有理解 在这些发展检查点。 我们假设存在这些不同的受体结构来伴侣 BCR相关的信号分子IgA和IGB与质膜。在 质膜，IGA和IGB以非配体的方式产生信号。 该假设坚持认为，BCR和BCR样结构用于发展B 细胞也能够依赖配体依赖（在成熟的BCR中） 作为非配体无关的功能（BCR表达的所有阶段）。存在， 这些独立于配体的“补品”的调节和生物学相关性 信号代表拟议研究的广泛目标。具体来说，目的 1我们建议通过 在正常生理控制的背景下的BCR，并将其定义为 它在多大程度上与依赖聚集的信号传导不同。在 目的2我们将确定与配体无关滋补的生物学相关性 信号传导以及靶向IgA/IGB复合物到质膜的程度 定义了在定义的检查点上选择正选择的最小要求 在B细胞发育中。最后，在计划为AIM 3的研究中，我们希望 在上下文中定义BCR滋补信号的结构要求 B细胞发育期间的阳性选择和周围生存期。 基于强烈支持的初步数据 这些研究，完成这些具体目标将为新的 了解B细胞抗原受体在调节中的作用 发育和成熟B细胞的发展和存活。