Role of the BCR in B lymphocyte survival and development

描述（由申请人提供）：正常细胞之间的划分 体内平衡和恶性转化是通过调节 细胞死亡和存活、增殖和分化之间的平衡。 细胞表面受体，其信号影响这些细胞之间的平衡 命运，往往这样做的方式，取决于分化和 细胞的激活状态和产生的信号强度。B 细胞抗原受体（BCR）可以产生信号，导致多种 结果取决于B细胞的发育阶段和 和受体聚集的持久性。遗传和生物化学研究 表明在B细胞的特定阶段表达各种形式的BCR 发展尽管这些受体的表达是发育所必需的， 对于B细胞，我们目前对信号是如何产生的知之甚少 在这些发展的关卡。 我们假设这些不同的受体结构的存在是为了陪伴蛋白质的合成。 BCR相关信号分子伊加和IgB进入质膜。在 质膜、伊加和IgB以配体非依赖性方式产生信号。 这一假说认为，发育中的B细胞上的BCR和BCR样结构 细胞也能够配体依赖性（在成熟BCR的情况下 作为配体非依赖性功能（BCR表达的所有阶段）。存在， 调节和生物相关性，这些配体独立的“补品” 信号代表了拟议研究的广泛目标。具体而言，在Aim 1我们建议建立配体独立信号的存在，通过 在正常生理控制的背景下的BCR，并定义为 它在生物化学上与聚集依赖性信号传导的不同程度。在 目的2我们将确定配体非依赖性滋补品的生物相关性 信号传导和在多大程度上将伊加/IgB复合物靶向质膜 定义了在定义的检查点进行正选择的最低要求， 在B细胞发育中。最后，在为目标3计划的研究中，我们希望 定义BCR紧张性信号传导的结构要求， 在B细胞发育和外周存活期间的正选择。 根据初步数据，强烈支持的中心假设， 这些研究，实现这些具体目标将提供一个新的 了解B细胞抗原受体在调节 发育和成熟B细胞的发育和存活。

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.