Role of the BCR in B lymphocyte survival and development

描述(申请人提供)：正常细胞之间的分割 动态平衡和恶性转化是通过调节 细胞死亡与存活、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，通常以一种取决于分化和 电池的激活状态和产生的信号的强度。B类 细胞抗原受体(BCR)可以产生信号，从而导致多种 结果取决于B细胞的发育阶段和程度 受体聚集的持久性。基因和生化研究已经 显示不同形式的BCR在B细胞的特定阶段表达 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 在这些发育检查点。 我们假设，这些不同的受体结构存在，以陪伴 BCR相关信号分子IgA和Igb与质膜结合。在 质膜、免疫球蛋白和免疫球蛋白以不依赖于配体的方式产生信号。 这一假说认为，发育B上的BCR和BCR样结构 细胞也能够依赖配体(在成熟的BCR的情况下) 作为配体独立的功能(bcr表达的所有阶段)。这种存在， 这些配体非依赖的“补药”的调节和生物学相关性 信号代表了拟议研究的广泛目标。具体地说，在AIM 1我们建议通过以下方法证明配体非依赖信号的存在 在正常生理控制的情况下的BCR，并定义 它与聚集依赖的信号在生化上有多大的不同。在……里面 目的2我们将确定非配体非依赖性紧张剂的生物学相关性。 IGA/IGB复合体与质膜的信号转导及靶向程度 定义在已定义的检查点进行正选择的最低要求 在B细胞发育过程中。最后，在为目标3计划的研究中，我们预计 在以下背景下定义BCR音调信令的结构要求 外周B细胞发育和存活过程中的阳性选择。 基于初步数据，这些数据有力地支持了 这些研究，实现这些具体目标，将提供一个新的 对B细胞抗原受体在调节中作用的认识 发育成熟的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.