IDENTITY OF POSSIBLE LIGANDS FOR THE PREB CELL RECEPTOR

描述（改编自研究者摘要）：B和T淋巴细胞 发育的特征是基因片段的进行性重排 在祖细胞中形成功能性抗原受体 在成熟细胞上。祖细胞组装独特的阶段特异性版本 在这些受体中，前B细胞受体（pre-BCR）和前T细胞受体（pre-T cell receptor （TCR前）。这些受体复合物的表达对于细胞的生长至关重要。 淋巴细胞谱系的正常发育，因为它们中的任何一个突变， 组分损害谱系的成熟。然而，在 尽管经过多年的努力，前BCR和前TCR 其功能尚不清楚，仍存在很大争议。一个模型表明， 受体的组装导致组成性的 激活信号，允许（或诱导）持续发展的 脉另一种模型认为受体与配体结合， 激活受体信号机制，导致持续的 选择细胞的发展。间接证据支持 已经有了一些假设，但缺乏直接的证据。在这 R21的应用，我们建议测试的假设，前BCR的配体 存在.我们已经生成了前BCR的可溶形式，并希望使用它来 测试可能作为配体的分子的存在， 前BCR。具体目标是：1）鉴定表达分子的细胞 与前BCR相互作用，并决定 2）为了分离和表征由相互作用结合的分子， 受体，作为确定其功能的前奏;和3）确定是否 可溶性受体可抑制B祖细胞之间的相互作用 和配体表达（基质？）细胞，体内或体外。这些实验 可能提供了第一个直接的证据，为配体的存在， 前B细胞受体，并将建立额外的研究的可行性 以表征这些分子在B细胞发育中的功能。通过 类似地，这些研究也可能为T细胞发育提供新的见解。

DESCRIPTION (Adapted from Investigator's Abstract): B and T lymphocyte development is characterized by the progressive rearrangement of gene segments in progenitor cells to form the functional antigen receptors that are expressed on mature cells. The progenitor cells assemble unique stage-specific versions of these receptors, the pre-B cell receptor (pre-BCR) and pre-T cell receptor (pre-TCR). The expression of these receptor complexes is critical for the normal development of the lymphocyte lineages, since a mutation in any of their components compromises the maturation of the lineage. Nevertheless, and in spite of years of effort, the mechanism(s) by which the pre-BCR and pre-TCR function is unknown, and remains highly controversial. One model suggests that the assembly of the receptors results in the generation of a constitutive activation signal, which permits (or induces) the continued development of the lineage. Another model suggests that the receptor engages a ligand, which then activates the receptor signaling machinery, leading to the continued development of the selected cell. Circumstantial evidence supporting both hypotheses has been obtained but direct evidence for either is lacking. In this R21 application, we propose to test the hypothesis that ligands for the pre-BCR exist. We have generated a soluble form of the pre-BCR and wish to use it to test for the existence of molecules that might serve as ligands for the pre-BCR. The specific aims are: 1) To identify cells that express molecules that interact with the pre-BCR, and determine the specificity of the interaction(s); 2) To isolate and characterize the molecules bound by the receptor, as a prelude to determining their function; and 3) To determine if the soluble receptor can inhibit the interactions between progenitor B cells and ligand-expressing (stromal?) cells, in vivo or in vitro. These experiments may provide the first direct evidence for the existence of ligands for the pre-B cell receptor, and will establish the feasibility of additional studies to characterize the function of these molecules in B cell development. By analogy, these studies may also provide novel insights into T cell development.