IDENTITY OF POSSIBLE LIGANDS FOR THE PREB CELL RECEPTOR

描述(改编自调查人员摘要)：B和T淋巴细胞 发育的特点是基因片段的渐进重排 在祖细胞中形成表达的功能性抗原受体 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 (TCR之前)。这些受体复合体的表达对 淋巴细胞谱系的正常发育，因为它们的任何一个突变 组件会影响血统的成熟度。尽管如此，在 经过多年的努力，前BCR和前TCR的机制(S) 其功能尚不清楚，也一直备受争议。一种模型表明， 受体的组装导致了构成成分的产生 激活信号，它允许(或诱导) 血统。另一种模型认为，受体与一种配体结合，然后 激活受体信号机制，导致持续 选定单元格的开发。支持这两种说法的间接证据 假说已经得到，但缺乏任何一种的直接证据。在这 R21应用，我们建议检验BCR前配体的假设 是存在的。我们已经生成了Pre-BCR的可溶形式，并希望使用它来 测试是否存在可能作为配体的分子 BCR之前。具体的目标是：1)识别表达分子的细胞 它们与前BCR相互作用，并决定了 相互作用(S)；2)分离和鉴定与之结合的分子 受体，作为确定其功能的前奏；以及3)确定是否 可溶性受体可抑制祖细胞B细胞间的相互作用 和配体表达(间质？)体内或体外的细胞。这些实验 可能为配体的存在提供第一个直接证据。 前B细胞受体，并将确定进一步研究的可行性 研究这些分子在B细胞发育过程中的功能。通过 以此类推，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.