REGULATION OF TCRB CHAIN GENE REARRANGEMENT

描述(改编自《调查者摘要》)：淋巴细胞抗原 受体基因是通过定点重组过程组装起来的，参考文献 到AS V(D)J重组，这在以下背景下受到严格监管 淋巴细胞发育。 是适当的淋巴细胞发育阶段所必需的。因此， 对淋巴细胞发育的分子基础的重要见解。T细胞 D-β到J-β重排先于V-β到D-β重排。 此外，V-β到D-β的重排在以下情况下受到调节 等位基因排斥。他们已经证明了V-β到D-β的重排是 重组信号序列(RSS)超出12/23兼容性。的目标 负责通过5‘D-β偶联V-β到D-β重排， RSS并了解它们在调节TCRβ有序组装中的作用 T细胞发育过程中的基因。这将通过三个阶段完成 明确的目标。1.将对5‘D-beta RSS进行突变分析以 确定V-β与D-β偶联的区域 重新编排。此外，他们将确定是否通过特定的方式进行耦合 2.机制 负责通过5‘D-βRSS将V-β与D-β重排偶联 将会被澄清。他们将确定是否对5英寸的要求 D-beta RSS严格意义上是顺式作用的。如果需要反式作用因素，他们 将试图隔离这些因素。转录启动的作用， 从5‘D-beta RSS中的Tata框，在V-beta与D-beta的耦合中 将决定重新安排。3.他们将确定TCR-beta是否 等位基因排斥伴随着转录活性的变化， 此外, V-β到D-β重排偶联的潜在机制作用 将对影响等位基因排除的因素进行评估。

DESCRIPTION (Adapted from the Investigator's abstract): Lymphocyte antigen receptor genes are assembled by a site-specific recombination process, referred to as V(D)J recombination, which is tightly regulated within the context of lymphocyte development. Furthermore, expression of antigen receptor chains is required for appropriate lymphocyte developmental stage progression. Therefore, understanding the mechanistic basis of V(D)J recombination will provide important insights into the molecular basis of lymphocyte development. T-cell receptor (TCR) beta gene rearrangement is ordered during development with D-beta to J-beta rearrangement preceding V-beta to D-beta rearrangement. Furthermore, V-beta to D-beta rearrangement is regulated in the context of allelic exclusion. They have shown that V-beta to D-beta rearrangement is mechanistically coupled through constraints placed on this step by the D-beta recombination signal sequence (RSS) beyond 12/23 compatibility. The goals of the studies described in this proposal are to elucidate the mechanisms responsible for coupling of V-beta to D-beta rearrangement by the 5' D-beta, RSS and to understand their role in regulating the ordered assembly of TCR beta genes during T-cell development. This will be accomplished through three specific aims. 1. Mutational analyses of the 5' D-beta RSS will be conducted to determine the regions responsible for coupling of V-beta to D-beta rearrangement. In addition, they will determine whether coupling by specific RSSs is generalizable to other rearrangement steps. 2. The mechanisms responsible for coupling V-beta to D-beta rearrangement by the 5' D-beta RSS will be elucidated. They will determine whether the requirement for the 5' D-beta RSS is strictly cis-acting. If trans-acting factors are required, they will attempt to isolate these factors. The role of transcriptional initiation, from the TATA box in the 5' D-beta RSS, in coupling V-beta to D-beta rearrangement will be determined. 3. They will determine whether TCR-beta allelic exclusion is accompanied by changes in transcriptional activity, methylation and/or chromatin structure of V-beta gene segments. In addition, the potential mechanistic role of V-beta to D-beta rearrangement coupling in effecting allelic exclusion will be assessed.