Bright Function in the Immune System

描述（由申请方提供）：了解B淋巴细胞如何发育以及免疫球蛋白如何产生，对于开发有效疫苗和干预抗体过度或不足表达的免疫疾病至关重要。适当的免疫球蛋白表达与正常的B细胞发育直接相关。转录因子Bright（免疫球蛋白重链转录的B细胞调节因子）增强免疫球蛋白转录，并与X连锁免疫缺陷病中的缺陷酶布鲁顿酪氨酸激酶（Btk）相关。患有Btk缺陷的小鼠和患者表现出B细胞分化受阻，导致血清免疫球蛋白水平异常低。现在的数据表明，Bright活动非常需要Btk功能。因此，本提案的目的是确定Bright活性是如何调节的，以及它是否是正常B细胞发育和免疫球蛋白产生所必需的。已经产生了产生显性阴性Bright的转基因小鼠，并将评估其适当的免疫反应和B细胞亚群的发育。第三种蛋白质与Bright功能有关，将对其进行进一步表征，并将使用常规报告基因测定来解决其对Bright活性和重链转录的贡献。此外，将通过直接分析Bright启动子，通过鉴定Bright转录所需的信号传导中间体和通过确定Bright复合物成员之间蛋白质相互作用的要求来鉴定导致活性Bright复合物信息的转录和翻译后调节事件。这些实验的结果将有助于我们理解免疫球蛋白重链转录的一般，并将提供重要的见解之间的关系明亮的活动，正常B细胞的发展和免疫缺陷疾病。

DESCRIPTION (provided by applicant): Understanding how B lymphocytes develop and how immunoglobulin is produced is critical for development of effective vaccines and for intervention in immunologic diseases where antibodies are either over-or under-expressed. Appropriate immunoglobulin expression is directly linked to normal B cell development. The transcription factor, Bright (B cell regulator of immunoglobulin heavy chain transcription) enhances immunoglobulin transcription and associates with Bruton's tyrosine kinase (Btk), the defective enzyme in X-linked immunodeficiency disease. Mice and patients with Btk deficiencies exhibit blocks in B cell differentiation that result in abnormally low serum immunoglobulin levels. Data now suggest that Bright activity critically requires Btk function. Therefore, the objectives of this proposal are to determine how Bright activity is regulated and whether it is required for normal B cell development and immunoglobulin production. Transgenic mice producing dominant negative Bright have been produced and will be assessed for appropriate immune responses and development of B cell subpopulations. A third protein has been implicated in Bright function, and it will be further characterized and its contribution to Bright activity and heavy chain transcription will be addressed using conventional reporter assays. In addition, the transcriptional and post-translational regulatory events that result information of active Bright complexes will be identified by direct analysis of the Bright promoter, by identifying signaling intermediates necessary for Bright transcription and by determining the requirements for protein interactions among members of the Bright complex. The results of these experiments will contribute to our understanding of immunoglobulin heavy chain transcription in general, and will provide important insights regarding the relationships between Bright activity, normal B cell development and immunodeficiency disease.