Bright Function in the Immune System

免疫系统的明亮功能

• 批准号: 7210618
• 负责人: Carol F Webb
• 金额: $ 29.3万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7210618
• 关键词: Address; Affect; Agammaglobulinaemia tyrosine kinase; Antibodies; Antigens; B cell differentiation; B-Cell Development; B-Lymphocytes; Biological Assay; Breeding; CD40 Ligand; Cell Culture System; Cell surface; Co-Immunoprecipitations; Complex; DNA Sequence; Data; Defect; Development; Disease; Dominant Genes; Dominant-Negative Mutation; Electrophoretic Mobility Shift Assay; Enzymes; Event; Exhibits; Family; Genetic Transcription; Heavy-Chain Immunoglobulins; Human; Immune System Diseases; Immune response; Immune system; Immunoglobulins; Immunologic Deficiency Syndromes; In Vitro; Interleukin-5; Intervention; Link; Mediator of activation protein; Modeling; Modification; Mus; Pathway interactions; Patients; Phosphorylation; Production; Proliferating; Proteins; Receptors, Antigen, B-Cell; Reporter; Role; Serum; Signal Transduction; Stimulus; Surface Immunoglobulins; TFII Transcription Factors; Tertiary Protein Structure; Testing; Transgenic Animals; Transgenic Mice; Transgenic Organisms; Vaccines; inhibitor/antagonist; insight; member; mutant; promoter; research study; response; transcription factor

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.

描述（由申请人提供）：了解B淋巴细胞如何发展以及如何产生免疫球蛋白对于开发有效疫苗和干预抗体过度表达或表达抗体的免疫疾病至关重要。适当的免疫球蛋白表达直接与正常的B细胞发育有关。转录因子，明亮的（免疫球蛋白重链转录的B调节剂）增强了免疫球蛋白转录，并与Bruton的酪氨酸激酶（BTK）（BTK）（X连锁免疫缺陷疾病中的有缺陷的酶）相关。小鼠和BTK缺乏症患者在B细胞分化中表现出阻滞，导致血清免疫球蛋白水平异常低。现在的数据表明，明智的活动需要BTK功能。因此，该提案的目标是确定如何调节明亮的活动，以及是否需要正常的B细胞发育和免疫球蛋白产生。已经产生了产生显性负明亮的转基因小鼠，并将评估适当的免疫反应和B细胞亚群的发展。第三种蛋白质与明亮的功能有关，它将进一步表征，其对明亮活性的贡献，并使用常规的记者分析来解决重链转录。此外，通过识别明亮转录所需的信号传导中间体并确定明亮复合物成员之间蛋白质相互作用的需求，将通过直接分析明亮启动子来识别产生活性亮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对免疫球蛋白重链转录的理解，并将提供有关明亮活性，正常B细胞​​发育和免疫缺陷疾病之间关系的重要见解。