Bright Function in the Immune System

免疫系统的明亮功能

• 批准号: 7393813
• 负责人: Carol F Webb
• 金额: $ 28.74万
• 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/7393813
• 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 淋巴细胞如何发育以及免疫球蛋白如何产生对于开发有效疫苗以及干预抗体过度表达或表达不足的免疫疾病至关重要。适当的免疫球蛋白表达与正常 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）可增强免疫球蛋白转录，并与布鲁顿酪氨酸激酶 (Btk)（X 连锁免疫缺陷病中的缺陷酶）相关。 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 活动迫切需要 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正常 B 细胞发育和免疫球蛋白生产是否需要它。产生显性失活 Bright 的转基因小鼠已经生产出来，并将对其适当的免疫反应和 B 细胞亚群的发育进行评估。第三种蛋白质与 Bright 功能有关，将对其进行进一步表征，并使用传统的报告基因检测来解决其对 Bright 活性和重链转录的贡献。此外，通过直接分析 Bright 启动子、识别 Bright 转录所需的信号中间体以及确定 Bright 成员之间蛋白质相互作用的要求，将鉴定产生活性 Bright 复合物信息的转录和翻译后调控事件。复杂的。这些实验的结果将有助于我们对免疫球蛋白重链转录的总体理解，并将提供有关 Bright 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。