Transcriptional Control of AICDA Expression

AICDA 表达的转录控制

基本信息

批准号：
6909937
负责人：
FERENC LIVAK
金额：
$ 7.43万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2007-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Immunoglobulin somatic hypermutation and class switch recombination increase the specificity and expand the functionality of the antibody repertoire in response to antigenic challenge to provide better protection against infections. Both processes involve highly ordered, temporal destabilization of the genome in mature B lymphocytes. Regulation of this genomic destabilization appears to be crucial in controlling lymphoid tumorgenesis. One important regulatory mechanism is the transcriptional control of expression of the activation-induced cytidine deaminase (AICDA) gene. AICDA provides a central catalytic activity to both hypermutation and class switch recombination, is the only known lymphoid-specific component of both processes and its transcription is predominantly restricted to germinal center B-lymphocytes. Characterization of the transcriptional control of AICDA gene expression is essential to understand the physiological regulation of hypermutation and class switch recombination and could illuminate potential pathological aberrations that lead to uncontrolled genomic instability and tumorgenesis. We have characterized the transcription of the AICDA gene in murine B-cell lines, determined the transcription start site in established cell lines and primary, splenic B-cells and identified a putative promoter of the AICDA gene which is evolutionarily conserved. In this application, we propose to perform experiments to: i) identify additional regulatory regions within the AICDA locus, ii) establish transgenic models to test the function of candidate regulatory elements, and iii) perform biochemical characterization of DNA-protein interactions of the regulatory elements in vivo to identify candidate transcription factors that may be critical in the control of AICDA expression. The results of this pilot proposal will allow us to begin studies on the cellular signal transduction pathways and transcriptional regulatory factors that control somatic hypermutation and class switch recombination of immunoglobulin genes.

描述（由申请人提供）：免疫球蛋白体细胞超誉和类开关重组提高了特异性并扩大抗体库的功能，以应对抗原挑战，以更好地保护感染。这两个过程都涉及成熟B淋巴细胞中基因组的高度有序的暂时稳定。这种基因组不稳定的调节似乎对于控制淋巴肿瘤发生至关重要。一种重要的调节机制是激活诱导的胞苷脱氨酶（AICDA）基因表达的转录控制。 AICDA为超成名和类转换重组提供了中心催化活性，这是两种过程中唯一已知的淋巴特异性成分，其转录主要限于生发中心B-淋巴细胞。 AICDA基因表达的转录控制的表征对于了解过度突变和类转换重组的生理调节至关重要，并且可以阐明导致不受控制的基因组不稳定和肿瘤发生的潜在病理性畸变。我们已经表征了AICDA基因在鼠B细胞系中的转录，并确定了已建立的细胞系和原代脾B细胞中的转录起始位点，并确定了AICDA基因的推定启动子，该基因在进化上保守。在此应用中，我们建议执行实验：i）确定AICDA基因座内的其他调节区域，ii）建立转基因模型来测试候选调节元素的功能，iii）执行DNA-蛋白质相互作用的生化特征，以识别候选转录因子的调节元素可以识别出对Criencation Cartive contercess the Aniicda aicicda aicicda siicda siicda aikicda sicicda sista aiceDa cantercription nectripation元素的相互作用。该试点建议的结果将使我们能够开始研究控制体超孕和免疫球蛋白基因的类转换重组的细胞信号转导途径和转录调节因素。