Mechanism of Immunoglobulin Hypermutation

免疫球蛋白超突变机制

基本信息

批准号：
7882585
负责人：
URSULA B STORB
金额：
$ 46.81万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-05-01 至 2012-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): This is a proposal for the continuation of studies of the molecular basis of somatic hypermutation (SHM) of immunoglobulin (Ig) genes. The discovery of the cytidine deaminase, AID, has clearly identified the deamination of C as the first step in SHM. Based on the current knowledge, the mutation process can be viewed as follows: AID specifically associates with Ig genes (and a few other genes, such as BCL6, IgD, and IgD. AID creates C to U deaminations in both the top and bottom strand of the targeted gene, starting within 200 bp from the promoter and extending for about 1 to 2 kb. The 3' end of the gene is spared. The uracil is repaired in an error-prone fashion, resulting in an excess of transitions over transversions from all four nucleotides. The details of the process are not understood. They can be considered as three major complexes of questions. 1) How are Ig genes (and a few other genes) specifically targeted by AID and how are the mutations restricted to the first 1-2 kb from the promoter? 2) Since AID in vitro is highly restricted to C-deamination in single-stranded, not double-stranded DMA, how can both strands be equally targeted during SHM? 3) How does error-prone repair become involved in the process and how are mutations from A and T created? It is proposed in this grant application to study these questions. The planned experiments are important for determining how the varied repertoire of Ig genes is created with the potential to react against any foreign antigenic substance, including tumor cell antigens. Somatic hypermutation has also been implicated in autoimmune diseases. Furthermore, many B cell lymphomas arise apparently as a consequence of the somatic mutation process. It is likely that understanding the components involved in somatic mutation will aid in understanding the genetic and environmental causes of autoimmunity, and the treatment of infectious diseases and tumors.

描述（由申请人提供）：这是继续研究免疫球蛋白（IG）基因的体细胞超突变（SHM）的研究的建议。细胞丁胺脱氨酶AID的发现清楚地将C的脱氨酸是SHM的第一步。基于当前的知识，突变过程可以如下：辅助工具与Ig基因（以及其他一些基因（例如Bcl6，IgD和Igd。辅助）在目标基因的顶部和底部链中创造了c c c c c c c c o deaminations c o deaminations of the靶基因的基因，从200 bp的200 bp中开始，从启动子开始，并扩展了1至2 kb的基因，该基因是3''inter in 3''in 3''in 3''in 3''ene of 3''in 3''ene of the 3''ene the 3''ene the 3''ene the 3''ins of the 3''ene the n of。从所有四个核苷酸的横向上，易用的方式都无法理解该过程的细节。 2）由于体外的援助高度限于单链而不是双链DMA中的C解调，因此在SHM期间，这两个链如何被同样靶向？ 3）如何参与该过程，如何创建A和T突变？在此赠款申请中提出了研究这些问题。计划的实验对于确定如何创建Ig基因的各种曲目，其潜力可能与任何外国抗原物质（包括肿瘤细胞抗原）反应。躯体超突变也与自身免疫性疾病有关。此外，许多B细胞淋巴瘤显然是由于体细胞突变过程而产生的。了解躯体突变所涉及的成分可能有助于理解自身免疫性的遗传和环境原因，以及治疗传染病和肿瘤的治疗。