Regulation and Dysregulation of Antibody Diversification

抗体多样化的调节和失调

• 批准号: 8304390
• 负责人: MATTHEW STROUT
• 金额: $ 17.44万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-10 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8304390
• 关键词: Affect; Alternative Splicing; Animals; Antibodies; B lymphoid malignancy; B-Cell Lymphomas; B-Lymphocytes; Base Excision Repairs; Biology; Cell Line; Cellular Stress; Chromosomal Instability; Chronic Lymphocytic Leukemia; Cytidine; Cytosine; DNA; DNA Repair; DNA Repair Pathway; DNA-Directed DNA Polymerase; Data; Deamination; Development; Disease; Equilibrium; Event; Frequencies; Gene Expression; Gene Mutation; Genes; Genetic; Genome; Genome Stability; Genomic Instability; Genomics; Genotoxic Stress; Goals; Guanine; Hematologic Neoplasms; Hepatitis C virus; Human; Immune; Immunoglobulin Class Switching; Immunoglobulin Genes; Immunoglobulin Somatic Hypermutation; Immunoglobulin Switch Recombination; Immunoglobulins; Infection; Instruction; Knockout Mice; Left; Lesion; Malignant - descriptor; Malignant lymphoid neoplasm; Mediating; Mismatch Repair; Modeling; Molecular; Molecular Profiling; Mus; Mutate; Mutation; Nature; Pathogenesis; Pathway interactions; Pattern; Phase; Physiological; Play; Point Mutation; Principal Investigator; Printing; Process; Proto-Oncogenes; Regulation; Research; Research Proposals; Role; Specimen; Structure of germinal center of lymph node; T-Lymphocyte; Testing; Transgenic Mice; Uracil; Variant; Virus Diseases; activation-induced cytidine deaminase; foot; infected B cell; insight; leukemia/lymphoma; mouse model; neoplastic; repaired; stressor; transition mutation

Activation-Induced cytidine deaminase (AID) is expressed in germinal center B cells and is required for somatic hypermutation (SHM) and class switch recombination (CSR) of immunoglobulin genes. Aberrant targeting of AID to proto-oncogenes has also been implicated in the pathogenesis of B cell malignancies. AID has the potential to trigger mutations and chromosome instability throughout the genome but many genes are protected by high-fidelity DNA repair of AID-mediated events. The mechanisms responsible for guiding AID to its genetic target and determining whether a mutation will be repaired in a high-fidelity or low- fidelity manner are not understood. The central hypothesis underlying this proposal is that B cells have a specific mechanism for maintaining genomic stability in the face of SHM and CSR and that events leading to the breakdown of this mechanism contribute to AID-mediated genomic instability and malignant transformation. Here, a combination of animal and cell line models will be used to study the dynamic relationship of AID activity and DNA repair under both normal and neoplastic conditions. In Specific Aim 1, mouse models of AID expression and DNA repair will be used to identify the lineage-specific mechanism that protects the B cell genome during SHM and investigate the contribution of AID-associated DNA repair pathways to the pathogenesis of lymphoid malignancy. In Specific Aim 2, exogenous cellular stressors that perturb the balance of high-fidelity and low-fidelity DNA repair following AID activity will be characterized and used as a means for identifying factors that regulate the mutation threshold and in an actively mutating B cell. In Specific Aim 3, the role of AID in the pathogenesis of B cell chronic lymphocytic leukemia (B-CLL) will be defined in a mouse model of this disease and the functional nature of AID will be characterized in human B-CLL cell lines and primary B-CLL specimens. We anticipate that this research will provide insight into the basic mechanism that regulates immune diversification in B cells and serve a long-term objective of identifying the molecular steps involved in the pathogenesis of lymphoid malignancy. RELEVANCE (See Instructions): Aberrant targeting of natural immune diversification processes contributes to mutations of genes associated with certain types of leukemia and lymphoma of B cell origin. This research will serve to identify how genes are normally protected from this activity and will define how a breakdown of protective mechanisms leads to the development of hematologic cancers.

激活诱导的胞苷脱氨酶（AID）在生发中心B细胞中表达，需要 免疫球蛋白基因的体细胞超突变（SHM）和类开关重组（CSR）。异常 对原始基因的辅助靶向也与B细胞恶性肿瘤的发病机理有关。 援助有可能在整个基因组中触发突变和染色体不稳定性 基因受辅助介导的事件的高保真DNA修复的保护。负责的机制 引导援助其遗传靶标，并确定是否将在高保真度或低 - 忠实的方式不了解。该提议的基本假设是B细胞具有A 在SHM和CSR面前维持基因组稳定性的特定机制以及导致的事件 这种机制的分解有助于辅助介导的基因组不稳定性和恶性肿瘤 转型。在这里，将使用动物和细胞系模型的组合来研究动态 在正常和肿瘤条件下，援助活动和DNA修复的关系。在特定的目标1中， 辅助表达和DNA修复的小鼠模型将用于确定谱系特异性机制 在SHM期间保护B细胞基因组并研究与AID相关的DNA修复的贡献 淋巴恶性肿瘤发病机理的途径。在特定的目标2中，外源性细胞应激源 在助攻活动后，高保真性和低保真DNA修复的平衡将被表征，并且 用作识别调节突变阈值并在积极突变B中的因素的手段 细胞。在特定的目标3中，辅助在B细胞慢性淋巴细胞性白血病（B-CLL）中的作用 将在该疾病的小鼠模型中定义，辅助的功能性质将在 人B-CLL细胞系和主要B-CLL标本。我们预计这项研究将提供洞察力 进入调节B细胞中免疫多样化的基本机制，并具有长期目标 识别淋巴恶性肿瘤发病机理所涉及的分子步骤。 相关性（请参阅说明）： 自然免疫多样化过程的异常靶向有助于相关基因的突变 具有某些类型的白血病和B细胞起源的淋巴瘤。这项研究将有助于确定基因 通常受到保护免受此活动的保护，并将定义保护机制的分解如何导致 血液学癌症的发展。