RNA-directed targeting of AID in immunity and cancer

RNA定向靶向AID在免疫和癌症中的作用

基本信息

批准号：
10664029
负责人：
Jayanta Chaudhuri
金额：
$ 53.1万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10664029
关键词：
Antigen Presentation Antigens B lymphoid malignancy B-Cell Activation B-Cell Lymphomas B-Lymphocytes Base Pairing Binding Cell Death Cells Cellular Immunity Chromatin Chromosomal translocation Cytidine Deaminase DNA DNA Double Strand Break DNA Structure Deamination Defect Deoxycytidine Deoxyuridine Double Strand Break Repair Exons Failure Funding Future G-Quartets Gene Expression Gene Expression Regulation Generations Genes Genetic Transcription Genome Goals Growth Guanine Guide RNA Heavy-Chain Immunoglobulins Human Humoral Immunities IGH@ gene cluster Immune response Immunity Immunoglobulin Class Switching Immunoglobulin Genes Immunoglobulin Somatic Hypermutation Immunoglobulin Switch Recombination Immunologic Deficiency Syndromes Induced Mutation Ions Knock-in Mouse Knowledge Lead Lesion Lymphoma Lymphomagenesis Malignant Neoplasms Mature B-Lymphocyte Mediating Memory B-Lymphocyte Molecular Conformation Mus Mutate Mutation Oncogenic Pathologic Patients Physiological Plasma Cells Process Proteins RNA RNA Splicing Reaction Residencies Rest Role Shelter facility Structure Structure of germinal center of lymph node Testing Text Transcript activation-induced cytidine deaminase cancer type experimental study gene correction genome integrity genome-wide humoral immunity deficiency interest large cell Diffuse non-Hodgkin&apos s lymphoma novel preservation recruit response

项目摘要

ABSTRACT Upon encountering antigens, mature B cells express activation induced cytidine deaminase (AID) and undergo immunoglobulin heavy chain (Igh) class switch recombination (CSR) and somatic hypermutation (SHM). CSR proceeds through the obligate generation of DNA double strand breaks (DSBs), which constitute one of the most toxic lesions that can occur in a cell. A single unrepaired DSB can cause cell death or potentiate chromosomal translocations that are hallmarks of many types of cancer, including lymphomas. Thus, mechanisms that promote generation of DSBs and facilitate DSB repair are intergral to both immunity and preservation of genomic integrity. In this proposal we test the notion that non-canonical DNA structures such as G-quadruplexes target the DNA deaminase AID to the chromatin during CSR (aim 1) and that AID can regulate expression of non-Ig genes to influence B cell responses (aim 2). Successful completion of the experiments will have far reaching implications in our understanding of both B cell immunity and B cell lymphomas.

抽象的遇到抗原后，成熟 B 细胞表达激活诱导的胞苷脱氨酶 (AID)，并经历免疫球蛋白重链 (Igh) 类转换重组 (CSR) 和体细胞超突变 (SHM)。企业社会责任通过必然产生 DNA 双链断裂 (DSB) 来进行，这构成了 DNA 双链断裂之一细胞中可能发生的大多数毒性损伤。单个未修复的 DSB 可导致细胞死亡或增强染色体易位是许多类型癌症（包括淋巴瘤）的标志。因此，促进 DSB 生成和促进 DSB 修复的机制对于免疫和免疫系统都是不可或缺的。保持基因组完整性。在这个提案中，我们测试了非规范 DNA 结构的概念，例如因为 G-四链体在 CSR 过程中将 DNA 脱氨酶 AID 靶向染色质（目标 1），并且 AID 可以调节非 Ig 基因的表达以影响 B 细胞反应（目标 2）。圆满完成了实验将对我们对 B 细胞免疫和 B 细胞的理解产生深远的影响淋巴瘤。