Isotype Exclusion and Hypermutation in the Nurse Shark

护士鲨的同种型排斥和超突变

• 批准号: 6838254
• 负责人: ELLEN HSU
• 金额: $ 25.44万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6838254
• 关键词: antibody receptor; gene expression; gene mutation; gene rearrangement; genetic regulation; immunogenetics; immunoglobulin genes; immunoglobulin isotypes; polymerase chain reaction; receptor expression; sharks

DESCRIPTION (provided by applicant): Sharks and skates are representatives of the earliest vertebrates with an immune system based on immunoglobulin (Ig) receptors that diversify by gene rearrangement and somatic mutation. The recognition motifs and enzymatic machinery involved in the two processes point to mechanistically unrelated pathways that arose independently. We hypothesize that, before sharks, the prototype antigen receptor may have diversified only by mutation; the mechanism of rearrangement became introduced later in evolution and is not an intrinsic part of the regulatory process for expression. We propose to: (1) investigate the role of rearrangement in the shark, which carries multiple Ig loci and germline-rearranged genes. We will establish whether the shark Ig receptors are clonally expressed, if there is a hierarchy of activation among the many loci, and if productive rearrangements, germline or somatic, feed back to modulate expression of others. (2) investigate a novel mechanism in L chain mutants, non-templated insertion. Our goal is to examine the patterns of change to determine how such structures are formed during the hypermutation process. We will also study H chain mutation, to obtain a comprehensive picture of somatic hypermutation in one species of this early vertebrate. The information emerging from this research will provide new understanding for the evolution of mechanisms for antibody diversification and the rearrangement process and give insight into the emergence of a specific, clonal recognition of the pathogenic non-self.

描述（由申请人提供）：鲨鱼和鳐鱼是最早具有基于免疫球蛋白（Ig）受体的免疫系统的脊椎动物的代表，该受体通过基因重排和体细胞突变而多样化。这两个过程中涉及的识别基序和酶机制指向独立产生的机械上不相关的途径。我们假设，在鲨鱼出现之前，原型抗原受体可能仅通过突变而多样化；重排机制是在进化后期引入的，并不是表达调节过程的固有部分。我们建议： (1) 研究重排在鲨鱼中的作用，鲨鱼携带多个 Ig 位点和种系重排基因。我们将确定鲨鱼 Ig 受体是否克隆表达，多个基因座之间是否存在激活层次结构，以及生产性重排（种系或体细胞）是否反馈以调节其他基因座的表达。 (2)研究L链突变体的新机制，非模板插入。我们的目标是检查变化模式，以确定这些结构在超突变过程中是如何形成的。我们还将研究 H 链突变，以获得这种早期脊椎动物的一个物种体细胞超突变的全面图景。 这项研究中出现的信息将为抗体多样化和重排过程的机制进化提供新的理解，并深入了解致病性非自我的特异性克隆识别的出现。