Emergence of developmental and genomic complexity in a basal vertebrate

基础脊椎动物发育和基因组复杂性的出现

• 批准号: 8117647
• 负责人: Chris T. Amemiya
• 金额: $ 53.31万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8117647
• 关键词: Antibodies; Antibody Diversity; Antigens; Binding; Biochemical; Biological; Biological Process; Biomedical Research; Cells; Complex; DNA Sequence; DNA Sequence Rearrangement; Data; Development; Embryo; Embryonic Development; Evolution; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Face; Fc Receptor; Gene Rearrangement; Genes; Genetic; Genetic Recombination; Genetic Screening; Genome; Genomics; Goals; Growth; Hagfish; Immune; Immune response; Immune system; Immunoglobulin Genes; Immunoglobulins; Immunologic Receptors; Immunologist; Investigation; Lampreys; Leucine-Rich Repeat; Ligands; Link; Literature; Logic; Lymphocyte; Lymphoid; Mammals; Mediating; Methods; Molds; Molecular; Monoclonal Antibodies; Natural History; Nature; Organogenesis; Pattern; Play; Positioning Attribute; Process; Receptor Gene; Research; Research Infrastructure; Role; Solutions; Structure; System; Taxon; Time; Vertebrates; Work; adaptive immunity; base; clinically relevant; comparative; crystal-8; hematopoietic tissue; immune function; innovation; interest; novel; programs; public health relevance; receptor; repository; research study; vaccinology

DESCRIPTION (provided by applicant): The existence of an adaptive immune system in the lamprey, a jawless basal vertebrate, was posited 40 years ago based on histological analysis and classical immune challenge experiments. Many comparative immunologists believed that lampreys must possess immunoglobulins because mammals employ them in their immune response. However, evidence for immunoglobulins was evasive. Finally, in 2004, Max Cooper and colleagues discovered that the lamprey lack immunoglobulins but rather employ an altogether different receptor species as an antibody. This lamprey antibody, known as the variable lymphocyte receptor (VLR) uses leucine rich repeat motifs to make its receptor face. Analogous to the immunoglobulin system, though probably not because of common ancestry, the VLRs also utilize a genetic recombination mechanism to generate vast somatic antibody diversity. This finding was unexpected, given the ancient natural history of the lamprey and its accepted use by comparative biologists as a primitive vertebrate "outgroup." This finding has led to intense interest in the immunological aspects of the VLR system. Despite its basal position, the lamprey has proven to be a valuable repository of new information as much for its differences as for its similarities. To that extent, we have recently discovered that: (1) VLR plays a key role in early embryonic development in addition to its role as an antibody receptor; (2) VLR is involved in providing the cellular microenvironment for building the immune system that subsequently yields the cells that express these antibodies; and (3) programmed genome rearrangements restructure the VLR locus during embryogenesis. The Specific Aims of our proposal are focused around these three observations and take advantage of the complementary expertise of the two PIs, the tractability of the lamprey for experimental work, and the large infrastructure that has been created at Caltech for its functional study. We propose an integrated set of experiments that further define the developmental role of VLRs and elucidate the early VLR repertoire and logic by which the embryonic genomic rearrangements occur at the VLR locus. Our overarching goal in this line of investigation is to understand the biological strategies that allow the amalgamation of complex basic processes that, in this case, involve both immune protection and development. The three independent Aims are inextricably linked by aspects of the VLR system and comprise a mixture of necessary fundamental, as well as more venturesome, experiments. PUBLIC HEALTH RELEVANCE: The emergence of "adaptive immunity" is considered a major innovation in the origin of the vertebrates, and efforts to understand its genetic underpinnings and molecular mechanisms have been at the forefront of biomedical research and vaccinology for the last few decades. The variable lymphocyte receptor (VLR) is a novel modular receptor system that has recently been discovered in a lineage representing an early offshoot in vertebrate evolution. Its role in adaptive immunity has been shown to be analogous to that of immunoglobulins, and recent literature has referred to VLRs as "antibodies" despite that fact that they are structurally very different than immunoglobulins. We now have strong evidence that the VLRs are additionally involved in building the early embryo, a completely different role than its antibody function and one that may seem paradoxical for several reasons, particularly with regard to self/non-self recognition and the functional biological limits inherent in a highly diversified receptor system. At a fundamental level, it is of interest to know how such a modular receptor system could have emerged, how it functions, and how it can be molded for deployment in vastly different biological contexts. The VLRs are also of biotechnological [and possibly clinical] relevance since the molecules can be manipulated to encompass many of the same features as conventional monoclonal antibodies.

描述（由申请人提供）：七鳃鳗是一种无颌的基底脊椎动物，40年前根据组织学分析和经典的免疫攻击实验提出七鳃鳗存在适应性免疫系统。许多比较免疫学家认为，七鳃鳗必须拥有免疫球蛋白，因为哺乳动物在免疫反应中使用它们。然而，免疫球蛋白的证据是回避。最后，在2004年，Max库珀和同事发现七鳃鳗缺乏免疫球蛋白，而是使用一种完全不同的受体作为抗体。这种七鳃鳗抗体，被称为可变淋巴细胞受体（VLR），使用富含亮氨酸的重复基序使其受体面对。与免疫球蛋白系统类似，尽管可能不是因为共同的祖先，但VLR也利用遗传重组机制来产生大量的体细胞抗体多样性。考虑到七鳃鳗的古老自然历史以及比较生物学家将其作为原始脊椎动物“外群”的公认用法，这一发现是出人意料的。“这一发现引起了人们对VLR系统免疫学方面的浓厚兴趣。尽管它的基础地位，七鳃鳗已被证明是一个有价值的新信息库，因为它的差异和相似之处。在这种程度上，我们最近发现：（1）VLR除了作为抗体受体的作用外，还在早期胚胎发育中发挥关键作用;（2）VLR参与提供用于构建免疫系统的细胞微环境，随后产生表达这些抗体的细胞;（3）程序性基因组重排在胚胎发生期间重构VLR基因座。我们提案的具体目标围绕这三个观察结果，并利用两个PI的互补专业知识，实验工作中七鳃鳗的易处理性，以及加州理工学院为其功能研究创建的大型基础设施。我们提出了一套完整的实验，进一步定义的发展作用的VLR和阐明的早期VLR剧目和逻辑胚胎基因组重排发生在VLR基因座。我们在这方面的调查的首要目标是了解生物学策略，允许合并复杂的基本过程，在这种情况下，涉及免疫保护和发展。这三个独立的目标是由VLR系统的各个方面紧密联系在一起的，包括必要的基本实验和更冒险的实验。 公共卫生相关性：“适应性免疫”的出现被认为是脊椎动物起源的重大创新，并且在过去几十年中，理解其遗传基础和分子机制的努力一直处于生物医学研究和疫苗学的最前沿。 可变淋巴细胞受体（VLR）是最近在脊椎动物进化的早期分支中发现的一种新的模块化受体系统。其在适应性免疫中的作用已显示类似于免疫球蛋白的作用，并且最近的文献将VLR称为“抗体”，尽管事实上它们在结构上与免疫球蛋白非常不同。我们现在有强有力的证据表明，VLR还参与了早期胚胎的构建，这是一个与其抗体功能完全不同的作用，而且由于多种原因，特别是在自我/非自我识别和功能生物学方面，这似乎是自相矛盾的。高度多样化的受体系统中固有的限制。 在基本层面上，了解这样一个模块化受体系统是如何出现的，它是如何发挥作用的，以及它是如何被塑造成在截然不同的生物环境中部署的，是很有意义的。VLR也具有生物技术[和可能的临床]相关性，因为可以操纵分子以包含与常规单克隆抗体相同的许多特征。