The Molecular Basis of Allorecognition in Social Amoeba

社会阿米巴同种异体识别的分子基础

• 批准号: 8320434
• 负责人: GAD SHAULSKY
• 金额: $ 10.65万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8320434
• 关键词: Acquired Immunodeficiency Syndrome; Adhesions; Alleles; Amino Acids; Amoeba genus; Autoimmune Diseases; Biochemical; Biological Models; Candidate Disease Gene; Cell Adhesion; Cells; Communication; Computing Methodologies; Cooperative Behavior; Data; Defect; Development; Dictyostelium; Dictyostelium discoideum; Equilibrium; Evolution; Extracellular Domain; Family Study; Gene Family; Genes; Genetic; Genetic Polymorphism; Genome; Genomics; Health; Human; Human Development; Human Genome; Immune; Immune system; Immunoglobulin Variable Region; Individual; Integral Membrane Protein; Knock-out; Life; Mediating; Membrane Proteins; Methods; Modeling; Molecular; Molecular Genetics; Mutagenesis; Mutation Analysis; Natural Immunity; Organ; Organism; Pathway interactions; Patients; Physiological; Population; Process; Property; Protein Binding; Protein Family; Proteins; Resolution; Role; Signal Transduction; Specificity; Structure; System; Testing; Tissues; Work; base; cancer transplantation; cell type; gene function; gene replacement; genome sequencing; mutant; protein protein interaction; research study; segregation; social; tool

DESCRIPTION (provided by applicant): Self/nonself recognition is a fundamental aspect of life. The evolution of cellular cooperation that led to tissues, organs and multicellular organisms is thought to have required the development of robust mechanisms of self/nonself recognition, or allorecognition, to preclude exploitation by genetically dissimilar competitors. The social amoeba, Dictyostelium discoideum, is an excellent model system in which cell adhesion, signaling and tissue formation during development have been studied extensively and for which powerful molecular genetic tools have been developed. We propose that cells integrate adhesion and communication during D. discoideum development to optimize cellular cooperation through a process of allorecognition that favors communal sporulation between genetically related individuals. Wild isolates of D. discoideum display cooperative behavior that is directly proportional to their genetic relatedness and we have uncovered a family of proteins that may form part of the molecular basis for this cooperation. This idea is based on our findings that the adhesion protein LagC1 and the related protein LagB1 are required for the cellular cooperation needed to integrate cells into a multicellular tissue, their genes are co-regulated, both display evidence of positive or balancing selection, suggestive of adaptive evolution, and their sequence polymorphism correlates well with allorecognition. Genes of the LagC1 type are abundant and polymorphic in the human genome as well, suggesting that the mechanisms we find in Dictyostelium would be relevant and applicable to human development and innate immunity. We hypothesize that highly polymorphic membrane proteins may mediate allorecognition in general, and that the specific proteins LagB1 and LagC1 interact functionally to mediate allorecognition through allele-specific intercellular adhesion and signaling, thus favoring cooperative sporulation of genetically similar individuals. To test these hypotheses, we will search the Dictyostelium genome for genes that encode polymorphic transmembrane proteins and test their correlation with allorecognition (segregation) between wild strains. We will further study the role of the most correlated proteins in allorecognition using mutagenesis and gene replacement approaches following the example of studying the specific roles of LagB1 and LagC1 in the process. PUBLIC HEALTH RELEVANCE: Allorecognition (self/nonself recognition) in humans is mainly achieved by our adaptive immune system whose high efficiency obscures the potential activity of other mechanisms, such as innate immunity systems that are conserved between numerous species. Nevertheless, there are groups of patients in which the adaptive immune system is failing due to AIDS or immune suppressive treatments in cases of cancer, transplantation or autoimmune diseases. The protein family we are studying is well represented in the human genome but little is known about its function in allorecognition, so studies in a simple model system such as Dictyostelium discoideum would allow us to understand their function using high-resolution methods that are either unavailable or hard to implement in humans.

描述（由申请人提供）：自我/非自我认知是生活的一个基本方面。人们认为，导致组织、器官和多细胞生物体的细胞合作的进化需要发展强大的自我/非自我识别或同种异体识别机制，以防止基因不同的竞争对手的利用。社会性变形虫，盘基网柄菌，是一种优秀的模型系统，在发育过程中细胞粘附、信号传导和组织形成已被广泛研究，并为此开发了强大的分子遗传工具。我们提出，细胞在盘状 D. discoideum 发育过程中整合粘附和通讯，通过有利于遗传相关个体之间公共孢子形成的同种异体识别过程来优化细胞合作。盘状 D. discoideum 的野生分离株表现出与其遗传相关性成正比的合作行为，我们发现了一个蛋白质家族，它们可能构成这种合作的分子基础的一部分。这个想法基于我们的发现，即粘附蛋白LagC1和相关蛋白LagB1是细胞整合到多细胞组织所需的细胞合作所必需的，它们的基因是共同调节的，两者都显示出正选择或平衡选择的证据，暗示适应性进化，并且它们的序列多态性与同种异体识别密切相关。 LagC1 类型的基因在人类基因组中也很丰富且具有多态性，这表明我们在盘基网柄菌中发现的机制与人类发育和先天免疫相关并适用。我们假设高度多态性的膜蛋白通常可能介导同种异体识别，并且特定蛋白 LagB1 和 LagC1 在功能上相互作用，通过等位基因特异性细胞间粘附和信号传导介导同种异体识别，从而有利于遗传相似个体的合作孢子形成。为了检验这些假设，我们将在盘基网柄菌基因组中搜索编码多态性跨膜蛋白的基因，并测试它们与野生菌株之间同种异体识别（分离）的相关性。我们将按照研究 LagB1 和 LagC1 在同种异体识别过程中的具体作用的例子，进一步研究最相关的蛋白质在同种异体识别中的作用。公共健康相关性：人类的同种异体识别（自我/非自我识别）主要是通过我们的适应性免疫系统实现的，其高效率掩盖了其他机制的潜在活性，例如在许多物种之间保守的先天免疫系统。然而，有些患者的适应性免疫系统由于艾滋病或癌症、移植或自身免疫性疾病的免疫抑制治疗而出现故障。我们正在研究的蛋白质家族在人类基因组中得到了很好的体现，但对其在同种异体识别中的功能知之甚少，因此在盘基网柄菌等简单模型系统中进行研究将使我们能够使用高分辨率方法来了解它们的功能，而这些方法在人类中不可用或难以实施。