The molecular basis of allorecognition and its roles in development and evolution of the social amoeba D. discoideum

同种异体识别的分子基础及其在社会性盘状变形虫发育和进化中的作用

• 批准号: 9067758
• 负责人: GAD SHAULSKY
• 金额: $ 50.28万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-12 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9067758
• 关键词: Affinity; Amino Acid Sequence; Amoeba genus; Animal Model; Binding; Biological Models; Cell Polarity; Cell physiology; Cells; Cellularity; Chemicals; Chemotaxis; Cues; Cyclic AMP; Development; Dictyostelium; Dictyostelium discoideum; Embryonic Development; Essential Genes; Event; Evolution; Food; Gene Expression; Genetic Polymorphism; Genome; Graft Rejection; Health; Immune system; Individual; Infection; Inflammation; Life; Link; Longitudinal Studies; Major Histocompatibility Complex; Mammals; Mediating; Medicine; Membrane Proteins; Molecular; Molecular Genetics; Natural Immunity; Organism; Parasites; Pathway interactions; Population; Process; Property; Proteins; Role; Signal Transduction; Societies; Soil; Specificity; Surface; System; Tissues; base; cell behavior; cost; extracellular; interest; marine organism; public health relevance; segregation; social; tool

 DESCRIPTION (provided by applicant): Allorecognition is defined as the ability of organisms to distinguish self from non-self, a common theme in many organisms and a central component in the evolution of multicellularity and cooperation. In mammals, allorecognition is mediated by the Major Histocompatibility Complex (MHC), which is part of the immune system. The MHC facilitates identification of parasites in infection processes and graft rejection in transplantatin medicine. There is evidence for the involvement of other proteins in graft rejection but there are very few model systems available to study these proteins. There are numerous allorecognition systems in non- mammalian systems, notably in marine organisms, but most of them are not amenable to manipulation with molecular genetic tools. We have found an allorecognition system in the social soil amoeba Dictyostelium discoideum, opening the field to molecular genetic exploration of concepts in allorecognition and cooperation at various levels - from molecules and cells to tissues, genomes and societies. The Dictyostelium allorecognition system is based on two proteins, TgrB1 and TgrC1, that share many properties with mammalian MHC proteins, but not their amino acid sequences. These trans-membrane proteins are highly polymorphic in natural Dictyostelium populations and they are necessary and sufficient for allorecognition. Dictyostelium cells live as free amoebae in the soil when food is abundant but they aggregate into multicellular organisms when starved. Aggregation involves chemotaxis to extracellular cAMP and Dictyostelium is one of the best model systems for the study of chemotaxis, which is a central process in embryogenesis and in innate immunity. When Dictyostelium cells encounter cells that carry incompatible TgrB1 and TgrC1 during aggregation, they segregate from one another and form separate multicellular organisms. This segregation protects cells from cheaters, which are individuals that take advantage of social benefits without paying the full cost of cooperation. We propose that TgrB1 on the surface of one cell binds TgrC1 on the surface of an adjacent cell and that binding initiates a signal transduction cascade that alters cell behavior. We plan to investigate this system at four levels. At the protein level, we will explore the properties that define TgrB1-TgrC1 binding affinity and specificity and the mechanisms that mediate downstream signal transduction. At the cell level, we will study the pathways that transduce the allorecognition signals immediately after TgrB1 binds TgrC1, leading to changes in chemotaxis and cell polarity. At the developmental level, we will study the long-term events that change gene expression and cell physiology after cells segregate from incompatible cells and cooperate with compatible cells to form tissues. At the genome level, we are interested in how the two developmentally essential genes co-evolve and maintain polymorphism in the population.

 描述（由申请人提供）：同种异体识别被定义为生物体区分自我与非自我的能力，这是许多生物体的共同主题，也是多细胞进化和合作的核心组成部分。在哺乳动物中，同种异体识别由主要组织相容性复合物（MHC）介导，其是免疫系统的一部分。MHC有助于在感染过程中识别寄生虫和在移植医学中识别移植物排斥。有证据表明其他蛋白质参与移植排斥反应，但很少有模型系统可用于研究这些蛋白质。在非哺乳动物系统中，特别是在海洋生物中，存在许多同种异体识别系统，但它们中的大多数不适合用分子遗传工具操纵。我们已经发现了一个allocrecognition系统中的社会土壤阿米巴Dictyosteelium discoideum，开放领域的概念在allocrecognition和合作的分子遗传学探索在各个层面-从分子和细胞的组织，基因组和社会。网骨藻同种异体识别系统基于两种蛋白质TgrB 1和TgrC 1，它们与哺乳动物MHC蛋白质共享许多特性，但不共享它们的氨基酸序列。这些跨膜蛋白在天然网骨藻种群中具有高度多态性，它们是同种识别所必需的。当食物充足时，网骨藻细胞以游离阿米巴的形式生活在土壤中，但当饥饿时，它们聚集成多细胞生物。聚集涉及对细胞外cAMP的趋化性，而网柄菌是研究趋化性的最佳模型系统之一，趋化性是胚胎发生和先天免疫的核心过程。当网骨藻细胞在聚集过程中遇到携带不相容的TgrB 1和TgrC 1的细胞时，它们彼此分离并形成单独的多细胞生物体。这种隔离保护细胞免受骗子的侵害，骗子是那些利用社会利益而不支付合作全部成本的个人。我们提出，一个细胞表面上的TgrB 1结合相邻细胞表面上的TgrC 1，并且结合启动改变细胞行为的信号转导级联。我们计划在四个层面上研究这个系统。在蛋白质水平上， 我们将探索定义TgrB 1-TgrC 1结合亲和力和特异性的特性以及介导下游信号转导的机制。在细胞水平上，我们将研究TgrB 1结合TgrC 1后立即抑制同种识别信号的途径，从而导致趋化性和细胞极性的变化。在发育水平上，我们将研究细胞从不相容细胞分离并与相容细胞合作形成组织后改变基因表达和细胞生理的长期事件。在基因组水平上，我们感兴趣的是这两个发育必需基因如何共同进化并保持种群中的多态性。