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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

基本信息

批准号：
9272919
负责人：
GAD SHAULSKY
金额：
$ 40.16万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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：
2016-05-12 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9272919
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 Integral Membrane Protein Link Longitudinal Studies Major Histocompatibility Complex Mammals Mediating Medicine 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 cell motility cost extracellular interest marine organism protein complex public health relevance segregation social tool

项目摘要

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.