The role of nuclear architecture in adaptation

核结构在适应中的作用

• 批准号: 8145489
• 负责人: MEGAN C KING
• 金额: $ 249.35万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145489
• 关键词: Affect; Antigenic Variation; Architecture; Bacterial Adhesins; Biological Assay; Cell Surface Proteins; Data; Elements; Environment; Exposure to; Family member; Fission Yeast; Genes; Genetic; Genetic Recombination; Genetic Screening; Genome; Genomics; Goals; Growth; Immune system; Infection; Intervention; Microbe; Modeling; Mutation; Nuclear; Nuclear Envelope; Organism; Peripheral; Positioning Attribute; Probability; Process; Proteins; Regulation; Role; Signal Transduction; Stress; Testing; Virulence; abstracting; base; combat; coping; novel; pathogen; public health relevance; response

DESCRIPTION (Provided by the applicant) Abstract: The ability of an organism to thrive pits two fundamental processes against each other: the desire to maintain genomic integrity with the necessity to explore different genetic states in order to adapt to a changing environment. In this proposal, I suggest that the genomic context can influence the likelihood for genetic change at a given locus, providing a mechanism to ""target"" alterations to specific genes. Further, I suggest a model in which tethering of change-vulnerable loci to elements of the nuclear architecture restrains genetic change under supportive growth conditions, whereas stress releases such constraints, leading to an increase in genetic change. I propose to study genetic changes in loci encoding cell surface proteins in fission yeast as a model for antigenic variation employed by many pathogens. Primarily, we will utilize assays for intra- and intergenic recombination within and between copies of genes encoding adhesin family members. We will examine the effect of environmental stress on the probability of changes in the adhesin loci. Based on our preliminary data, we will pursue the hypothesis that adhesin loci are associated with the nuclear periphery, which we believe represses recombination. In addition to investigating how exposure to stress affects the nuclear position of adhesin loci, we will also identify the molecules that serve as nuclear envelope tethers. This model predicts that loss of these peripheral tethers will recapitulate the effects of stress on recombination, which we will test. Lastly, we will carry out genetic screens to reveal how stress triggers release of adhesin loci from the nuclear periphery. The ability to intervene during this signaling cascade would provide new avenues to combat the pathogenecity of a wide array of microbes. Public Health Relevance: In order to cope with an environmental insult, organisms respond by adaptive change. Although a substantial response can be achieved through regulation of the genome, pathogenic organisms utilize genetic change to increase the potential for expressing novel proteins that support virulence and allow them to evade the host immune system. The goal of this proposal is to discover how pathogens mobilize the adaptive response so that interventions might be devised to more effectively treat infection.

描述（由申请人提供） 摘要：生物体的茁壮成长能力使两个基本过程相互对立：保持基因组完整性的愿望与探索不同遗传状态以适应不断变化的环境的必要性。在这个提议中，我认为基因组环境可以影响给定位点的遗传变化的可能性，提供了一种机制来“靶向“特定基因的改变。此外，我建议一个模型中，拴系的变化易受影响的基因座的元素的核架构抑制遗传变化的支持性生长条件下，而压力释放这样的限制，导致增加遗传变化。我建议研究基因座编码细胞表面蛋白质的裂变酵母作为模型的抗原变异采用了许多病原体的遗传变化。首先，我们将利用检测粘附素家族成员编码基因拷贝内和拷贝间的基因内和基因间重组。我们将研究环境应激对粘附素位点变化概率的影响。基于我们的初步数据，我们将追求的假设，即粘附素位点与核周边，我们认为抑制重组。除了研究暴露于压力如何影响粘附素基因座的核位置，我们还将确定作为核膜系链的分子。这个模型预测，这些外围系绳的损失将重演的重组，我们将测试压力的影响。最后，我们将进行基因筛选，以揭示压力如何触发细胞核周边粘附素位点的释放。在这种信号级联过程中进行干预的能力将为对抗各种微生物的致病性提供新的途径。 公共卫生相关性：为了科普环境的侮辱，生物体通过适应性变化做出反应。虽然可以通过基因组的调节实现实质性的反应，但病原生物体利用遗传变化来增加表达支持毒力的新型蛋白质的可能性，并使它们能够逃避宿主免疫系统。该提案的目标是发现病原体如何动员适应性反应，以便设计干预措施以更有效地治疗感染。