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（申请人提供） 摘要：生物体繁衍生息的能力相互对抗两个基本过程：维持基因组完整性的愿望是探索不同遗传状态以适应不断变化的环境的必要性。在此提案中，我建议基因组环境可以影响给定基因座的遗传变化的可能性，从而为特定基因的“靶”变化提供了一种机制。此外，我建议了一个模型，在该模型中，将变化基因座绑定到核结构元素上，限制了支持性生长条件下的遗传变化，而应力释放了这种限制，从而导致遗传变化的增加。我建议研究裂变酵母中编码细胞表面蛋白的遗传变化，作为许多病原体使用的抗原变异的模型。首先，我们将利用测定法进行编码粘附素家族成员的基因副本内和之间的基因间重组。我们将研究环境压力对粘附素基因座变化概率的影响。根据我们的初步数据，我们将提出一个假设，即粘合素基因座与核外围有关，我们认为这会抑制重组。除了研究胁迫的暴露如何影响粘合蛋白基因座的核位置外，我们还将确定用作核包膜系的分子。该模型预测，这些外围系tether的损失将概括压力对重组的影响，我们将测试。最后，我们将进行遗传筛选，以揭示应力触发粘合剂基因座从核周围释放。在此信号传导级联过程中进行干预的能力将提供新的途径来应对各种微生物的病原体。 公共卫生相关性：为了应对环境侮辱，生物体会通过适应性变化做出反应。尽管可以通过调节基因组来实现重大反应，但致病生物利用遗传变化来增加表达支持毒力并逃避宿主免疫系统的新型蛋白质的潜力。该提案的目的是发现病原体如何动员适应性反应，从而设计干预措施以更有效地治疗感染。