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：生物体的繁衍能力使两个基本过程相互矛盾：维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。在这个提案中，我建议基因组背景可以影响给定基因座遗传变化的可能性，提供一种“针对”特定基因改变的机制。此外，我提出了一个模型，其中将易受变化影响的基因座与核结构的元素联系起来，在支持性生长条件下抑制遗传变化，而压力则释放这种限制，导致遗传变化的增加。我建议研究裂殖酵母中编码细胞表面蛋白的基因座的遗传变化，作为许多病原体所采用的抗原变异的模型。首先，我们将利用编码粘附素家族成员的基因拷贝内部和拷贝之间的基因内和基因间重组分析。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，我们将追求粘附素位点与核外围相关的假设，我们认为核外围抑制重组。除了研究压力如何影响粘附素位点的核位置之外，我们还将鉴定充当核膜系链的分子。该模型预测，这些外围系绳的丧失将重现压力对重组的影响，我们将对此进行测试。最后，我们将进行遗传筛选，以揭示压力如何触发粘附素基因座从核外围释放。在这种信号级联过程中进行干预的能力将为对抗多种微生物的致病性提供新途径。 公共卫生相关性：为了应对环境侵害，生物体通过适应性变化做出反应。尽管通过基因组调控可以实现实质性反应，但病原生物利用基因变化来增加表达支持毒力的新型蛋白质的潜力，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调动适应性反应，以便设计干预措施来更有效地治疗感染。