Influence of Retrotransposition on DNA Damage and Repair in Aging Cells

逆转录转座对衰老细胞 DNA 损伤和修复的影响

• 批准号: 7588482
• 负责人: PATRICK H MAXWELL
• 金额: $ 8.07万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-15 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7588482
• 关键词: Address; Age; Aging; Animal Model; Awareness; Biological Assay; Biomedical Research; Cell Aging; Cell Death; Cell physiology; Cells; Chromosomes; DNA Repair; DNA Sequence Rearrangement; DNA Sequencing Facility; Data; Development; Educational workshop; Elderly; Elements; Flow Cytometry; Frequencies; Gene Silencing; Genes; Genetic; Genome; Genome Stability; Genomic Instability; Goals; Growth; Health; Human; Instruction; Lead; Link; Longevity; Maintenance; Measurement; Mediating; Mentors; Methods; Modeling; Molecular; Mutation; Mutation Spectra; Open Reading Frames; Organism; Pathway interactions; Phase; Phenotype; Population; Quality of life; Research; Research Personnel; Resources; Retrotransposition; Retrotransposon; Role; Roswell Park Cancer Institute; Saccharomyces cerevisiae; Site; Speed; Structure; Symptoms; System; Technical Expertise; Testing; Time; Transcript; Work; Yeast Model System; Yeasts; age related; base; cell age; cell growth; chromosome mutation; design; disease-causing mutation; experience; improved; innovation; mutant; programs; reproductive; research study; skill acquisition; symposium; tool; transposon/insertion element; tumor

DESCRIPTION (provided by applicant): This project's immediate research objective is to identify the potential role of mobile DNA elements known as retrotransposons in promoting aging-related genome instability, since retrotransposons are associated with chromosome rearrangements and mutations in human cells. This is part of a broader goal to establish an independent research program to address how retrotransposons influence genome stability and organization and how changes in genome stability relate to aging. The work will be conducted in a yeast model system. Similarities exist between yeast and humans in the genetic control and genetic consequences of aging, and yeast provides one of the only facile experimental systems to study endogenous retrotransposons. The mentored portion of the project will involve developing and obtaining preliminary data from experimental systems designed to test the influence of retrotransposons on the rate of chromosome rearrangements and mutations in aging yeast cells. Preliminary measurements of lifespans of mutant yeast strains with increased or decreased rates of mutations or chromosome rearrangements will also be made. During the independent phase, aging-related chromosome rearrangements will be analyzed at a sequence level. In addition, the influence of retrotransposition on mutation spectra during aging and the influence of compromising specific pathways crucial for genome maintenance on lifespan will be more fully explored. Interactions with the candidate's mentor and several other investigators in related research fields at the Wadsworth Center and access to core flow cytometry, microarray, and DNA sequencing facilities will provide necessary technical expertise to promote research independence. Technical expertise, guidance interpreting data, and discussions of current issues in aging research will be provided by a co-mentor at Roswell Park Cancer Institute. Attendance at courses, workshops, and conferences will also provide awareness of current issues in aging research. Acquisition of these skills and experiences will allow the establishment of an independent research program distinct from the research focus of the mentor for this project. RELEVANCE (See instructions): Damage and change to genetic information is associated with aging in many organisms, including yeast and humans. The goal of this project is to take advantage of the speed and efficiency of conducting research in yeast to identify a specific mechanism that contributes to genetic damage and changes during aging. This mechanism will then serve as a potential target for therapies to improve human health during aging.

描述（由申请人提供）：该项目的直接研究目标是确定被称为逆转录座子在促进与衰老相关的基因组不稳定性中的移动DNA元件的潜在作用，因为逆转录子座与人类细胞中的染色体重排和突变有关。这是建立独立研究计划的更广泛目标的一部分，以解决逆转录转座子如何影响基因组稳定性和组织以及基因组稳定性的变化与衰老之间的关系。这项工作将在酵母模型系统中进行。酵母与人之间的相似之处在衰老的遗传控制和遗传后果中存在，酵母提供了研究内源性逆转座子的唯一便利的实验系统之一。该项目的指导部分将涉及从实验系统中开发和获得初步数据，旨在测试逆转录座子对衰老酵母菌细胞中染色体重排和突变速率的影响。还将对突变酵母菌菌株的寿命进行初步测量，并增加突变速率或降低染色体重排的寿命。在独立阶段，将以序列水平分析与衰老相关的染色体重排。此外，将更充分地探索逆转译来对衰老过程中突变光谱的影响以及对基因组维持至关重要的寿命至关重要的特定途径的影响。与候选人的导师和沃兹沃思中心相关研究领域的其他一些研究人员的互动，并获得核心流式细胞仪，微阵列和DNA测序设施将提供必要的技术专业知识，以促进研究独立性。罗斯威尔公园癌症研究所的联合学人将提供技术专长，指导数据的指导，并讨论当前的老龄化研究问题。参加课程，研讨会和会议还将提供对当前衰老研究问题的认识。获得这些技能和经验将允许建立与该项目的导师研究重点不同的独立研究计划。相关性（请参阅说明）：遗传信息的损害和变化与包括酵母和人类在内的许多生物的衰老有关。该项目的目的是利用在酵母中进行研究的速度和效率，以确定有助于遗传损害和衰老期间变化的特定机制。然后，这种机制将成为疗法在衰老过程中改善人类健康的潜在靶标。