Comparative genomes of longevity

长寿基因组比较

• 批准号: 9531623
• 负责人: Vera Gorbunova
• 金额: $ 5万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9531623
• 关键词: Address; Age of Onset; Aging; Aging-Related Process; Anabolism; Animal Model; Animals; Balaena; Beavers; Bioinformatics; Biology; CDKN2A gene; Cells; Collaborations; Collection; Comparative Biology; Comparative Study; DNA Double Strand Break; DNA Repair; Defect; Disease; Double Strand Break Repair; Etiology; Freezing; Genes; Genome; Genome Stability; Genomic approach; Genomics; Goals; Gray unit of radiation dose; Health; Human; Hyaluronan; Investigation; Knowledge; Laboratory Animals; Lead; Learning; Longevity; Maintenance; Malignant Neoplasms; Mammals; Modeling; Modernization; Mole Rats; Molecular; Molecular Weight; Mus; Mutagenesis; Mutation; Pathway interactions; Phylogenetic Analysis; Porcupines; Positioning Attribute; Premature aging syndrome; Prevention; Principal Investigator; Process; Program Research Project Grants; Property; Rattus; Research; Research Personnel; Resistance; Resources; Rodent; Role; Squirrel; TERF1 gene; Testing; Time; Tissues; Tumor Suppression; Work; age related; blind; comparative; comparative genomics; improved; insight; novel; prevent; programs; public health relevance; repaired; synergism; therapy development; transcriptomics; tumor; whole genome

DESCRIPTION (provided by applicant): The Overarching goal of this Program Project Grant (PPG), entitled "Comparative Genomics of Longevity," is to identify molecular mechanisms responsible for more efficient DNA repair and high cancer resistance in long-lived rodent species, with implications for human health. Rodents are an Ideal group for comparative aging studies because they are phylogenetically related, even though their lifespans are extremely diverse, ranging from 2-4 years in mice and rats to over 20 years in naked mole rats, beavers, porcupines, and squirrels. The mechanisms responsible for these vast differences in aging rates between species are largely unknown. Characterization of the processes responsible for this disparity in lifespan may enable the development of interventions to extend the human lifespan and prevention of age-related diseases. Preliminary studies show that long-lived rodents have more efficient DNA double-strand break (DSB) repair and that some of the long-lived species are highly resistant to cancer. The central hypothesis of this PPG, therefore, is that long-lived species have evolved more efficient mechanisms to maintain genome stability and prevent cancer. Efforts will focus on testing this hypothesis and understanding the exact molecular mechanisms responsible for more efficient DNA repair and cancer resistance in long-lived rodents. This PPG is comprised of four highly integrated projects. Project 1 (Vera Gorbunova) will identify mechanisms responsible for more efficient DSB repair in long-lived species. Project 2 (Andrei Seluanov) will examine mechanisms responsible for anticancer properties of high molecular weight hyaluronan found in long-lived rodents. Project 3 (Jan Vijg) will test whether more efficient DSB repair and hyaluronan prevent accumulation of mutations in long-lived species using novel high throughput approaches. Project 4 (Vadim Gladyshev) will use genomic and transcriptomic approaches to identify genes and pathways involved in DSB repair and hyaluronan biosynthesis that are differentially regulated in long-lived species. Thus, the research team consists of five investigators dedicated to longevity research who are experts in comparative biology and DNA repair (Gorbunova), cancer-resistance and long-lived rodents (Seluanov), mutagenesis and high throughput approaches (Vijg), comparative genomics (Gladyshev), and bioinformatics (Zhang, Core C). Moreover, the team has developed a collection of primary rodent cells and tissues specifically to facilitate comparative studies of longevity (Seluanov, Core B). This joining of expertise will allow unprecedented insight into the biology of longevity; In summary, this team of investigators is uniquely positioned to pursue integrated studies of longevity across rodent species using a combination of cell, molecular, and genomic approaches.

描述（由申请人提供）：该计划项目赠款（PPG）的总体目标，标题为“寿命的比较基因组学”，是为了确定持久啮齿动物物种中负责更有效的DNA修复和高癌症抗性的分子机制，对人类健康的影响。啮齿动物是比较衰老研究的理想群体，因为它们在系统发育上相关，即使它们的寿命极为多样，范围从小鼠和大鼠的2 - 4年到裸鼠大鼠，海狸，豪猪和松鼠的20多年。造成这些物种之间衰老率这些巨大差异的机制在很大程度上未知。在寿命中造成这种差异的过程的表征可以使干预措施的发展能够延长人类的寿命并预防与年龄相关的疾病。初步研究表明，长寿命啮齿动物具有更有效的DNA双链破裂（DSB）修复，并且一些长寿命的物种对癌症具有高度抵抗力。因此，该PPG的中心假设是，长寿物种已经发展出更有效的机制，以维持基因组稳定性并预防癌症。努力将着重于检验这一假设，并理解负责长寿命啮齿动物中更有效的DNA修复和抗癌性的确切分子机制。该PPG由四个高度集成的项目组成。项目1（Vera Gorbunova）将确定负责长寿命物种的DSB修复的机制。项目2（Andrei Seluanov）将检查负责长寿命啮齿动物中发现的高分子浓度透明质酸的抗癌特性的机制。项目3（Jan Vijg）将测试使用新型的高吞吐量方法，是否可以更有效地使用更有效的DSB修复和透明质酸来防止长寿物种中突变的积累。项目4（Vadim Gladyshev）将使用基因组和转录组方法来识别与DSB修复和透明质酸生物合成有关的基因和途径，这些基因和透明质酸生物合成在长寿物种中受到差异调节。因此，研究小组由五名致力于长寿研究的研究人员组成，他们是比较生物学和DNA修复专家（Gorbunova），抗癌和长期寿命啮齿动物（Seluanov），诱变和高吞吐量方法（VIJG），比较基因组学（GLADYSHEV）以及BioInformatics（Zhang，C）。此外，该团队已经开发了一系列的原代啮齿动物细胞和组织，以促进寿命的比较研究（Seluanov，Core B）。这种专业知识的加入将​​使人们对长寿生物学的前所未有的见解。总而言之，该研究人员的独特定位是使用细胞，分子和基因组方法的组合来对啮齿动物物种的寿命进行综合研究。