Comparative genomes of longevity

描述(由申请人提供)：这项名为“长寿比较基因组学”的计划项目拨款(PPG)的主要目标是确定对人类健康有影响的长寿啮齿动物物种中更有效的DNA修复和高抗癌能力的分子机制。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是相关的，尽管它们的寿命非常不同，从小鼠和大鼠的2-4年到裸鼠、海狸、豪猪和松鼠的20多年不等。导致物种间衰老速度如此巨大差异的机制在很大程度上是未知的。对造成这种寿命差异的过程进行定性，可能有助于制定干预措施，以延长人类寿命和预防与年龄有关的疾病。初步研究表明，长寿啮齿动物具有更有效的DNA双链断裂(DSB)修复能力，其中一些长寿物种对癌症具有高度抵抗力。因此，这一PPG的中心假设是，长寿物种进化出了更有效的机制来维持基因组稳定和预防癌症。努力将重点放在验证这一假说和了解导致长寿啮齿动物更有效的DNA修复和抗癌能力的确切分子机制上。这个PPG由四个高度整合的项目组成。项目1(Vera Gorbunova)将确定对长寿物种进行更有效的DSB修复的机制。项目2(Andrei Seluanov)将研究在长寿啮齿动物中发现的高分子量透明质酸的抗癌特性的机制。项目3(Jan Vijg)将使用新的高通量方法测试更有效的DSB修复和透明质酸是否可以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学方法来确定参与DSB修复和透明质酸生物合成的基因和途径，这些基因和途径在长寿物种中受到不同的调节。因此，研究团队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(Gorbunova)、抗癌和长寿啮齿动物(Seluanov)、突变和高通量方法(Vijg)、比较基因组学(Gladyshev)和生物信息学(张，核心C)的专家。此外，该团队还专门开发了一组原始啮齿动物细胞和组织，以促进对寿命的比较研究(Seluanov，核心B)。这种专业知识的加入将使人们能够前所未有地深入了解长寿的生物学；总而言之，这个研究团队处于独特的地位，可以利用细胞、分子和基因组方法的组合来进行跨啮齿动物物种的长寿综合研究。

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.