Comparative Genomics of Longevity: Supplement 1-High molecular weight hyaluronan as a potential Alzheimer disease therapy.

这项计划项目资助（PPG）的OYereconomic目标，题为“长寿的比较基因组学”，是 确定负责更有效的DNA修复和高癌症抗性的分子机制， 长寿的啮齿动物物种，对人类健康的影响。啮齿动物是比较的理想群体 衰老研究，因为他们是遗传相关的，即使他们的寿命是非常不同的， 从小鼠和大鼠的2-4年到裸鼹鼠、海狸、豪猪的20年以上， 松鼠造成物种之间衰老速度巨大差异的机制主要是 未知对造成这种寿命差异的过程进行表征， 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，长寿的啮齿类动物具有更高效的DNA双链断裂（DSB）修复能力 一些长寿的物种对癌症有很强的抵抗力。这个PPG的中心假设， 长寿物种进化出了更有效的机制来维持基因组 稳定性和预防癌症。努力将集中在测试这一假设和理解 负责更有效的DNA修复和癌症抗性的确切分子机制， 长寿的啮齿动物这一项目规划组由四个高度综合的项目组成。项目1（Vera Gorbunova） 将确定机制负责更有效的DSB修复长寿物种。项目2（安德烈 Seluanov）将研究负责高分子量的抗癌特性的机制 在长寿啮齿类动物中发现的透明质酸。项目3（Jan Vijg）将测试更有效的DSB修复和 透明质酸使用新高通量方法防止长寿物种中突变的积累。 项目4（Vadim Gladyshev）将使用基因组学和转录组学方法来识别基因， 参与DSB修复和透明质酸生物合成的途径，这些途径在长寿命的 物种因此，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（Gorbunova）、抗癌和长寿啮齿动物专家 （Seluanov），诱变和高通量方法（Vijg），比较基因组学（Gladyshev），和 生物信息学（Zhang，Core C）。此外，该团队还开发了一系列初级啮齿动物细胞， 组织，特别是促进寿命的比较研究（Seluanov，核心B）。这种专业知识的结合 将使人们对长寿的生物学有前所未有的深入了解;总之，这支研究团队 独特的定位，追求跨啮齿动物物种寿命的综合研究，使用的组合 细胞、分子和基因组方法。 相关性（参见说明）; 哺乳动物物种在衰老速度上存在显着差异，但导致这些差异的机制 是未知的。该计划项目将确定负责更有效的DNA修复的机制， 长寿啮齿类动物的癌症抵抗力更高。这些知识将有助于制定干预措施 延长人类寿命，延缓与年龄有关的疾病的发生。·

The OYerarching 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 ofthe 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 moiecuiar 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. RELEVANCE (See instructions); Mammalian species differ dramatically in their aging rates, but mechanisms responsible for these differences are unknown. This program project will identify mechanisms responsible for more efficient DNA repair and higher cancer resistance in long-lived rodents. This knowledge will enable the development of interventions to extend the human lifespan and delay the onset of age-related diseases. ·