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

长寿的比较基因组学：补充剂 1-高分子量透明质酸作为潜在的阿尔茨海默病疗法。

• 批准号: 9520835
• 负责人: Vera Gorbunova
• 金额: $ 15.4万
• 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/9520835
• 关键词: Address; Age of Onset; Aging; Aging-Related Process; Alzheimer' s Disease; 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; Instruction; 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; repaired; synergism; therapy development; transcriptomics; tumor; whole genome

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. ·

这项名为“长寿的比较基因组学”的计划项目拨款(PPG)的主要目标是 为了确定导致更有效的DNA修复和高抗癌能力的分子机制 长寿啮齿动物物种，对人类健康有影响。啮齿动物是比较研究的理想群体 衰老研究是因为它们是系统发育相关的，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。造成物种间衰老速度巨大差异的机制很大程度上是 未知。对造成这种寿命差异的过程进行表征可能会使 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，长寿的啮齿动物有更有效的DNA双链断裂(DSB)修复 一些长寿物种对癌症有很强的抵抗力。这个PPG的中心假设是， 因此，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。努力将重点放在检验这一假说和理解 更有效的DNA修复和癌症耐药性的确切分子机制 长寿的啮齿动物。这个PPG由四个高度整合的项目组成。项目1(维拉·戈尔布诺娃) 将确定对长寿物种更有效的DSB修复负责的机制。项目2(Andrei Seluanov)将研究高分子量抗癌特性的机制 长寿啮齿动物体内发现的透明质酸。项目3(Jan Vijg)将测试更高效的DSB修复和 透明质酸使用新的高通量方法防止长寿物种中突变的积累。 项目4(Vadim Gladyshev)将使用基因组和转录组方法来识别基因和 参与DSB修复和透明质酸生物合成的通路在长寿命中存在差异调节 物种。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方面的专家 (Seluanov)、诱变和高通量方法(Vijg)、比较基因组学(Gladyshev)以及 生物信息学(张，核心C)。此外，该团队还开发了一组原始啮齿动物细胞和 专门用于比较长寿研究的组织(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洞察；总而言之，这支研究团队是 独一无二的定位，可以使用以下组合进行啮齿动物物种寿命的综合研究 细胞、分子和基因组方法。 相关性(见说明)； 哺乳动物物种的衰老速度差异很大，但导致这些差异的机制 都是未知的。该计划项目将确定负责更有效的DNA修复和 长寿啮齿动物对癌症的抵抗力更强。这一知识将使干预措施的发展成为可能 延长人类寿命，延缓老年性疾病的发生。·