Functional Genomic Study of Aging and Aging Interventions

衰老和衰老干预的功能基因组研究

• 批准号: 8736538
• 负责人: Sige Zou
• 金额: $ 57.04万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8736538
• 关键词: Address; Age; Aging; Aging-Related Process; Autistic Disorder; Binding; Bioinformatics; Biological; Biological Process; Biology of Aging; Caenorhabditis elegans; Cells; Collaborations; Complex; Cytoplasmic Granules; DNA; DNA Repair; Data; Databases; Degenerative Disorder; Disease; Drosophila genus; FMRP; Fragile X Mental Retardation Protein; Fragile X Syndrome; Future; Gene Expression; Gene Proteins; Genes; Genetic; Genome; Genomics; Gerontology; Goals; Human; Intellectual functioning disability; Intervention; Invertebrates; Life; Link; Longevity; Mental Health; Messenger RNA; Metabolism; Methods; Mission; Modeling; Molecular; Molecular Biology; Molecular Genetics; Molecular Profiling; Mutation; Nature; Neuromuscular Junction; Neurons; Neurosciences; Organism; Paper; Phenotype; Physiological; Polyribosomes; Proteins; Protocols documentation; Publications; Publishing; RNA; Relative (related person); Research; Resources; Rodent; Role; Schizophrenia; Sequence Homologs; Stress; Synapses; Systems Biology; Topoisomerase; Work; Yeasts; age related; base; effective intervention; fly; functional genomics; healthy aging; insight; link protein; nervous system disorder; neurodevelopment; nonhuman primate; novel; tool

Aging is a biological process that can be characterized as a gradual decline of various physiological functions. There are numerous age-related changes, including changes in gene expression, that are shared in various organisms ranging from yeast, worm, fly, rodent, non-human primates and humans. One of the important questions in the aging field is whether and how these age-related changes modulate healthspan and lifespan. Invertebrate models, including C. elegans and D. melanogaster, are in the forefront of studies to determine the molecular mechanisms underlying aging processes. The advantages of using invertebrates for aging studies include not only their relative short lifespan, typically in shorter than a few months for the ease to follow their whole life, but also the availability of rich genetic and genomic resource for powerful genetic and molecular studies. We have summarized the important of invertebrate models in aging research in a review paper published Ageing Research Reviews (2013). We have also detailed aging protocols in Drosophila in a review paper published in Methods in Molecular Biology 2013. These publications should provide valuable guidance for aging research in invertebrates, especially C. elegans and D. melanogaster. Like many other organisms, aging is associated with expression changes of thousands of genes in two powerful invertebrate models, C. elegans and D. melanogaster. A central question related to these molecular changes is whether they provide any molecular insight relevant to human aging. One approach to address this issue is to identify which molecular changes are evolutionarily conserved between C. elegans and D. melanogaster. The conserved changes will likely help understand molecular mechanisms applicable to human aging. However, despite of many bioinformatic approaches available to identify conserved genes and proteins mostly based on sequence homolog, tools are limited to identify genes and proteins with low sequence similarity but conserved function, the latter of which likely consist of a significant portion of genome. To address this issue, in collaboration with several intramural groups directed by Drs. Kevin Becker and Ilya Goldberg, we have developed a bioinformatic tool for high throughput functional analysis of large number of gene sets between C. elegans and D. melanogaster. We have demonstrated the utility of these gene sets in systems biology studies of complex biological phenotypes, including aging. This line of work has been published in BMC Genomics 2013. The tool and database described in this paper will allow us taking better advantage of large amount of genomic data available in many organisms including humans and facilitate the studies of functional conservation in various biological processes, such as aging, in the future studies. Among the conserved proteins related to aging processes are topoisomerases, which are known to be essential to solve DNA topological protein and critical for aging-related biological processes, such as DNA repair. RNA metabolism has been shown to be crucial in almost all biological processes, including aging, and many diseases, such as age-related degenerative diseases. However, none of eukaryotic topoisomerases have been linked to RNA metabolism. In collaboration with Dr. Weidong Wangs group, we identified Top3β as the first eukaryotic RNA topoisomerase, which is present in polyribosome and stress granule in the cell. We further demonstrated that Top3β interacts with Fragile X protein (FMRP) to regulate synaptic formation at the neuromuscular junction (NMJ) in Drosophila. FMRP is a major protein linked to Fragile X syndrome, a common form of intellectual disability, and autism. We have shown that Top3β and FMRP bind a number of common sets of mRNAs, including those encoded by genes with neuronal functions related to schizophrenia and autism. Top3β mutations have been shown to be associated with schizophrenia and intellectual disability in humans. These findings suggest Top3β acts as an RNA topoisomerase in RNA metabolism and interacts with FMRP in promoting neural development and mental health. This line of work has been published in Nature Neuroscience (2013). Demonstration of the first eukaryotic RNA topoisomerase will facilitate determining the role of RNA metabolism, especially topology, in aging and neurological diseases, which opens a novel line of research in the aging field. In summary, we have made significant progress towards understanding molecular mechanisms underlying aging and age-related diseases. We have developed a bioinformatic tool for high throughput functional studies of genomic data. We have identified the first RNA topoisomerase and demonstrated its role in maintaining mental health. These studies are valuable for advancing the objectives of the Translational Gerontology Branch and the mission of the NIA to understand the basic biology of aging and develop efficient interventions for humans.

衰老是一种生物过程，其特征是各种生理功能逐渐衰退。酵母、蠕虫、苍蝇、啮齿动物、非人类灵长类动物和人类等多种生物体都有许多与年龄相关的变化，包括基因表达的变化。老龄化领域的重要问题之一是这些与年龄相关的变化是否以及如何调节健康寿命和寿命。 无脊椎动物模型，包括线虫和黑腹果蝇，处于确定衰老过程分子机制研究的前沿。使用无脊椎动物进行衰老研究的优点不仅包括它们的寿命相对较短（通常不到几个月，以便于跟踪它们的整个一生），还包括丰富的遗传和基因组资源可用于强大的遗传和分子研究。我们在《衰老研究评论》（Aging Research Reviews，2013）发表的一篇评论文章中总结了无脊椎动物模型在衰老研究中的重要性。我们还在 2013 年《分子生物学方法》中发表的一篇评论论文中详细介绍了果蝇的衰老方案。这些出版物应该为无脊椎动物，特别是线虫和黑腹果蝇的衰老研究提供有价值的指导。 与许多其他生物体一样，衰老与两种强大的无脊椎动物模型（秀丽隐杆线虫和黑腹果蝇）中数千个基因的表达变化有关。与这些分子变化相关的一个核心问题是它们是否提供了与人类衰老相关的任何分子见解。解决这个问题的一种方法是确定线虫和黑腹果蝇之间哪些分子变化在进化上是保守的。这些保守的变化可能有助于理解适用于人类衰老的分子机制。然而，尽管有许多生物信息学方法可用于识别主要基于序列同源物的保守基因和蛋白质，但工具仅限于识别序列相似性低但功能保守的基因和蛋白质，后者可能由基因组的很大一部分组成。为了解决这个问题，与博士领导的几个校内团体合作。 Kevin Becker 和 Ilya Goldberg 开发了一种生物信息学工具，用于对线虫和黑腹果蝇之间的大量基因集进行高通量功能分析。 我们已经证明了这些基因组在复杂生物表型（包括衰老）的系统生物学研究中的实用性。该系列工作已发表在BMC Genomics 2013上。本文中描述的工具和数据库将使我们能够更好地利用包括人类在内的许多生物体中可用的大量基因组数据，并在未来的研究中促进各种生物过程（例如衰老）中功能保护的研究。 拓扑异构酶是与衰老过程相关的保守蛋白之一，众所周知，拓扑异构酶对于解决 DNA 拓扑蛋白至关重要，并且对于 DNA 修复等与衰老相关的生物过程至关重要。 RNA 代谢已被证明在几乎所有生物过程中都至关重要，包括衰老和许多疾病，例如与年龄相关的退行性疾病。然而，没有一种真核拓扑异构酶与 RNA 代谢有关。我们与Weidong Wang博士团队合作，发现Top3β是第一个真核RNA拓扑异构酶，存在于细胞内的多核糖体和应激颗粒中。我们进一步证明，Top3β 与脆性 X 蛋白 (FMRP) 相互作用，调节果蝇神经肌肉接头 (NMJ) 的突触形成。 FMRP 是与脆性 X 综合征（一种常见的智力障碍和自闭症）相关的主要蛋白质。我们已经证明 Top3β 和 FMRP 结合了许多常见的 mRNA 组，包括由具有与精神分裂症和自闭症相关的神经元功能的基因编码的 mRNA。 Top3β 突变已被证明与人类精神分裂症和智力障碍有关。这些发现表明 Top3β 在 RNA 代谢中充当 RNA 拓扑异构酶，并与 FMRP 相互作用，促进神经发育和心理健康。该系列工作已发表在《自然神经科学》（2013）上。第一个真核RNA拓扑异构酶的展示将有助于确定RNA代谢，特别是拓扑结构，在衰老和神经系统疾病中的作用，这开辟了衰老领域的一条新的研究路线。 总之，我们在理解衰老和年龄相关疾病的分子机制方面取得了重大进展。我们开发了一种生物信息学工具，用于基因组数据的高通量功能研究。我们已经鉴定出第一个 RNA 拓扑异构酶，并证明了它在维持心理健康方面的作用。这些研究对于推进转化老年学分支的目标和 NIA 的使命非常有价值，即了解衰老的基本生物学并为人类开发有效的干预措施。