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.

衰老是一种生物学过程，可以表征为各种生理功能的逐渐下降。有许多与年龄相关的变化，包括基因表达的变化，这些变化在酵母，蠕虫，苍蝇，啮齿动物，非人类灵长类动物和人类的各种生物中共享。老龄化领域中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状态和寿命。 包括秀丽隐杆线虫和梅拉诺氏菌在内的无脊椎动物模型处于研究的最前沿，以确定衰老过程的分子机制。使用无脊椎动物进行衰老研究的优点不仅包括它们相对短的寿命，通常比几个月的时间较短，因此可以轻松地遵循其一生，还包括丰富的遗传和基因组资源的可用性，用于强大的遗传和分子研究。我们总结了一份评论论文发表的《老化研究评论》（2013年），总结了无脊椎动物模型的重要性。我们还在果蝇中详细介绍了果蝇的老化方案，该论文在《分子生物学方法》 2013年的方法中发表。这些出版物应为无脊椎动物的衰老研究提供宝贵的指导，尤其是秀丽隐杆线虫和梅拉诺氏菌。 与许多其他生物一样，衰老与两个强大的无脊椎动物模型（秀丽隐杆线虫和D. melanogaster）中成千上万基因的表达变化有关。与这些分子变化有关的一个核心问题是它们是否提供与人衰老相关的任何分子洞察力。解决此问题的一种方法是确定哪些分子变化在秀丽隐杆线虫和梅拉诺氏菌之间是进化保守的。保守的变化可能有助于理解适用于人衰老的分子机制。但是，尽管有许多可用于鉴定保守基因和蛋白质的生物信息学方法，主要基于序列同源物，但工具仅限于识别具有低序列相似性但保守功能的基因和蛋白质，后者可能由大部分基因组组成。为了解决这个问题，与DRS指导的几个壁内团体合作。凯文·贝克尔（Kevin Becker）和伊利亚·戈德伯格（Ilya Goldberg），我们开发了一种生物信息学工具，用于对秀丽隐杆线虫和D. melanogaster之间的大量基因集进行高吞吐量的功能分析。 我们已经证明了这些基因集在包括衰老在内的复杂生物学表型的系统生物学研究中的实用性。这项工作已发表在BMC Genomics 2013中。本文所述的工具和数据库将使我们能够更好地利用许多生物中可用的大量基因组数据，包括人类，并促进在衰老等各种生物学过程中的功能保护研究。 在与衰老过程有关的保守蛋白中，有拓扑异构酶，这对于求解DNA拓扑蛋白是必不可少的，对于与衰老相关的生物学过程（例如DNA修复）至关重要。 RNA代谢已被证明在几乎所有生物学过程中至关重要，包括衰老和许多疾病，例如与年龄相关的退行性疾病。但是，没有任何真核拓扑异构酶与RNA代谢有关。与Weidong Wangs Group合作，我们将TOP3β确定为第一个真核RNA拓扑酶，它存在于细胞中的多核糖体和应力颗粒中。我们进一步证明，TOP3β与脆弱的X蛋白（FMRP）相互作用，以调节果蝇中神经肌肉连接（NMJ）处的突触形成。 FMRP是与脆弱X综合征有关的主要蛋白质，X综合征是智力障碍和自闭症的常见形式。我们已经表明，TOP3β和FMRP结合了许多共同的mRNA，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的精神分裂症和智力残疾有关。这些发现表明TOP3β充当RNA代谢中的RNA拓扑异构酶，并与FMRP相互作用在促进神经发育和心理健康方面相互作用。这项工作已发表在《自然神经科学》（2013年）中。第一个真核RNA拓扑异构酶的演示将促进确定RNA代谢，尤其是拓扑，拓扑，在衰老和神经系统疾病中的作用，这在衰老领域开辟了新的研究系列。 总而言之，我们已经取得了重大进展，以理解衰老和与年龄有关的疾病的分子机制。我们已经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。我们已经确定了第一个RNA拓扑异构酶，并展示了其在维持心理健康中的作用。这些研究对于促进翻译老年病的目标以及NIA了解衰老的基本生物学的使命是有价值的，并为人类开发有效的干预措施。