Molecular Mechanisms of Mammalian SIRT6 Function

哺乳动物 SIRT6 功能的分子机制

基本信息

  • 批准号:
    9282767
  • 负责人:
  • 金额:
    $ 37.44万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-06-01 至 2021-03-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Our research seeks to understand how chromatin regulatory mechanisms influence nuclear and epigenetic programs, and how de-regulation of these mechanisms contributes to aging and disease. SIRT6 is a chromatin regulatory factor in the sirtuin family of enzymes. SIRT6-deficiency in mice leads to shortened lifespan and phenotypes associated with aging, cancer, and metabolism. Conversely, SIRT6 over-expression in mice protects against metabolic disease and extends lifespan. Thus, studying SIRT6 function promises to elucidate fundamental mechanisms that underlie healthy aging and longevity. Previously, we showed that SIRT6 selectively regulates specific chromatin marks associated with epigenetic and gene-regulatory functions. We linked chromatin regulation by SIRT6 to key nuclear processes that impact on aging and cancer, including telomere maintenance, DNA repair, and aging-associated gene expression changes. Here, we focus on new functions of SIRT6 in chromatin silencing mechanisms that are deregulated in aging. We propose molecular, genomic, and functional studies to study the role of SIRT6 in maintaining heterochromatin silencing at repetitive DNA elements, and ask how impaired silencing is linked to aging-associated cellular dysfunction. In Aim 1, we will study the molecular mechanisms of SIRT6 in heterochromatin silencing of repetitive satellite DNA elements at centromeres. Defects in pericentric heterochromatin are observed in the contexts of both aging and cancer. We will characterize the biochemical activity of SIRT6 at pericentric chromatin and study downstream higher order chromatin changes. Our studies will provide insights for cancer cell biology, where SIRT6 loss may contribute to cancer progression, and for human somatic cells, where SIRT6 may guard against cellular senescence or age-dependent decline in epigenetic plasticity. In Aim 2, we will characterize the functional effects of heterochromatin maintenance by SIRT6 on cellular homeostasis. We will test the hypotheses that pericentric heterochromatin defects trigger abnormal mitoses, chromosome segregation defects, and cellular senescence, or facilitate the oncogenic process of cellular immortalization. We will also examine functional interplay between SIRT6 and other SIRT enzymes in these processes. These studies should elucidate how heterochromatin breakdown is translated into cellular phenotypes or functional decline that contributes to aging and disease. In Aim 3, we will investigate the role of SIRT6 in heterochromatin maintenance at another class of repetitive DNA elements that are deregulated in aging and cancer - endogenous retrotransposable elements. We will ask if impaired silencing of these elements is associated with genomic instability that can affect cellular function, or to aberrant transcription of aging-related genes. Together, these studies should provide insights into fundamental chromatin mechanisms in aging biology.
 描述(由申请人提供):我们的研究旨在了解染色质调控机制如何影响核和表观遗传程序,以及这些机制的失调如何导致衰老和疾病。SIRT 6是sirtuin酶家族中的染色质调节因子。小鼠的SIRT 6缺乏会导致寿命缩短以及与衰老、癌症和代谢相关的表型缩短。相反,SIRT 6在小鼠中的过表达可以防止代谢疾病并延长寿命。因此,研究SIRT 6的功能有望阐明健康衰老和长寿的基本机制。以前,我们发现SIRT 6选择性地调节与表观遗传和基因调控功能相关的特定染色质标记。我们将SIRT 6对染色质的调节与影响衰老和癌症的关键核过程联系起来,包括端粒维持,DNA修复和衰老相关的基因表达变化。在这里,我们专注于SIRT 6在衰老中失调的染色质沉默机制中的新功能。我们提出了分子,基因组和功能研究,研究SIRT 6在维持异染色质沉默的重复DNA元件的作用,并询问如何受损沉默与衰老相关的细胞功能障碍。 目的1:研究SIRT 6在异染色质中沉默着丝粒重复卫星DNA元件的分子机制。在衰老和癌症的背景下都可以观察到臂间异染色质的缺陷。我们将描述SIRT 6在臂间染色质的生化活性,并研究下游高阶染色质的变化。我们的研究将为癌细胞生物学提供见解,其中SIRT 6损失可能有助于癌症进展,以及为人类体细胞提供见解,其中SIRT 6可以防止细胞衰老或表观遗传可塑性的年龄依赖性下降。在目标2中,我们将描述SIRT 6对细胞稳态的异染色质维持的功能作用。我们将测试的假设,即臂间异染色质缺陷触发异常有丝分裂,染色体分离缺陷,细胞衰老,或促进细胞永生化的致癌过程。我们还将研究SIRT 6和其他SIRT酶在这些过程中的功能相互作用。这些研究应该阐明异染色质分解是如何转化为细胞表型或功能下降,有助于衰老和疾病。在目标3中,我们将研究SIRT 6在异染色质维持中的作用,该异染色质维持在另一类在衰老和癌症中失调的重复DNA元件-内源性逆转录转座元件。我们将询问这些元件的沉默受损是否与影响细胞功能的基因组不稳定性或衰老相关基因的异常转录有关。 总之,这些研究应该提供深入了解衰老生物学的基本染色质机制。

项目成果

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Katrin F Chua其他文献

Katrin F Chua的其他文献

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{{ truncateString('Katrin F Chua', 18)}}的其他基金

Medical Scientist Training Program
医学科学家培训计划
  • 批准号:
    10410260
  • 财政年份:
    2022
  • 资助金额:
    $ 37.44万
  • 项目类别:
BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
  • 批准号:
    10594020
  • 财政年份:
    2022
  • 资助金额:
    $ 37.44万
  • 项目类别:
Medical Scientist Training Program
医学科学家培训计划
  • 批准号:
    10621959
  • 财政年份:
    2022
  • 资助金额:
    $ 37.44万
  • 项目类别:
Histone Deacetylation Signaling in Aging and Cancer Pathways
衰老和癌症途径中的组蛋白脱乙酰化信号转导
  • 批准号:
    10651829
  • 财政年份:
    2021
  • 资助金额:
    $ 37.44万
  • 项目类别:
Histone Deacetylation Signaling in Aging and Cancer Pathways
衰老和癌症途径中的组蛋白脱乙酰化信号转导
  • 批准号:
    10819057
  • 财政年份:
    2021
  • 资助金额:
    $ 37.44万
  • 项目类别:
Histone Deacetylation Signaling in Aging and Cancer Pathways
衰老和癌症途径中的组蛋白脱乙酰化信号转导
  • 批准号:
    10448391
  • 财政年份:
    2021
  • 资助金额:
    $ 37.44万
  • 项目类别:
Molecular Mechanisms of Mammalian SIRT6 Function
哺乳动物 SIRT6 功能的分子机制
  • 批准号:
    9107282
  • 财政年份:
    2016
  • 资助金额:
    $ 37.44万
  • 项目类别:
Molecular Mechanisms of Mammalian SIRT6 Function
哺乳动物 SIRT6 功能的分子机制
  • 批准号:
    9901411
  • 财政年份:
    2016
  • 资助金额:
    $ 37.44万
  • 项目类别:
Molecular Mechanisms of Mammalian SIRT6 Function
哺乳动物 SIRT6 功能的分子机制
  • 批准号:
    9118549
  • 财政年份:
    2015
  • 资助金额:
    $ 37.44万
  • 项目类别:
MOLECULAR INTERACTIONS AND SUBSTRATES OF MAMMALIAN SIRT6 LONGEVITY REGULATOR
哺乳动物 SIRT6 寿命调节剂的分子相互作用和底物
  • 批准号:
    8363767
  • 财政年份:
    2011
  • 资助金额:
    $ 37.44万
  • 项目类别:

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