Dietary Polyphenols Are Consequential Epigenetic Modulators of Gene Expression

膳食多酚是基因表达的重要表观遗传调节剂

• 批准号: 7455988
• 负责人: BAO-TING ZHU
• 金额: $ 34.97万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-25 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7455988
• 关键词: Address; Animal Model; Apoptosis; Applications Grants; Area; Bioflavonoid; Biological Process; Cell Cycle Regulation; Cells; Chemicals; Class; Classification; Clinical; Coffee; Condition; Cultured Cells; DNA Methylation; DNA Modification Methylases; DNA Repair; DNA Sequence; Daily; Data; Development; Diet; Dietary Polyphenol; Epigallocatechin Gallate; Epigenetic Process; Future; Gene Expression; Gene Silencing; Genes; Goals; Health; Human; In Vitro; Inflammation; Kinetics; Methylation; Molecular; Mus; Nude Mice; Outcome; Outcome Study; Pattern; Phenotype; Physiological; Promoter Regions; Purpose; Research; Structure-Activity Relationship; Therapeutic; Xenograft procedure; angiogenesis; base; bioactive food component; blastomere structure; cancer cell; concept; cytotoxic; human disease; in vivo; inhibitor/antagonist; interest; molecular modeling; novel; polyphenol; success

DESCRIPTION (provided by applicant): DNA methylation represents an important epigenetic mechanism that regulates a wide array of important biological processes. Abnormality in DNA methylation patterns is associated with various human disease conditions. In recent years, there has been a surge in research interest to address the potential modulating effect of various bioactive food components on DNA methylation, gene silencing, and reactivation. The overall objective of this application is aimed at providing systematic experimental evidence to establish a broad novel concept that many of the catecholic and noncatecholic polyphenols (e.g., tea catechins, bioflavonoids/isoflavonoids, coffee polyphenols) abundantly present in our daily diet constitute a major class of highly effective and consequential modulators of DNA methylation in vivo. This hypothesis is proposed on the basis of extensive preliminary data showing that dietary polyphenolic compounds can effectively modulate DNA methylation status in vitro and also in cultured cells. To achieve the goals, four broad-scoped but tightly-interlaced specific aims are planned to: 1) Determine in vitro inhibition of human DNMTs by various dietary polyphenols, and also study the kinetic mechanisms of human DNMT inhibition; 2) Conduct molecular modeling studies to determine the precise molecular mechanisms of human DNMT inhibition by active dietary polyphenols, and also to probe the structure-activity relationship of human DNMT inhibition by these dietary chemicals; 3) Study the effect of dietary polyphenols on DNA methylation and gene expression in human cancer cells grown in culture and in nude mice as xenografts; and 4) Study the effect of dietary polyphenols on DNA methylation, gene reactivation, and also on epigenetically-controlled phenotypes in mouse embryonic cells in culture and also in an intact animal model. It is expected that the outcomes of the proposed studies will have direct clinical utility in the near future and far-reaching human health implications.

描述（由申请人提供）： DNA甲基化是一种重要的表观遗传机制，可调节广泛的重要生物学过程。 DNA甲基化模式的异常与各种人类疾病有关。近年来，研究兴趣激增，以解决各种生物活性食品成分对DNA甲基化，基因沉默和重新激活的潜在调节作用。该应用的总体目标旨在提供系统的实验证据，以建立一个广泛的新颖概念，即许多catecolic和非催化的多酚（例如茶儿茶素，生物黄酮/异黄素，咖啡多酚）在我们日常饮食中大量存在于高效和有效的模块化中。提出的假设是根据广泛的初步数据提出的，表明饮食多酚化合物可以有效地在体外和培养细胞中调节DNA甲基化状态。为了实现目标，计划通过各种饮食中的多酚确定体外抑制人DNMT的四个广泛但紧密相互交流的特定目的，并研究人类DNMT抑制的动力学机制； 2）进行分子建模研究，以确定主动饮食多酚抑制人DNMT的精确分子机制，并探测这些饮食化学物质对人DNMT抑制的结构活性关系； 3）研究饮食中多酚对培养物和裸鼠在异种移植物中生长的人类癌细胞中DNA甲基化和基因表达的影响； 4）研究饮食多酚对培养物和完整动物模型中小鼠胚胎细胞中表观遗传控制的表型的DNA甲基化，基因重新激活以及对表观遗传控制的表型的影响。预计拟议的研究的结果将在不久的将来和深远的人类健康影响中直接具有临床实用性。