Epigenetic mechanisms of maternal diets in human health and disease prevention

孕产妇饮食对人类健康和疾病预防的表观遗传机制

• 批准号: 9223256
• 负责人: Yuanyuan Li
• 金额: $ 11.39万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9223256
• 关键词: Adult; Affect; Alabama; Applications Grants; Area; Award; Basic Science; Biology; Blood Chemical Analysis; Body Composition; Body Weight; Breast Cancer Prevention; Broccoli - dietary; Chemoprevention; Chemopreventive Agent; Clinical Research; Comprehensive Cancer Center; Core Facility; Development; Diet; Dietary Component; Dietary Intervention; Disease; Disease Outcome; Disease susceptibility; ERBB2 gene; Early Intervention; Effectiveness; Embryo; Embryonic Development; Energy Metabolism; Environment; Environmental Exposure; Environmental Impact; Environmental Risk Factor; Epigenetic Process; Etiology; Exposure to; FVB/N Mouse; Fetal Development; Funding; Gene Activation; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic; Genistein; Goals; Health; Hematology; Human; In Vitro; Incidence; Individual; Institutes; Institution; Instruction; Intervention; Investigation; Isothiocyanates; Knowledge; Laboratories; Lead; Life; Malignant Neoplasms; Maternal Exposure; Medicine; Mentored Research Scientist Development Award; Mentors; Metabolic; Metabolic Diseases; Microarray Analysis; Molecular; Mus; Nutritional; Obesity; Obesity associated disease; Outcome; Pathway interactions; Phenotype; Plants; Play; Predisposition; Prevention; Process; Property; Publications; Regimen; Regulation; Regulator Genes; Research; Research Activity; Research Infrastructure; Research Personnel; Resources; Series; Signal Pathway; Simian virus 40; Soybeans; Sulforaphane; Testing; Time; Training; Transgenic Mice; Universities; Work; Writing; anticancer research; cancer initiation; cancer prevention; career; cruciferous vegetable; design; dietary supplements; differential expression; disorder prevention; epigenetic regulation; epigenomics; experience; genome-wide; human disease; imprint; improved; in utero; in vivo; innovation; instructor; interest; malignant breast neoplasm; member; methylome; mouse model; novel; nutrition; obesity prevention; offspring; oncology; postnatal; pregnant; prenatal; programs; public health relevance; research study; response; skills; tumor

Project Summary The Candidate The Candidate for this K01 award, Dr. Yuanyuan Li, is an Instructor in the Division of Hematology and Oncology of the Department of Medicine at the University of Alabama at Birmingham (UAB). Dr. Li started her research studies in dietary epigenetic cancer research under the direction of Dr. Trygve Tollefsbol, the primary Mentor of this K01 award, since 2006. Dr. Li's research interest centers on exploring the molecular epigenetic mechanisms of disease initiation and discovering potential interactions between epigenetic regulations and environmental impacts on human disease development and susceptibility. Dr. Li has established remarkable research contributions as a result of her significant of publications and research awards in the area. Dr. Yuanyuan Li is committed to acquire necessary training, practical experience and knowledge to become an independent research investigator. During the first two years of the award, she will focus on building up her research publication record and improving her skills in scientific writing including research articles and grant applications. From the third year of this K01 award, Dr. Li will actively seek long- term funding support that will allow her to become a fully independent investigator after completion of this K01 award. Dr. Li's long-term career goal is to establish an innovative and independent research program to understand how genes and environment interact to influence disease development, and to explore novel dietary intervention regimens for early disease prevention. Institutional Environment UAB is one of the top research institutions in the U.S. and has outstanding resources for trainees. There are state of the art laboratories for work in basic and clinical research and outstanding core facilities for supporting molecular and clinical research activities. The candidate's more immediate research environment is the Department of Biology and Wallace Tumor Institute (WTI) in the Division of Hematology and Oncology of the Department of Medicine at UAB. The candidate is a member of the UAB Comprehensive Cancer Center (CCC) and the Nutrition Obesity Research Center (NORC), both of which will provide additional resources and infrastructure that will facilitate the completion of this project. Research Summary The etiology of most human diseases involves complicated interactions of multiple environmental factors with individual genetic background which is initially generated early in human life, for example, during the processes of embryogenesis and fetal development in utero. Maternal exposure to certain diets with properties in influencing epigenetic processes may influence the epigenetic reprograming processes during early embryogenesis, which may consequently influence gene expression patterns and eventually affect phenotype outcome in the offspring such as differences in disease susceptibility. The bioactive dietary components, sulforaphane (SFN), an isothiocyanate enriched in cruciferous vegetables such as broccoli sprouts (BSp), and genistein (GE) in soybean products are strong epigenetic modulators and robust chemopreventive agents against various human diseases such as cancers and obesity-related diseases in vitro and in vivo. We now have compelling evidence showing that maternal dietary BSp or GE treatments influence offspring susceptibility to diseases and metabolic disorders such as breast cancer and obesity in adult life. We hypothesize that BSp or GE bioactive natural plant products impact early embryonic development by affecting epigenetic profiles resulting in different susceptibility to breast cancer and metabolic disorders such as obesity later in life. The specific aims of this proposal are therefore to 1) determine the temporal effects of early BSp or GE administration on development of breast cancer and obesity in mouse models, 2) evaluate gene expression and epigenetic alterations of specific epigenetic-controlled genes in response to early BSp or GE treatment and 3) assess the impacts of maternal BSp or GE diet on epigenomic profiles including methylome and acetylome alterations as well as determination of key candidate epigenetic genes in control of early disease chemoprevention by this regimen. The goal of this proposal is to determine the effectiveness of maternal BSp and GE diets on early-life disease intervention and the potential epigenetic mechanisms. This study may lead to translational disease chemoprevention potential that benefits human health by appropriate administration of prenatal and/or postnatal dietary supplements leading to early prevention of multiple human diseases including breast cancer, obesity and obesity-related human diseases. The Candidate anticipates being able to complete the studies within a five-year award period through collaborative efforts with her Mentors and collaborators.

项目概要 候选人 本次 K01 奖的候选人李媛媛博士是 阿拉巴马大学伯明翰分校 (UAB) 医学系的血液学和肿瘤学。 李博士在Trygve博士的指导下开始了饮食表观遗传癌症研究 Tollefsbol 自 2006 年起担任 K01 奖项的主要导师。李博士的研究兴趣集中在探索 疾病发生的分子表观遗传机制和发现之间潜在的相互作用 表观遗传调控和环境对人类疾病发展和易感性的影响。李博士 由于她大量的出版物和研究，做出了卓越的研究贡献 领域内的奖项。李媛媛博士致力于获得必要的培训、实践经验和 成为一名独立研究人员的知识。在获奖的头两年里，她将 专注于建立她的研究发表记录并提高她的科学写作技能，包括 研究文章和资助申请。从获得K01奖的第三年开始，李博士将积极寻求长期 定期资助支持将使她能够在完成本 K01 课程后成为一名完全独立的研究者 奖。李博士的长期职业目标是建立一个创新的、独立的研究项目，以 了解基因和环境如何相互作用影响疾病的发展，并探索新的 早期疾病预防的饮食干预方案。 机构环境 UAB 是美国顶尖的研究机构之一，拥有杰出的研究成果 为学员提供的资源。有最先进的实验室用于基础和临床研究工作 支持分子和临床研究活动的杰出核心设施。候选人更多 直接的研究环境是生物系和华莱士肿瘤研究所 (WTI) 阿拉巴马大学医学系血液学和肿瘤学部。候选人是以下组织的成员 UAB 综合癌症中心 (CCC) 和营养肥胖研究中心 (NORC) 这将提供额外的资源和基础设施，促进该项目的完成。 研究摘要 大多数人类疾病的病因涉及多种因素的复杂相互作用。 具有个体遗传背景的环境因素最初在人类生命早期产生， 例如，在子宫内的胚胎发生和胎儿发育过程中。母亲接触某些 具有影响表观遗传过程特性的饮食可能会影响表观遗传重编程过程 在早期胚胎发生期间，这可能会影响基因表达模式并最终影响 后代的表型结果，例如疾病易感性的差异。生物活性饮食 成分，萝卜硫素 (SFN)，一种富含十字花科蔬菜（如西兰花）的异硫氰酸盐 豆制品中的豆芽 (BSp) 和金雀异黄酮 (GE) 是强表观遗传调节剂，具有强大的 针对各种人类疾病的化学预防剂，例如癌症和肥胖相关疾病 体外和体内。我们现在有令人信服的证据表明，母亲饮食 BSP 或 GE 治疗 影响后代对疾病和代谢紊乱（如乳腺癌）的易感性 成人生活中的肥胖。我们假设 BSp 或 GE 生物活性天然植物产品影响早期胚胎 通过影响表观遗传图谱导致对乳腺癌和代谢的不同易感性的发育 晚年出现肥胖等疾病。因此，本提案的具体目标是 1) 确定 早期 BSP 或 GE 给药对小鼠乳腺癌和肥胖发展的时间影响 模型，2）评估特定表观遗传控制基因的基因表达和表观遗传改变 对早期 BSp 或 GE 治疗的反应，3) 评估母亲 BSp 或 GE 饮食对表观基因组的影响 包括甲基化组和乙酰化组改变以及关键候选表观遗传测定的概况 通过该方案控制早期疾病化学预防的基因。该提案的目标是确定 母亲 BSP 和 GE 饮食对生命早期疾病干预的有效性以及潜在的表观遗传 机制。这项研究可能会带来转化疾病化学预防的潜力，造福于人类 通过适当施用产前和/或产后膳食补充剂来促进健康 预防多种人类疾病，包括乳腺癌、肥胖症和与肥胖相关的人类疾病。 候选人预计能够在五年奖励期内完成研究 与她的导师和合作者的共同努力。