Epigenetic mechanisms of maternal diets in human health and disease prevention

项目摘要 本次K01奖项的候选人，李渊源博士，是一名 伯明翰阿拉巴马大学(UAB)医学系血液学和肿瘤学。 李博士在Trygve博士的指导下开始了她在饮食表观遗传癌症研究方面的研究 Tollefsbol，自2006年以来一直是这一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学机制和发现潜在的相互作用 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 由于她发表了大量的出版物和研究成果，她在研究方面做出了显著的贡献 该地区的奖项。李元元博士致力于获得必要的培训、实践经验和 成为一名独立研究调查员的知识。在获奖的头两年，她将 专注于建立她的研究发表记录和提高她的科学写作技能，包括 研究文章和拨款申请。从这个K01奖项的第三个年头开始，李博士将积极寻求长期- 定期资助，使她在完成这项K01后成为一名完全独立的调查员 获奖。李博士的长期职业目标是建立一个创新和独立的研究计划，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养生法。 制度环境UAB是美国顶尖的研究机构之一，拥有杰出的 为学员提供的资源。有最先进的实验室进行基础和临床研究， 卓越的核心设施，支持分子和临床研究活动。候选人有更多的 直接的研究环境是生物系和华莱士肿瘤研究所(WTI) 加州大学伯克利分校内科血液和肿瘤科。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)，都是 这将提供额外的资源和基础设施，以促进这一项目的完成。 研究综述大多数人类疾病的病因学涉及多种因素的复杂相互作用 最初在人类生命早期产生的具有个人遗传背景的环境因素，例如 例如，在胚胎发育和胎儿宫内发育的过程中。母亲接触到某些 具有影响表观遗传过程的特性的饮食可能会影响表观遗传重编程过程 在早期胚胎发育过程中，这可能会影响基因表达模式，并最终影响 子代的表型结果，如疾病易感性的差异。生物活性饮食 萝卜硫素(SFN)，一种富含于西兰花等十字花科蔬菜中的异硫氰酸酯 豆制品中的芽(BSP)和染料木素(GE)是强表观遗传调节剂和健壮的 针对各种人类疾病的化学预防药物，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，母亲饮食中的BSP或GE治疗 影响后代对疾病和代谢紊乱的易感性，如乳腺癌和 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 通过影响表观遗传学特征导致不同乳腺癌易感性和代谢的发育 诸如晚年肥胖之类的疾病。因此，本提案的具体目标是：1)确定 BSP或Ge早期给药对小鼠乳腺癌和肥胖的影响 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变化 对早期BSP或GE治疗的反应以及3)评估母亲BSP或GE饮食对表观基因组的影响 包括甲基组和乙酰组改变以及关键候选表观遗传学的确定 通过这种方案控制早期疾病化学预防的基因。这项提案的目标是确定 母体BSP和Ge饮食在早期疾病干预中的效果及其潜在的表观遗传学 机械装置。这项研究可能导致转化性疾病的化学预防潜力，使人类受益 通过适当地服用产前和/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、肥胖和与肥胖相关的人类疾病。 应聘者期望能够在五年内完成学业，直至 与她的导师和合作者共同努力。

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.