Lifecourse dietary exposures and offspring hepatic fat in early childhood: a nutrigenomic approach

项目摘要/摘要 非酒精性脂肪性肝病(NAFLD)是儿童最常见的慢性肝病， 极大的代谢和肝脏相关的健康风险。尽管NAFLD通常在青春期被诊断出来， 在青春期前后，患者在确诊时可能会有不同的疾病严重程度，有些人 脂肪性肝炎或晚期纤维化，表明疾病的发病机制比诊断早得多， 但却是“沉默的”。从营养的角度来看，我们检查与肝脏相关的饮食风险因素是至关重要的 脂肪，特别是在其发育的早期，以更好地了解疾病的最佳饮食目标和时机 预防。为了解决这一知识差距，拟议的研究将利用来自健康人群的数据/样本 Start Study是科罗拉多州的一个纵向产前队列，跟踪了大约1400名来自 从怀孕到童年早期。具体的目的是：(1)检查饮食的独立关联 在不同的生活阶段(宫内、婴儿期和儿童期)暴露于4-10岁的纵向肝脏脂肪； (2)评估多次生命周期膳食暴露对儿童肝脏脂肪的联合和中介作用；(3) 评估NAFLD的遗传风险因素是否会改变饮食与肝脏脂肪的关系。中心假设是 在整个生命过程中，肥胖饮食暴露将预测早期肝脏脂肪沉积较高。 与非携带者相比，NAFLD的遗传风险等位基因携带者与非携带者之间的相关性将有所不同。 申请者是一位多产的博士科学家和注册营养师，她的长期职业目标是建立 一项独立的研究计划，调查营养暴露与儿童NAFLD的关系 评估风险和严重程度，然后将这些发现转化为预防NAFLD的有效营养干预措施。 为了促进这一目标和实现拟议的研究目标，申请者制定了一项全面的 培训计划，这将是她先前背景/培训的合理扩展，包括以下目标： 1)获得生命周期研究和纵向分析方面的知识/技能；2)获得基因组学知识/技能 和营养遗传学；3)在儿童非酒精性脂肪肝的发育起源和临床治疗方面建立专业知识；4) 获得设计和管理临床研究的经验；5)增强研究网络和专业技能。 科罗拉多大学丹佛-安舒茨医学院是一家杰出的研究机构，拥有 需要资源和合作者来促进申请者在这些领域的培训。所产生的结果 这项提案将产生初步数据，作为未来赠款申请的基础，包括 职业发展奖，在此期间，申请者将从事观察和临床-翻译 旨在促进我们对儿科疾病的生命过程决定因素和后果的理解的研究 NAFLD。总的来说，拟议的研究和培训将使申请者能够战略性地扩展她 知识、技能和专业知识，并帮助她过渡到独立的儿科营养研究员。

PROJECT SUMMARY/ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and carries substantial metabolic and liver-related health risks. Although NAFLD is commonly diagnosed in adolescence, around or after pubertal onset, patients can have varying disease severity at diagnosis, with some having steatohepatitis or advanced fibrosis, suggesting that disease pathogenesis begins much earlier than diagnosis, but is “silent”. From a nutrition perspective, it’s critical that we examine dietary risk factors associated with hepatic fat, especially early on in its development, to better understand the optimal dietary targets and timing for disease prevention. To address this knowledge gap, the proposed research will leverage data/samples from the Healthy Start Study, a longitudinal pre-birth cohort in Colorado that has followed ~1,400 mother-child dyads from pregnancy through early childhood. The specific aims are to: (1) examine independent associations of dietary exposures during distinct lifestages (in utero, infancy, and childhood) with longitudinal hepatic fat from 4-10 yrs; (2) assess the joint and mediating effects of multiple lifecourse dietary exposures on childhood hepatic fat; (3) evaluate whether genetic risk factors for NAFLD modify diet-hepatic fat associations. The central hypothesis is that obesogenic dietary exposures throughout the lifecourse will predict higher hepatic fat deposition in early childhood and that associations will differ in carriers of genetic risk alleles for NAFLD compared to non-carriers. The applicant is a productive PhD scientist and Registered Dietitian, and her long-term career goal is to establish an independent research program that investigates associations of nutritional exposures with pediatric NAFLD risk and severity, and then translates these findings into effective nutrition interventions for preventing NAFLD. To further this goal and to achieve the proposed research aims, the applicant has developed a comprehensive training plan, which will be a logical expansion of her prior background/training and includes the following goals: 1) gain knowledge/skills in lifecourse research and longitudinal analysis; 2) gain knowledge/skills in genomics and nutrigenetics; 3) build expertise in the developmental origins and clinical treatment of pediatric NAFLD; 4) gain experience designing and managing clinical research; 5) enhance research network and professional skills. The University of Colorado Denver-Anschutz Medical Campus is an outstanding research institute with the resources and collaborators needed to facilitate the applicant’s training in these areas. The findings generated from this proposal will generate preliminary data to serve as the foundation for future grant applications, including a career development award, during which the applicant will pursue both observational and clinical-translational research aiming to advance our understanding of the lifecourse determinants and consequences of pediatric NAFLD. Collectively, the proposed research and training will enable the applicant to strategically expand her knowledge, skills, and expertise, and facilitate her transition to independent pediatric nutrition researcher.