A multi-center study of the microbiome in biliary atresia

项目摘要/摘要： 尽管胆道闭锁(BA)的发病率为1：8,000-1：18,000，但仍是儿童肝脏的主要适应症 移植。BA是一种病因不明的进行性肝外胆管狭窄症。 Kasai门肠吻合术(KP)是一种允许胆汁流动的外科手术，是目前治疗BA的唯一方法 除了肝脏移植。KP术后成功的胆汁流动改善了发病率，并预测了早期肝移植的自由 结果2，3然而，接受及时KP的婴儿中有50%需要肝移植或在前两个月死亡 7，8因此，迫切需要了解导致这种疾病的病理生理因素 KP术后无胆流者或有胆流者。最近的研究表明，存在双向相互作用。 在肠道微生物群和胆汁酸动态平衡之间。虽然胆汁可以改变微生物群，但由于 我们令人兴奋的初步数据，我们认为微生物因素可能是BA结果的关键。因此，赠款的 假说是微生物群通过影响胆汁流量来影响BA的结局。对…的前瞻性研究 胆汁淤积症婴儿的微生物组和BA将允许在3个目标中验证这一假说。在目标1中，一个多- 中心将开发来自胆汁淤积症婴儿的预期粪便生物库。在目标2中，胆汁流动对 在胆汁淤积症的婴儿中，将使用全基因组测序来比较早期微生物特征。在AIM 将确定与BA阳性结果相关的3个微生物签名。预期的结果是 我们将阐明胆汁淤积症婴儿的微生物群和胆汁流动的复杂关系， 具体地说就是BA。 Tessier博士是一名获得董事会认证的儿科胃肠病专家和终身教职助理教授 贝勒医学院。她的长期目标是成为一名由NIH资助的独立内科科学家 探讨小儿胆汁淤积症中微生物群的相互作用。研究的目的是支持PI的 在儿科胃肠病学背景的基础上进行职业发展，提供硕士学位 临床试验设计和实施、微生物组和全基因组测序分析以及 生物静态解释。这将通过1)指导和咨询团队来实现，该团队包括 国际公认的、独立资助的、在儿科胆汁淤积症方面有专长的研究人员， 特别是BA，婴儿微生物组和临床试验设计；2)生物信息学高级课程工作， 先进的测序技术和生物统计学；以及3)导致独立的学术活动。 最后，候选人的研究环境是世界上最好的学术研究机构 世界上最大的医疗中心与全国最大的儿童医院结盟。此环境将提供 富有成效和协作的氛围，及时完成她的研究和培训目标。在……里面 总结，这项培训计划将使特西尔博士成为一名独立资助的内科科学家 以患者为中心的研究，儿科胆汁淤积和微生物组。

PROJECT SUMMARY/ABSTRACT: Despite an incidence of 1:8,000-1:18,000, biliary atresia (BA) is the leading indication for pediatric liver transplantation. BA is a progressive fibrostenotic disease of the extrahepatic biliary tree of unknown etiology. The Kasai portoenterostomy (KP), a surgical procedure to allow bile flow, is currently the only treatment for BA besides liver transplant. Successful bile flow after KP improves morbidity and predicts early liver-transplant free outcomes.2,3 However 50% of infants who receive a timely KP require liver transplant or die in the first two years of life.7,8 Thus, there is desperate need to understand the pathophysiological factors responsible for the absence or presence of bile flow after KP. Recent investigations suggest that there is bidirectional interplay between the intestinal microbiome and bile acid homeostasis. While bile can change the microbiome, due to our exciting preliminary data, we believe that microbial factors may be key to BA outcomes. Thus, the grant’s hypothesis is that the microbiome influences BA outcomes by affecting bile flow. A prospective study of microbiome in infants with cholestasis and BA will allow testing of this hypothesis in 3 aims. In aim 1, a multi- center prospective stool biobank from cholestatic infants will be developed. In aim 2, the effects of bile flow on early microbial signatures will be compared using whole genome sequencing in infants with cholestasis. In aim 3 microbial signatures associated with positive outcomes in BA will be identified. The expected outcome is that we will elucidate the complex relationship of the microbiome and bile flow in infants with cholestasis, specifically BA. Dr. Tessier is a board-certified pediatric gastroenterologist and tenure-track Assistant Professor at Baylor College of Medicine. Her long-term goal is to become an independent NIH-funded physician-scientist investigating the interactions of the microbiome in pediatric cholestasis. The research aims support the PI’s career development by building on her background in pediatric gastroenterology to provide master’s level training in clinical trial design and implementation, microbiome and whole genome sequencing analysis and biostatical interpretation. This will be fulfilled via 1) A mentorship and advisory team which includes internationally-recognized, independently funded investigators with an expertise in pediatric cholestasis, particularly BA, the infant microbiome, and clinical trial design; 2) advanced course work in bioinformatics, advanced sequencing technologies and biostatistics; and 3) scholarly activities to lead to independence. Finally, the candidate’s research environment is a preeminent academic research institution in the world’s largest medical center allied with the nation’s largest children’s hospital. This environment will provide a productive and collaborative atmosphere to accomplish her research and training goals in a timely manner. In summary, this training plan will allow Dr. Tessier to become an independently funded physician scientist in patient-oriented research, pediatric cholestasis and microbiome.