A multi-center study of the microbiome in biliary atresia

胆道闭锁微生物组的多中心研究

• 批准号: 10392330
• 负责人: Mary Elizabeth McConnell Tessier
• 金额: $ 18.48万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10392330
• 关键词: Advisory Committees; Affect; Ancillary Study; Anti-Inflammatory Agents; Bifidobacterium; Bile Acids; Bile fluid; Biliary Atresia; Bioinformatics; Biometry; Bioreactors; Cell Culture Techniques; Child; Childhood; Cholestasis; Chronic; Clinical; Clinical Trials Design; Communities; Complex; Data; Disease; Disease model; Educational Status; Endotoxemia; Enterocytes; Environment; Etiology; Extrahepatic; Feces; Funding; Future; Gastroenterologist; Gastroenterology; Genes; Goals; Grant; Homeostasis; Human; Human Milk; Incidence; Infant; Infant Development; Inflammatory; Infrastructure; Institution; Institutional Review Boards; International; Intestines; Investigation; Lead; Learning; Life; Liver; Liver Fibrosis; Longitudinal Studies; Medical center; Medicine; Mentors; Mentorship; Metadata; Metagenomics; Microbe; Morbidity - disease rate; Multicenter Studies; National Institute of Diabetes and Digestive and Kidney Diseases; Observational Study; Operative Surgical Procedures; Outcome; Participant; Pathogenesis; Pathway interactions; Pediatric Hospitals; Physicians; Process; Production; Property; Prospective Studies; Publishing; Research; Research Personnel; Research Training; Role; Sampling; Scientist; Signal Transduction; Site; Techniques; Technology; Testing; Texas; Therapeutic; Time; Training; United States; United States National Institutes of Health; Whole-Genome Shotgun Sequencing; Work; bacterial community; base; biliary tract; biobank; career development; cohort; collaborative environment; college; cytokine; design; fecal microbiome; genome sequencing; gut microbiome; improved; innovation; liver transplantation; longitudinal database; microbial; microbial community; microbial signature; microbiome; microbiome alteration; microbiome research; microbiome sequencing; milk intake; novel; pathogen; patient oriented research; pressure; professor; prospective; recruit; repository; restoration; stool sample; tenure track; whole genome

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.

项目概要/摘要： 尽管胆道闭锁 (BA) 的发病率为 1:8,000-1:18,000，但它是小儿肝脏疾病的主要适应症 BA 是一种病因不明的肝外胆管树进行性纤维狭窄疾病。 Kasai 门肠造口术 (KP) 是一种允许胆汁流动的外科手术，是目前 BA 的唯一治疗方法 除了肝移植外，KP 后成功的胆汁流动可改善发病率并预测早期免肝移植。 结果。2,3 然而，50% 及时接受 KP 的婴儿需要肝移植或在前两次死亡 7,8 因此，迫切需要了解导致这一现象的病理生理因素 KP 后是否存在胆汁流动 最近的研究表明存在双向相互作用。 肠道微生物组和胆汁酸稳态之间的关系，而胆汁可以改变微生物组，因为 我们令人兴奋的初步数据表明，微生物因素可能是 BA 结果的关键。 一项前瞻性研究假设微生物组通过影响胆汁流量来影响 BA 结果。 患有胆汁淤积和 BA 的婴儿的微生物组将允许在 3 个目标中检验这一假设。 中心将开发胆汁淤积婴儿的前瞻性粪便生物库，目标 2 是胆汁流量对胆汁淤积的影响。 将使用全基因组测序来比较胆汁淤积婴儿的早期微生物特征。 将确定与 BA 中的积极结果相关的 3 个微生物特征，预期结果是： 我们将阐明胆汁淤积婴儿的微生物组和胆汁流量的复杂关系， 特别是文学士。 Tessier 博士是一名经过委员会认证的儿科胃肠病学家和终身教授助理教授 她的长期目标是成为一名由 NIH 资助的独立医师科学家。 研究微生物组在儿童胆汁淤积中的相互作用。该研究旨在支持 PI 的研究。 通过利用儿科胃肠病学背景提供硕士学位来实现职业发展 临床试验设计和实施、微生物组和全基因组测序分析方面的培训 这将通过 1) 指导和咨询团队来完成，其中包括 国际认可、独立资助的研究人员，具有小儿胆汁淤积方面的专业知识， 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； 先进的测序技术和生物统计学；3) 实现独立的学术活动。 最后，候选人的研究环境是国内杰出的学术研究机构 世界上最大的医疗中心与全国最大的儿童医院合作，将提供一个良好的环境。 富有成效和协作的氛围，以及时完成她的研究和培训目标。 总之，该培训计划将使 Tessier 博士成为一名独立资助的医师科学家 以患者为导向的研究，小儿胆汁淤积和微生物组。