Early-life Risk Factors for Inflammatory Bowel Disease

该项目将评估与炎症性肠病(IBD)相关的早期生命风险因素，这是 肠道炎症和肠道微生物群多样性丧失。应聘者：此应用程序的主要目标 是支持Manasi Agrawal博士的职业发展成为一名独立的、以患者为导向的调查员 IBD分子流行病学领域。阿格拉瓦尔博士的职业目标是成为一名研究人员和 确定IBD的可改变的早期风险因素，风险预测，并最终预防IBD。Dr。 阿格拉瓦尔计划在五个领域开展培训活动：1)高级和终身流行病学，2)高级 生物统计学方法论3)预测性生物标志物分析，4)免疫学数据分析原理和5) 科学和拨款方面的写作。为了实现这一目标，她组建了一个由英加博士领导的指导和咨询团队 彼得，西奈山遗传学和基因组科学系临时主席，也是 翻译组学和数据科学，以及范斯坦IBD中心主任让-弗雷德里克·科伦贝尔博士， Mont Sinai是IBD发病机制、预测和翻译研究的全球临床和翻译专家 预防。环境：位于西奈山的伊坎医学院有着优秀的传统 是美国国立卫生研究院资助的前20所医学院之一。西奈山胃肠病学部 一直被《美国新闻和世界报道》评为全国十大部门之一，是 IBD研究和临床护理的国际领先者。研究：IBD，包括克罗恩病(CD)和 溃疡性结肠炎(UC)是一种慢性、进行性、免疫介导的肠道疾病，具有显著的 发病率高，医疗费用高，而且无法治愈。IBD的发病机制涉及早期生命危险因素，但这些并不是 容易理解，这阻碍了早期干预和预防。较新的数据表明，IBD之前有 肠道炎症，失去微生物组多样性和独特的蛋白质组特征。发展中的IBD风险 预测模型将阐明IBD的发病机制，帮助识别高危个体，并指导治疗和 预防策略。此外，确定IBD危险因素对肠道炎症和 微生物组的变化将为IBD的发病机制和这些变化的相关性提供进一步的见解。 因此，我们的具体目标是(1)推导和验证使用早期非生命周期疾病预测CD和UC风险的模型 遗传风险因素(2)决定早期IBD风险因素是否与肠道炎症和缺失有关 肠道微生物群多样性以及基于其预测模型的IBD风险特征与肠道的关联 炎症(3)确定脐带血清中的炎性蛋白生物标志物是否与母体 母亲及其子代的IBD状态和肠道炎症。我们将学习丹麦语 目标1的基于人群的队列，以及胎粪，一种新的纵向队列的孕妇和 没有IBD和他们的后代的目标2和3。在这个奖项中发展的一般方法和技能 可应用于未来的研究，以更好地了解IBD的发病机制，并用于预防工作。

This project will evaluate early-life risk factors associated with inflammatory bowel diseases (IBD), biomarker of intestinal inflammation and loss of gut microbiome diversity. Candidate: The primary objective of this application is to support Dr. Manasi Agrawal’s career development into an independent patient-oriented investigator in the field of molecular epidemiology of IBD. Dr. Agrawal’s career goal is to become a researcher and leader in the identification of modifiable early-life risk factors for IBD, risk prediction and eventually, prevention of IBD. Dr. Agrawal’s proposed training activities are in five areas: 1) advanced and life-course epidemiology, 2) advanced biostatistical methodology 3) predictive biomarker analysis, 4) principles of immunological data analysis and 5) scientific and grant writing. To achieve this, she has assembled a mentoring and advisory team led by Dr. Inga Peter, Interim Chair of the Department of Genetics and Genomic Sciences at Mount Sinai and an expert in translational -omics and data science, and Dr. Jean-Frederic Colombel, Director of the Feinstein IBD Center, Mount Sinai, a global expert in clinical and translational investigation of IBD pathogenesis, prediction and prevention. Environment: The Icahn School of Medicine at Mount Sinai has a strong tradition of outstanding research and is one of the top 20 medical schools in NIH funding. The Mount Sinai Division of Gastroenterology is consistently considered one of the top 10 divisions in the country by US News and World Report and is an international leader in IBD research and clinical care. Research: IBD, including Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic, progressive, immune-mediated disease of the intestinal tract with significant morbidity, healthcare costs and has no cure. IBD pathogenesis involves early-life risk factors, but these are not well-understood, which impedes early intervention and prevention. Newer data suggest IBD is preceded by intestinal inflammation, loss of microbiome diversity and distinct proteomic signatures. Developing IBD risk prediction models will shed light on IBD pathogenesis, help identify at-risk individuals, and guide therapeutic and preventive strategies. In addition, determining the impact of IBD risk factors on intestinal inflammation and microbiome changes will provide further insights in IBD pathogenesis and the relevance of these changes. Therefore, our specific aims are to (1) derive and validate models to predict CD and UC risk using early-life non- genetic risk factors (2) determine if early-life IBD risk factors are associated with intestinal inflammation, and loss of gut microbiome diversity as well as correlate IBD risk signature based on its prediction model with intestinal inflammation (3) determine if inflammatory protein biomarkers in the cord serum are associated with maternal IBD status and with intestinal inflammation in the mothers and their offspring. We will study the Danish population-based cohort for Aim 1, and MECONIUM, a novel longitudinal cohort of pregnant women with and without IBD and their offspring for Aims 2 and 3. The general approaches and skills developed during this award can be applied to future studies to understand better IBD pathogenesis and toward preventive efforts.