The Role of Fiber in the Etiopathogenesis of Fecal Incontinence

项目总结/摘要 候选人是一位有成就的神经胃肠病学家，受过流行病学方法的正式培训， 致力于功能性胃肠道疾病研究的临床和转化研究。的 候选人的长期职业目标是成为一名独立资助的医生调查员， 功能性胃肠道疾病的临床研究计划。候选人的短期职业目标是：1）发展 基于已建立的队列的大型分析数据集; 2）设计和解释宏基因组数据，包括 微生物-环境相互作用方法学的应用; 3）掌握分析和解释的技能 肠道代谢组学数据; 4）将临床试验技能发展为多模式模型， 病因分析; 5）建立并维持一个纵向队列，详细的饮食，生活方式和生理 6）产生必要的数据和出版物，以过渡到成功的 R 01应用程序。此申请概述了机构的承诺，研究计划，职业发展 活动，以及参与的关键导师，以确保候选人实现这些目标。在先前的工作中， 一位候选人已经证明，膳食纤维与较低的大便失禁（FI）风险有关 在老年妇女中，这表明纤维在FI的发展中具有预防作用。尽管如此， 纤维在其他人群中的影响以及与FI相关的潜在生物学机制 缺乏。在这份提案中，考生寻求通过全面的考试来填补这一知识空白 纤维和肠道微生物环境改变之间的复杂相互作用在病因学中的作用 和严重程度。这项研究的具体目标是：1）估计增加膳食纤维的相对益处 在FI的发展和进展中使用大型良好表征的队列; 2）确定特定的 与流行FI相关的宏基因组谱，并确定膳食纤维对 FI; 3）检查纤维补充对症状严重程度，肛门直肠生理学和肠道的影响 IBS-D和FI女性中的微生物组。作为本建议书的一个组成部分，候选人的职业发展 将通过参加高级课程来补充，以发展营养流行病学方面的专业知识， 临床试验设计和实施，以及生物信息学，包括宏基因组学和代谢组学方法 数据一个正式的指导委员会，由营养流行病学的多学科专家组成， 微生物组和GI运动将为候选人提供监督，指导和帮助，以实现其 目标.研究环境，其中包括临床和转化流行病学单位，钱宁 实验室和哈佛公共卫生学院将提供一个丰富的，合作的，和智力 激励气氛，以确保候选人的成功。通过这个奖项，候选人将成为一个 独立的临床研究者，有助于我们理解纤维在发病机制中的作用， 通过一系列的研究，桥梁流行病学的相关性和疾病的因果关系。

PROJECT SUMMARY/ABSTRACT The candidate is an accomplished neurogastroenterologist with formal training in epidemiological methods and a commitment to a career in clinical and translational research in the study of functional GI disease. The candidate’s long-term career goal is to become an independently-funded physician investigator, maintaining a clinical research program in functional GI diseases. The candidate’s short-term career goals are to: 1) develop large analytic datasets based upon established cohorts; 2) design and interpret metagenomic data, including application of microbiota-environment interaction methodology; 3) acquire skills in the analysis and interpretation of gut metabolomics data; 4) evolve clinical trial skills into multimodal models with potential for mechanistic and causative analyses; 5) establish and maintain a longitudinal cohort with detailed dietary, lifestyle, and physiologic measurements of subjects with FI; 6) produce the data and publications necessary to transition into a successful R01 application. This application outlines the institutional commitment, research plan, career development activities, and key mentors involved to ensure the candidate accomplishes these goals. In prior work, the candidate has demonstrated that dietary fiber is associated with a lower risk of incident fecal incontinence (FI) among elderly women, suggesting a preventative role for fiber in the development of FI. Nonetheless, data on the influence of fiber in other populations and potential biological mechanisms underlying associations with FI are lacking. In this proposal, the candidate seeks to fill this knowledge gap through a comprehensive examination of the complex interaction between fiber and alterations in the intestinal microbial environment in the etiology and severity of FI. The specific goals of this study are to 1) estimate the relative benefit of increased dietary fiber in the development and progression of FI using large well-characterized cohorts; 2) determine specific metagenomic profiles associated with prevalent FI and determine the mediating effect of dietary fiber on risk of FI; 3) examine the effects of fiber supplementation on symptom severity, anorectal physiology, and the gut microbiome in women with IBS-D and FI. As an integral part of this proposal, the candidate’s career development will be complemented by participation in advanced coursework to develop expertise in nutritional epidemiology, clinical trial design and conduct, and bioinformatics including the approach to metagenomic and metabolomic data. A formal mentorship committee, consisting of multidisciplinary experts in nutritional epidemiology, the microbiome, and GI motility will provide supervision, guidance, and assistance for the candidate to achieve his goals. The research environment, which includes the Clinical and Translational Epidemiology Unit, the Channing Laboratory, and the Harvard School of Public Health will provide a rich, collaborative, and intellectually stimulating atmosphere to ensure the candidate’s success. Through this award, the candidate will emerge as an independent clinical investigator by contributing to our understanding of the role of fiber in the etiopathogenesis of FI through a series of studies that bridge epidemiologic correlation and disease causation.