The Role of Fiber in the Etiopathogenesis of Fecal Incontinence

项目摘要/摘要 应聘者是一位有经验的神经胃肠病专家，接受过流行病学方法和 致力于功能性胃肠道疾病的临床和转化性研究。这个 应聘者的长期职业目标是成为一名独立资助的内科研究员，保持 功能性胃肠道疾病的临床研究计划。应聘者的短期职业目标是：1)发展 基于已建立的队列的大型分析数据集；2)设计和解释元基因组数据，包括 微生物-环境相互作用方法论的应用；3)掌握分析和解释的技能 肠道代谢组学数据；4)将临床试验技术演变为具有潜在机械性和可操作性的多模式模型 原因分析；5)建立和维护详细的饮食、生活方式和生理方面的纵向队列 用FI对受试者进行测量；6)产生过渡到成功的 R01应用程序。这份申请概述了机构承诺、研究计划、职业发展 活动，以及关键导师参与，以确保候选人实现这些目标。在以前的工作中， 候选人已经证明，膳食纤维与发生大便失禁(FI)的风险较低有关 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，关于 纤维在其他种群中的影响及其与FI相关的潜在生物学机制 都是缺乏的。在这项建议中，考生试图通过全面的考试来填补这一知识空白 纤维之间的复杂相互作用与肠道微生物环境的改变在病因中的作用 和FI的严重程度。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的、特征良好的队列；2)确定具体的 与流行的FI相关的元基因组学特征并确定膳食纤维在FI风险中的中介作用 检查补充纤维对症状严重程度、肛门直肠生理和肠道的影响。 IBS-D和FI患者的微生物群。作为这项提议的一个组成部分，候选人的职业发展 将通过参加高级课程来发展营养流行病学的专业知识来补充， 临床试验设计和实施，以及生物信息学，包括代谢组学和代谢组学的方法 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 微生物组和胃肠动力将为候选人实现其目标提供监督、指导和帮助 目标。研究环境，包括临床和转化性流行病学股、查宁 实验室和哈佛公共卫生学院将提供丰富的、协作的和智力的 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 独立的临床研究人员，有助于我们理解纤维在病因中的作用 通过一系列研究，在流行病学相关性和疾病病因之间架起一座桥梁。

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.