Defining Small Intestinal Microbial Landscapes To Improve Therapeutics For Gastrointestinal Disease

项目摘要： 定义小肠微生物景观以改善胃肠道疾病的治疗 疾病相关性：肠易激综合征（IBS）是一种慢性疾病， 功能（一致性和/或频率）除腹痛外，影响7 - 16%的美国人群 并且每年与10亿美元的直接医疗保健费用相关。这项建议旨在更好地了解 IBS和开发更有效的治疗IBS。候选人和职业发展计划：我的长期 我的目标是通过领导一个尖端的研究项目，成为一个完全独立的医生科学家 在人类微生物群分析及其与临床数据的关联中， （分子遗传学，代谢组学，gnotobiotic小鼠模型），以阐明作用机制， 开发用于GI疾病的改进的微生物群定向治疗剂。通过我的临床训练， 准备成为诊断和治疗IBS的专家，通过我以前的研究培训，我很好 具备进行高分辨率人类和小鼠免疫学的技能。完全实现我的事业 成为IBS微生物与宿主相互作用专家的目标，我需要获得超越目前的技能 知识库该奖项将支持在微生物群分析，临床诊断方法， 研究，细菌分离和培养，和gnotobiotic小鼠模型。研究计划：总体规划 这项提案的研究目标是超越粪便，确定人类特定部位的微生物生态学 小肠IBS我们将构建人类肠道微生物群和代谢物的纵向地图 一个吞下的微生物采样胶囊装置。我已经成功地采用这种方法在健康 人类和拟议的研究将扩大样本收集，包括IBS患者样本分析， 微生物群测序，新型微生物群聚焦代谢组学（Aim 1），以及细菌分离和功能 测试（目标2），与gnotobiotic小鼠的补充研究（目标3），以确定宿主的基本方面， 小肠内微生物的相互作用。导师团队：为了实现这些目标，我组建了一个世界 具有翻译人类微生物组研究专业知识的班级导师团队（Justin Sonnenburg，小学 导师），从人体微生物组中分离和研究细菌（KC Huang，共同导师），以及治疗 和IBS的研究（琳达阮，共同导师）。环境与机构承诺：斯坦福大学 是人类微生物组研究和治疗胃肠病（GI）的世界领导者。我就能进入 导师、合作者和广泛的资源，将提供一个特殊的培训环境。 我的导师团队和斯坦福大学医学系的领导层致力于确保 我的成功在这个奖项下的科学培训，技能获取和职业发展将使我能够 成为一个完全独立的医生科学家和领导者在转化微生物群科学的胃肠道疾病。

Project Summary: Defining Small Intestinal Microbial Landscapes To Improve Therapeutics For Gastrointestinal Disease Disease Relevance: Irritable Bowel Syndrome (IBS) is a chronic disorder characterized by altered bowel function (consistency and/or frequency) in additional to abdominal pain, effecting 7-16% of the US population and associated with an $1 billion of direct health care costs annually. This proposal seeks to better understand IBS and to develop more effective treatments for IBS. Candidate and Career Development Plan: My long-term goal is to become a fully independent physician scientist through leadership of a cutting-edge research program in human microbiota analysis and its association with clinical data complemented using a variety of tools (molecular genetics, metabolomics, gnotobiotic mouse models) to clarify mechanisms of action that will enable development of improved microbiota directed therapeutics for GI disease. Through my clinical training I am poised to become an expert in diagnosing and treating IBS, and through my previous research training am well equipped with the skills to perform high-resolution human and mouse immunology. To fully actualize my career goals of becoming an expert in microbiota-host interactions in IBS I will need to gain skills beyond my current knowledge base. This award will support the needed additional training in microbiota analysis, methods of clinical research, bacterial isolation and culturing, and gnotobiotic mouse models. Research Plan: The overarching research goal of this proposal is to move beyond feces, to define the site-specific microbial ecology of the human small intestine in IBS. We will construct a longitudinal map of intestinal microbiota and metabolites in humans with a swallowed, microbiota sampling capsule device. I have successfully employed this approach in healthy humans and the proposed research will expand sample collection to include IBS patient samples analyzed with microbiota sequencing, novel microbiota-focused metabolomics (Aim 1), and bacterial isolation and functional testing (Aim 2), with complementary studies in gnotobiotic mice (Aim 3) to define fundamental aspects of host- microbe interactions in the small intestine. Mentorship Team: To achieve these Aims, I have assembled a world class mentorship team with expertise in translational human microbiome studies (Justin Sonnenburg, primary mentor), isolation and study of bacteria from the human microbiome (KC Huang, co-mentor), and the treatment and study of IBS (Linda Nguyen, co-mentor). Environment and Institutional Commitment: Stanford University is a world leader in human microbiome studies and treating Gastroenterological(GI) disease. I will have access to mentorship, collaborators, and a breadth of resources that will provide an exceptional training environment. My mentorship team and the leadership within the Stanford Department of Medicine are committed to ensuring my success. The scientific training, skill acquisition, and career development under this award will allow me to become a fully independent physician scientist and leader in the translational microbiota science of GI disease.