Fundamental Modification of the Gut Microbiota in Refractory Crohn's Disease

难治性克罗恩病肠道微生物群的根本改变

基本信息

批准号：
9254541
负责人：
Lindsey Albenberg
金额：
$ 18.64万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9254541
关键词：
Adult Adverse effects Advisory Committees Anaerobic Bacteria Anti-Inflammatory Agents Anti-inflammatory Antibiotics Antifungal Agents Award Bacteria C-reactive protein Child Childhood Chronic Clinical Colitis Combined Antibiotics Combined Modality Therapy Complex Computational Biology Crohn&apos s disease Data Development Disease Disease remission Effectiveness Enterocolitis Environment Environmental Risk Factor Feces Food Gastroenterologist Gene Dosage Genes Genetic Genetic Polymorphism Hereditary Disease Human Immune Immune Tolerance Immune response Immune system Immunomodulators Immunosuppression Incidence Infection Inflammatory Bowel Diseases Inflammatory disease of the intestine Intervention Intestines Irrigation Lead Leukocyte L1 Antigen Complex Literature Malignant Neoplasms Mediating Mentors Metadata Modality Modification Monitor Mus Oral Outcome Measure Pathogenesis Patients Pharmaceutical Preparations Physicians Play Primates Randomized Refractory Regimen Research Research Personnel Ribosomal RNA Risk Role Sampling Scientist Steroids Swab Testing Therapeutic Therapeutic immunosuppression Time Training Treatment Protocols Ulcerative Colitis Vulnerable Populations Wit base career career development clinical efficacy commensal microbes experience fungus gut microbiota improved inflammatory marker insight member microbiota mouse model novel novel therapeutic intervention novel therapeutics predicting response public health relevance rectal reduce symptoms research and development response skills targeted treatment treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The proposed training in the K23 application outlines an integrated plan of mentored research and career development activities as well as a specific strategy for this pediatric gastroenterologist to pursue an independent research career as a physician scientist. This award will allow her to refine existing and to gain additional skills wit the guidance of her mentors, Drs. Wu and Lewis. To facilitate career development, she will complete the research plan for hands on training. Additionally, she will pursue formal coursework and one- on-one training from her mentors and members of her advisory committee with a focus on computational biology. Inflammatory bowel disease (IBD) is a complex genetic disorder in which multiple genetic polymorphisms lead to dysregulation of the intestinal mucosal immune system in response to environmental factors, perhaps the most important of which is the gut microbiota. Fundamentally, the loss of immune tolerance leads to an unrestrained immune response to commensal microbes normally resident in the gut. Current modalities of treatments for IBD do not focus on restoring immune tolerance, but rather depend on immunosuppression. Although highly effective in inducing and maintaining remission for many patients, there is a substantial risk of side effects associated with the use of steroids, immunomodulators, and biologics. In addition, a significant proportion of patients experience a loss of response to immune suppression over time. And despite advances in the therapeutic approach to patients with IBD in the past decade, there are still patients who demonstrate primary nonresponse to even the most powerful therapies. Based on the notion that environmental factors play a greater role in the risk for the development of IBD relative to genetics, an alternative or adjunctive strategy to treat IBD might include altering the environment by deep modification of the gut microbiota. This proposal will test the overarching hypothesis that a therapeutic approach that more deeply alters the composition and bacterial/fungal load of the gut microbiota will lead to efficacy in patients with Crohn's disease (CD). The studies proposed here will evaluate the efficacy of a novel treatment regimen, employing microbiota-targeted, nonimmunosuppressive medications, in the management of refractory ileocolonic Crohn's disease (Aim 1). These studies will also advance the understanding of the role of the gut microbiota in this vulnerable population (Aims 2 and 3).

描述（由申请人提供）：K23 申请中拟议的培训概述了指导研究和职业发展活动的综合计划，以及该儿科胃肠病学家作为医师科学家追求独立研究职业的具体策略。她将在导师吴博士和刘易斯博士的指导下完善现有技能并获得额外的技能。为了促进职业发展，她还将完成实践培训的研究计划，她还将参加正式的课程和一对一的学习。一次培训来自她的导师和咨询委员会成员的研究，重点是计算生物学。炎症性肠病（IBD）是一种遗传复杂性疾病，其中多种遗传多态性导致肠粘膜免疫系统因环境因素而失调，这可能是最重要的。其中重要的是肠道微生物群，从根本上讲，免疫耐受性的丧失会导致对肠道中通常存在的共生微生物的免疫反应不受限制。恢复免疫耐受，而是依赖于免疫抑制，尽管对许多患者来说，诱导和维持缓解非常有效，但使用类固醇、免疫调节剂和生物制剂存在很大的副作用风险。随着时间的推移，尽管 IBD 患者的治疗方法取得了进步，但基于环境因素发挥作用的观点，仍有患者对最有效的疗法表现出原发性无反应。相对于遗传学而言，IBD 的发生风险更大，治疗 IBD 的替代或辅助策略可能包括通过深度改变肠道微生物群来改变环境，该提案将检验一个总体假设，即更深入的治疗方法。改变肠道微生物群的组成和细菌/真菌负荷将对克罗恩病 (CD) 患者产生疗效。本文提出的研究将评估采用微生物群靶向的新型治疗方案的疗效。这些研究还将促进对肠道微生物群在这一弱势群体中的作用的了解（目标 2 和 3）。