The Study of Families with Heritable Crohn's Disease to Support Rational Design of Microbiota-based Therapies

项目摘要/摘要 克罗恩病(CD)的病因被认为根植于遗传易感性之间的相互作用 以及暴露于环境因素，如特定的肠道微生物。不幸的是，这些问题的复杂性 相互作用使得很难理解CD风险的哪一部分是可修改的，尤其是肠道 微生物组的组成可以改变，以克服一个人潜在的和固定的遗传易感性。这 提案将解决CD的高遗传风险但从未患上疾病的人是否窝藏 具有肠道微生物特征的信号，表示对Cd的保护。它还将进一步解决是否 保护性微生物群可以被转移来减少、延缓或阻止其他微生物体内的镉活动。目标1将需要 用多重CD研究多代家庭--以家庭、共享共同为理论基础 生活环境、饮食和行为，将最大限度地减少人类微生物组研究的常见混杂因素。 将根据多基因风险得分对个体进行分层，以更好地识别那些遗传风险最高但仍保持不变的个体 没有疾病，并被假设为最有可能拥有肠道微生物组和代谢组 具有疾病保护特征的签名。在目标2中，选择粪便生物检疫菌(在目标1中收集) 含有假定的保护性微生物的模型将被移植到无菌CD小鼠模型中。这些老鼠 然后通过表型、微生物、代谢和免疫反应来表征和评估 用于疾病发病和严重程度的改变。这些研究将为微生物介导的 CD活性的调节剂；例如，澄清粪便移植为什么 只对一小部分炎症性肠病有效，为什么结果似乎很严重 依赖捐赠者。 将丰富的人类种群研究与动物模型相结合，对候选者进行机械测试 保护性微生物，将简化科学方法，加快有希望的研究的过渡 将发现转化为临床护理。科学建议和相关的培训计划将进一步准备PI， 这样她就有能力领导未来炎症性肠病宿主-微生物动力学的研究 疾病作为一个独立的翻译调查员。

Project Summary/Abstract The cause of Crohn's disease (CD) is believed to be rooted in the interactions between genetic susceptibilities and exposures to environmental factors, such as specific gut microbes. Unfortunately, the complexity of these interactions makes it difficult to understand what portion of CD risk is modifiable, and particularly whether gut microbiome compositions can be altered to overcome one's underlying and fixed genetic predisposition. This proposal will address whether individuals at high genetic risk for CD, but who never develop disease, harbor characteristic gut microbial signatures that signal protection from CD. It will furthermore address whether protective microbiomes can be transferred to diminish, delay, or prevent CD activity in others. Aim 1 will entail the study of multigenerational families with multiplex CD – with the rationale that families, sharing common living environments, meals, and behaviors, will minimize common confounders of human microbiome studies. Individuals will be stratified by a polygenic risk score to better identify those at highest genetic risk but remain disease-free and who are hypothesized as being most likely to harbor intestinal microbiomic and metabolomic signatures that characterize disease protection. In Aim 2, select fecal biospecimens (collected in Aim 1) containing putative protective microbiomes will be transplanted into a germ-free CD mouse model. These mice will then be characterized by their phenotypic, microbial, metabolomic, and immune responses and assessed for alterations in disease onset and severity. These studies will provide insights into microbially-mediated modulators of CD activity; for example, clarifying the yet unknown reason why fecal transplants are very effective for only a small portion of inflammatory bowel disease cases and why outcomes appear to be heavily donor-dependent. Coupling the study of an enriched human population with an animal model, to mechanistically test candidate protective microbiomes, will streamline the scientific approach and expedite the transition of promising study findings into clinical care. The scientific proposal and associated training plan will furthermore prepare the PI, so that she will be well-equipped to lead future studies of host-microbe dynamics in inflammatory bowel disease as an independent translational investigator.