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

对患有遗传性克罗恩病的家庭进行研究，以支持基于微生物群的疗法的合理设计

• 批准号: 9892576
• 负责人: LEA A CHEN
• 金额: $ 19.74万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-16 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892576
• 关键词: Address; Affect; Animal Model; Anti-Inflammatory Agents; Behavior; Biological; Characteristics; Cluster Analysis; Coupling; Crohn' s disease; Data; Development; Disease; Environment; Environmental Exposure; Environmental Risk Factor; Etiology; Exposure to; Family; Family Study; Family member; Functional disorder; Future; Genes; Genetic Determinism; Genetic Predisposition to Disease; Genetic Risk; Genotype; Germ-Free; Goals; Heritability; Histology; Human; Human Microbiome; Immune response; Immunosuppression; Incidence; Individual; Infection; Inflammatory Bowel Diseases; Interleukin-10; Intervention; Intestines; Lead; Left; Leukocyte L1 Antigen Complex; Maps; Measures; Mediating; Mentors; Microbe; Modeling; Multiomic Data; Mus; Onset of illness; Organism; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Phenotype; Plant Roots; Population; Predisposing Factor; Publishing; Research Personnel; Risk; Role; Sampling; Severity of illness; Signal Transduction; System; Testing; Therapeutic; Tissues; Training; Transplantation; base; career; clinical care; clinical development; cytokine; design; disorder risk; disorder subtype; experience; fecal transplantation; gut bacteria; gut microbes; gut microbiome; high risk population; inflammatory disease of the intestine; insight; metabolome; metabolomics; microbial; microbiome; microbiome composition; microbiome research; microbiota; mouse model; personalized medicine; polygenic risk score; prevent; risk sharing; risk variant; transcriptomics; translational scientist

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.

项目总结/摘要 克罗恩病（CD）的病因被认为是植根于遗传易感性之间的相互作用， 以及暴露于环境因素，例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改变的，特别是肠道是否 可以改变微生物组的组成，以克服一个人潜在的和固定的遗传易感性。这 这项提案将讨论那些有高遗传风险但从未患病的人， 特征性肠道微生物签名，信号保护免受CD。它还将讨论是否 保护性微生物组可以被转移以减少、延迟或防止其他人的CD活性。目标1要求 研究多代家庭与多重CD -与家庭的基本原理，共享共同的 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淆因素。 个体将通过多基因风险评分进行分层，以更好地识别那些遗传风险最高但仍 无疾病且被假设为最可能携带肠道微生物组学和代谢组学的患者 标志性的疾病保护。在目标2中，选择粪便生物标本（在目标1中采集） 将含有推定的保护性微生物组的细胞移植到无菌CD小鼠模型中。这些小鼠 然后将通过其表型、微生物、代谢组学和免疫反应进行表征，并进行评估 疾病发作和严重程度的改变。这些研究将为微生物介导的 CD活性的调节剂;例如，澄清粪便移植非常 仅对一小部分炎症性肠病病例有效，以及为什么结果似乎严重 依赖捐赠者 将富集人群的研究与动物模型相结合，以机械地测试候选物 保护性微生物组，将简化科学方法，加快有前途的研究的过渡 临床护理的发现。科学建议和相关培训计划将进一步准备PI， 这样她就有能力领导未来炎症肠道中宿主微生物动力学的研究 作为一名独立的翻译研究者。