The Microbiome, Metabolome, and Genome in Multiplex IBD Family Clusters

多重 IBD 家族簇中的微生物组、代谢组和基因组

• 批准号: 10681314
• 负责人: Elizabeth Spencer
• 金额: $ 16.59万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681314
• 关键词: Affect; Age; Area; Award; Birth Order; Characteristics; Childhood; Chronic; Clinical; Clinical Immunology; Cohort Studies; Collaborations; Complex; Data; Development; Diagnosis; Disease; Enrollment; Environment; Event; Evolution; Faith; Family; Family Research; Family member; Feces; First Degree Relative; Funding; Gastroenterology; Genetic; Genetic Risk; Genome; Genomics; Goals; Heritability; Immune; Immune response; Inflammatory; Inflammatory Bowel Diseases; Institution; International; Leadership; Life; Link; Longitudinal cohort; Measures; Mentors; Metagenomics; Modeling; Parents; Participant; Pathogenesis; Patients; Phase; Population; Prevention; Prevention Measures; Relative Risks; Research; Research Personnel; Risk; Risk Factors; Role; Running; Shapes; Siblings; Statistical Methods; Stratification; Training Activity; Twin Studies; United States National Institutes of Health; Validation; career; career development; clinical care; clinical center; cohort; disorder prevention; disorder risk; dysbiosis; genome sciences; genomic data; high risk; improved; indexing; inflammatory marker; medical schools; member; metabolome; metabolomics; microbial; microbiome; microbiome research; mid-career faculty; novel; patient oriented; personalized medicine; polygenic risk score; pre-clinical; professor; programs; random forest; risk prediction model; risk stratification; risk variant; skills; ward

This project will seek to define the relative risk contributions of microbial and genetic factors to the development of inflammatory bowel disease (IBD) within a cohort of high-risk multiplex (3 first-degree relatives affected) IBD families. Candidate: The primary objective of this application is to support Dr. Elizabeth Spencer’s career development into an independent, patient-oriented investigator in the field of prevention and personalized medicine for IBD patients. Dr. Spencer’s career goal is to become an independent researcher and leader in the application of risk stratification and prevention for IBD. Dr. Spencer’s proposed training activities are in five areas: 1) microbiomics, 2) metabolomics, 3) computational genomics and metagenomics, 4) longitudinal cohort building, and 5) leadership. To achieve this, she has assembled a mentoring team led by Dr. Marla Dubinsky, Co-Director of the IBD Clinical Center at Mount Sinai and Chief of the Division of Pediatric Gastroenterology, an expert in IBD risk stratification, Dr. Judy Cho, Ward-Coleman Professor, Vice-Chair of Genetics & Genomics & Gastroenterology, and Director of the Charles Bronfman Institute for Personalized Medicine (IPM) at the Icahn School of Medicine at Mount Sinai (ISMMS), an expert in the genetics of IBD, and Dr. Jeremiah Faith, Associate Professor of Genetics and Genomic Sciences and Clinical Immunology and Director of the Microbiome Translational Center, an expert in microbiomic analysis. Environment: The ISMMS has a strong tradition of outstanding research and is one of the top 20 medical schools in NIH funding. The Mount Sinai Division of Pediatric Gastroenterology is an international leader in IBD research and clinical care. Research: IBD is a heterogenous set of chronic inflammatory disorders that arise from the complex interplay of genetic, environmental and microbial factors, and immune responses. These complicated interactions arise before the identification of overt disease, making it difficult to tease out the causative factors behind disease inception given the need for a pre-clinical, high-risk cohort. The Multiplex Families Research Program at ISMMS provides a unique cohort of affected and unaffected members of multiplex families with IBD to examine the relative contribution of these factors. Dr. Spencer’s preliminary observations in this cohort have shown that siblings with IBD tend to cluster together in birth order, likely due to some environmental sharing, which could be attributed to microbial changes. We would like to explore this further by characterizing the microbial and genetic contributions to familial IBD to improve stratification of those at high-risk for developing both pre-clinical and overt IBD. Therefore, our specific aims are (1) to define the features of microbial and metabolomic profiles in sibling clusters of IBD and their association with genetic risk and (2) to develop an IBD risk score incorporating genetic, microbial, and metabolomic factors with validation in a similar, external cohort. The general approaches and skills developed during this award can be applied to further IBD risk stratification and continued exploration of possible inciting environmental triggers for those at high-risk for IBD.

该项目将旨在定义微生物和遗传因素的相对风险贡献 高风险多路复用队列中炎症性肠病（IBD）的发展（3个一级亲戚 受影响的）IBD家庭。候选人：本申请的主要目的是支持伊丽莎白博士 斯宾塞（Spencer）的职业发展成为一个独立的，以患者为导向的研究者 IBD患者的个性化药物。斯宾塞博士的职业目标是成为独立研究员 以及用于IBD风险分层和预防的领导者。斯宾塞博士的拟议培训 活动在五个领域：1）微生物学，2）代谢组学，3）计算基因组学和宏基因组学， 4）纵向队列建筑物和5）领导。为了实现这一目标，她组建了一个由 西奈山IBD临床中心的联合主任Marla Dubinsky博士，儿科司长 IBD风险分层专家胃肠病学，病房教授Judy Cho博士，副主席 遗传学与基因组学和胃肠病学，以及查尔斯·布朗夫曼个性化研究所的主任 IBD遗传学专家的Sinai Mount Sinai医学院的医学（IPM）， 遗传学和基因组科学与临床免疫学副教授耶利米·费菲斯（Jeremiah Faith）博士以及 微生物组转化中心主任，微生物分析专家。环境：ISMM 具有杰出研究的悠久传统，并且是NIH资助的前20名医学院之一。这 西奈山分校小儿胃肠病学是IBD研究和临床护理的国际领导者。 研究：IBD是由复杂相互作用引起的一组异源慢性炎症性疾病 遗传，环境和微生物因子以及免疫复杂。这些复杂的互动出现 在鉴定出明显疾病之前，很难取笑疾病背后的结构器 鉴于需要临床前的高风险队列。多元家庭研究计划 ISMM提供了一个独特的IBD多个家庭的受影响和未受影响的成员来检查 这些因素的相对贡献。 Spencer博士在此队列中的初步观察表明 与IBD的兄弟姐妹倾向于按照出生顺序聚集在一起，这可能是由于某些环境共享所致，这可能 归因于微生物变化。我们想通过表征微生物和 对家族IBD的遗传贡献，以改善高风险的人的分层，以发展这两种前临床前 和公开的IBD。因此，我们的具体目的是（1）定义微生物和代谢组剖面的特征 在IBD的同级群集及其与遗传风险的关联和（2）发展IBD风险评分 在类似的外部队列中纳入遗传，微生物和代谢组因子和验证。 该奖项期间开发的一般方法和技能可用于进一步的IBD风险分层和 继续探索IBD高风险的人可能煽动环境触发器。

项目成果

The Combination of Predictive Factors of Pharmacokinetic Origin Associates with Enhanced Disease Control during Treatment of Pediatric Crohn's Disease with Infliximab.

• DOI: 10.3390/pharmaceutics15102408
• 发表时间: 2023-09-30
• 期刊: Pharmaceutics
• 影响因子: 5.4
• 作者: Dubinsky MC;Rabizadeh S;Panetta JC;Spencer EA;Everts-van der Wind A;Dervieux T
• 通讯作者: Dervieux T

Single-center Experience With Upadacitinib for Adolescents With Refractory Inflammatory Bowel Disease.

Upadacitinib 用于治疗难治性炎症性肠病青少年的单中心经验。

• DOI: 10.1093/ibd/izad300
• 发表时间: 2023
• 期刊: Inflammatory bowel diseases
• 影响因子: 4.9
• 作者: Spencer,ElizabethA;Bergstein,Suzannah;Dolinger,Michael;Pittman,Nanci;Kellar,Amelia;Dunkin,David;Dubinsky,MarlaC
• 通讯作者: Dubinsky,MarlaC

Barriers to optimizing inflammatory bowel disease care in the United States.

• DOI: 10.1177/17562848231169652
• 发表时间: 2023
• 期刊: THERAPEUTIC ADVANCES IN GASTROENTEROLOGY
• 影响因子: 4.2
• 作者: Spencer, Elizabeth A.;Abbasi, Sadeea;Kayal, Maia
• 通讯作者: Kayal, Maia

Prognostication in inflammatory bowel disease.

• DOI: 10.3389/fmed.2022.1025375
• 发表时间: 2022
• 期刊: Frontiers in medicine
• 影响因子: 3.9

Poor prognostic factors of pharmacokinetic origin predict outcomes in inflammatory bowel disease patients treated with anti-tumor necrosis factor-α.

药代动力学起源的不良预后因素可预测接受抗肿瘤坏死因子-α 治疗的炎症性肠病患者的结果。

• DOI: 10.3389/fimmu.2024.1342477
• 发表时间: 2024
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Spencer,ElizabethA;Dubinsky,MarlaC;Kamm,MichaelA;Chaparro,Maria;Gionchetti,Paolo;Rizzello,Fernando;Gisbert,JavierP;Wright,EmilyK;Schulberg,JulienD;Hamilton,AmyL;McGovern,DermotPB;Dervieux,Thierry
• 通讯作者: Dervieux,Thierry