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.

该项目将寻求确定微生物和遗传因素对 炎症性肠病(IBD)在高危多发性肠病(3个一级亲属)队列中的发展 受影响的)IBD家庭。候选人：这个应用程序的主要目标是支持伊丽莎白博士 斯宾塞的职业生涯发展成为一名独立的、以患者为导向的预防和治疗领域的调查员 针对IBD患者的个性化用药。斯宾塞博士的职业目标是成为一名独立研究人员 在IBD风险分层和预防方面的应用方面处于领先地位。斯宾塞博士提议的培训 活动涉及五个领域：1)微生物学，2)代谢组学，3)计算基因组学和元基因组学， 4)纵向队列建设，5)领导力。为了实现这一目标，她组建了一个由 Marla Dubinsky博士，西奈山IBD临床中心联席主任兼儿科科长 胃肠病学，IBD风险分层专家，Ward-Coleman教授，副主席 遗传学、基因组学和胃肠病学，查尔斯·布朗夫曼个性化研究所所长 西奈山伊坎医学院(ISMMS)的医学(IPM)，IBD遗传学专家，以及 耶利米·费思博士，遗传学和基因组科学与临床免疫学副教授 微生物组翻译中心主任，微生物组分析专家。环境：ISMMS 拥有优秀研究的深厚传统，是NIH资助的前20所医学院之一。这个 西奈山儿科消化内科在IBD研究和临床护理方面处于国际领先地位。 研究：IBD是一组异质性慢性炎症性疾病，由复杂的相互作用引起 遗传、环境和微生物因素，以及免疫反应。这些复杂的相互作用就产生了 在确定显性疾病之前，很难找出疾病背后的致病因素 考虑到临床前、高风险队列的需要。多个家庭研究计划位于 ISMMS提供了患有IBD的多个家庭中受影响和未受影响的成员的独特队列以进行检查 这些因素的相对贡献。斯宾塞博士在这个队列中的初步观察表明 患有IBD的兄弟姐妹在出生顺序上倾向于聚集在一起，可能是因为一些共同的环境，这可能 可归因于微生物的变化。我们想通过对微生物和 对家族性IBD的遗传贡献以改善临床前发展的高危人群的分层 和公开的IBD。因此，我们的具体目标是(1)确定微生物和代谢组学的特征 在IBD的兄弟姐妹群中及其与遗传风险的关联以及(2)开发IBD风险评分 结合遗传、微生物和代谢因素，在类似的外部队列中进行验证。这个 在该奖项期间开发的一般方法和技能可应用于进一步的IBD风险分层和 继续探索对IBD高危人群可能的环境诱因。

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

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

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

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

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