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疾病的相对风险贡献。 在一组高危多重人群（3 名一级亲属）中发生炎症性肠病 (IBD) 受影响）IBD 家庭。候选人：此应用程序的主要目的是支持伊丽莎白博士 斯宾塞 (Spencer) 的职业发展成为预防和治疗领域独立的、以患者为中心的调查员 IBD 患者的个性化医疗。 Spencer博士的职业目标是成为一名独立研究员 IBD 风险分层和预防应用的领导者。斯宾塞博士提议的培训 活动涉及五个领域：1) 微生物组学，2) 代谢组学，3) 计算基因组学和宏基因组学， 4）纵向队列建设，5）领导力。为了实现这一目标，她组建了一个由以下人员领导的指导团队： Marla Dubinsky 博士，西奈山 IBD 临床中心联席主任兼儿科主任 胃肠病学，IBD 风险分层专家，Judy Cho 博士，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) 医学 (IPM)，IBD 遗传学专家， Jeremiah Faith 博士，遗传学和基因组科学以及临床免疫学副教授 微生物组转化中心主任，微生物组分析专家。环境：ISMMS 拥有杰出研究的优良传统，是 NIH 资助的前 20 名医学院之一。这 西奈山小儿胃肠科是 IBD 研究和临床护理领域的国际领先者。 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的出现 在发现明显疾病之前，很难找出疾病背后的致病因素 考虑到需要临床前高风险队列。多胞家庭研究计划 ISMMS 提供了一组独特的 IBD 多重家族受影响和未受影响成员的队列来进行检查 这些因素的相对贡献。斯宾塞博士对该队列的初步观察表明： 患有 IBD 的兄弟姐妹倾向于按出生顺序聚集在一起，这可能是由于一些环境共享，这可能 归因于微生物的变化。我们希望通过表征微生物和 遗传因素对家族性 IBD 的影响，以改善对发生临床前 IBD 的高风险人群的分层 和明显的 IBD。因此，我们的具体目标是（1）定义微生物和代谢组谱的特征 IBD 兄弟姐妹群及其与遗传风险的关联；(2) 制定 IBD 风险评分 将遗传、微生物和代谢组学因素纳入类似的外部队列中进行验证。这 该奖项期间开发的一般方法和技能可用于进一步 IBD 风险分层和 继续探索 IBD 高危人群可能的诱发环境诱因。

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