Understanding genetic architecture and host-microbiome interactions in Inflammatory bowel disease in under-represented minority populations and in patients with unmet medical need.

了解代表性不足的少数群体和医疗需求未得到满足的患者中炎症性肠病的遗传结构和宿主-微生物组相互作用。

基本信息

  • 批准号:
    10707113
  • 负责人:
  • 金额:
    $ 56.91万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-30 至 2027-06-30
  • 项目状态:
    未结题

项目摘要

Background: The inflammatory bowel diseases (IBD) are a chronic inflammatory disease of the gastrointestinal tract that are associated with a poor quality of life. There is no cure for IBD, and most people require lifelong immunosuppressive medication and also frequently need surgery. The cause of Crohn’s disease (CD) and ulcerative colitis (UC), the two most common forms of IBD, are unknown but it is widely accepted that they develop in genetically susceptible individuals in response to environmental factors for which the most compelling evidence is the microbiome. Traditionally regarded as diseases of Northern European (EUA) and Ashkenazi Jewish ancestry the prevalence of IBD is rapidly rising in minority populations such as Hispanic and African American populations who have been under-represented in research. The objectives of our study include: the delineation of the genetic architecture of IBD in Hispanics populations; describe the gene-microbiome interactions in Hispanics; an understanding of the underlying molecular causes of lack of response to the most widely used biologic therapies in IBD; and importantly, work that will determine some of the functional effects of these genetic variants. We will achieve these objectives by addressing the following specific aims. In aim 1 we will decipher genetic architecture of IBD and investigate host-microbiome interactions using a biomarker- based inference approach. In aim 2 we will use advanced technology investigating gene and protein expression in individual cells in the lining of the gut to identify signatures associated with response to medication. In aim 3 we will use human intestinal epithelial cell culture systems to screen for function of new IBD susceptibility genes. Research Design: in collaboration we will build the largest collection of IBD subjects of Hispanic ancestry and use state of the art genetic approaches to identify genetic signals associated with development of IBD. We anticipate that some of these signals will overlap with those we’ve observed in EUA subjects and others will be unique to the Hispanic population. Since there is significant admixture of Native American ancestry in the North American population, we anticipate that we will also identify some genetic signals that are ‘peculiar’ to Native Americans. There have been few studies investigating host-microbiome interactions in Non-EUA populations and we will address this by investigation serum markers that are surrogates for the microbiome thereby allowing us, for the first time, to investigate interactions between genetic variation and the microbiome in Hispanic populations. In parallel we will look at gene expression signatures in biopsies from the gut to determine the molecular signature that underlies a very important clinical issue of non-response to our most effective medications. Finally, we use model systems to determine the functional consequences of the genetic variants that we have identified. We will due this using the very large bank of cell lines that we have already collected and use innovative approaches to convert these to gut-like epithelium organoids. The cell lines will be prioritized based on the genetic variants that we discover in our large genetic studies including the Hispanic studies.
背景:炎症性肠病是一种慢性胃肠道炎症性疾病。 与生活质量不佳有关的地区。IBD没有治愈的方法,大多数人需要终生 免疫抑制药物治疗,也经常需要手术治疗。克罗恩病(CD)的病因和 溃疡性结肠炎(UC)是IBD的两种最常见的形式,目前尚不清楚,但人们普遍认为它们 在遗传易感个体中对环境因素的反应最令人信服 证据就是微生物群。传统上被认为是北欧(EUA)和阿什肯纳齐的疾病 犹太血统IBD在西班牙裔和非洲裔少数族裔人群中的患病率正在迅速上升 在研究中被低估的美国人口。我们的研究目标包括: 拉美裔人群IBD遗传结构的描绘描述基因-微生物组 拉美裔美国人之间的相互作用;对MOST缺乏反应的潜在分子原因的理解 在IBD中广泛使用的生物疗法;重要的是,将确定一些功能效应的工作 这些基因变异。我们将通过解决以下具体目标来实现这些目标。在目标1中 我们将破译IBD的遗传结构,并使用一种生物标记物-- 基于推理的方法。在目标2中,我们将使用先进的技术来研究基因和蛋白质的表达 在肠道衬里的单个细胞中识别与药物反应相关的信号。在AIM 3中 我们将使用人类肠道上皮细胞培养系统来筛选新的IBD易感基因的功能。 研究设计:我们将合作建立最大的拉美裔IBD受试者集合,并 使用最先进的遗传方法来识别与IBD发展相关的遗传信号。我们 预计其中一些信号将与我们在EUA受试者中观察到的信号重叠,其他信号将 这是西班牙裔人口所独有的。因为在北方有大量的美洲原住民血统 对于美国人,我们预计我们还将识别出一些原住民特有的遗传信号 美国人。在非EUA种群中,很少有研究宿主与微生物群的相互作用 我们将通过调查血清标志物来解决这个问题,这些血清标志物是微生物组的替代品,从而允许 美国首次研究西班牙裔美国人的基因变异和微生物群之间的相互作用 人口。同时,我们将观察肠道活检组织中的基因表达特征,以确定 分子签名,这是一个非常重要的临床问题,对我们最有效的药物无效 药物。最后,我们使用模型系统来确定遗传变异的功能后果 我们已经确认了。我们将使用我们已经收集的非常大的细胞系来完成这项工作 并使用创新的方法将这些转化为肠样上皮器官。将对细胞系进行优先排序 基于我们在包括西班牙裔研究在内的大型基因研究中发现的基因变异。

项目成果

期刊论文数量(129)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Myeloid ATG16L1 Facilitates Host-Bacteria Interactions in Maintaining Intestinal Homeostasis.
  • DOI:
    10.4049/jimmunol.1601293
  • 发表时间:
    2017-03-01
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Zhang H;Zheng L;McGovern DP;Hamill AM;Ichikawa R;Kanazawa Y;Luu J;Kumagai K;Cilluffo M;Fukata M;Targan SR;Underhill DM;Zhang X;Shih DQ
  • 通讯作者:
    Shih DQ
Dynamics of metatranscription in the inflammatory bowel disease gut microbiome.
  • DOI:
    10.1038/s41564-017-0089-z
  • 发表时间:
    2018-03
  • 期刊:
  • 影响因子:
    28.3
  • 作者:
    Schirmer M;Franzosa EA;Lloyd-Price J;McIver LJ;Schwager R;Poon TW;Ananthakrishnan AN;Andrews E;Barron G;Lake K;Prasad M;Sauk J;Stevens B;Wilson RG;Braun J;Denson LA;Kugathasan S;McGovern DPB;Vlamakis H;Xavier RJ;Huttenhower C
  • 通讯作者:
    Huttenhower C
Defects in NADPH Oxidase Genes NOX1 and DUOX2 in Very Early Onset Inflammatory Bowel Disease.
  • DOI:
    10.1016/j.jcmgh.2015.06.005
  • 发表时间:
    2015-09-01
  • 期刊:
  • 影响因子:
    7.2
  • 作者:
    Hayes P;Dhillon S;O'Neill K;Thoeni C;Hui KY;Elkadri A;Guo CH;Kovacic L;Aviello G;Alvarez LA;Griffiths AM;Snapper SB;Brant SR;Doroshow JH;Silverberg MS;Peter I;McGovern DP;Cho J;Brumell JH;Uhlig HH;Bourke B;Muise AA;Knaus UG
  • 通讯作者:
    Knaus UG
Organoids in gastrointestinal diseases: from experimental models to clinical translation.
  • DOI:
    10.1136/gutjnl-2021-326560
  • 发表时间:
    2022-09
  • 期刊:
  • 影响因子:
    24.5
  • 作者:
    Guenther, Claudia;Winner, Beate;Neurath, Markus F.;Stappenbeck, Thaddeus S.
  • 通讯作者:
    Stappenbeck, Thaddeus S.
Genome wide association (GWA) predictors of anti-TNFalpha therapeutic responsiveness in pediatric inflammatory bowel disease.
  • DOI:
    10.1002/ibd.21174
  • 发表时间:
    2010-08
  • 期刊:
  • 影响因子:
    4.9
  • 作者:
    Dubinsky, Marla C.;Mei, Ling;Friedman, Madison;Dhere, Tanvi;Haritunians, Talin;Hakonarson, Hakon;Kim, Cecilia;Glessner, Joseph;Targan, Stephan R.;McGovern, Dermot P.;Taylor, Kent D.;Rotter, Jerome I.
  • 通讯作者:
    Rotter, Jerome I.
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Dermot Patrick McGovern其他文献

Dermot Patrick McGovern的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Dermot Patrick McGovern', 18)}}的其他基金

Understanding genetic architecture and host-microbiome interactions in Inflammatory bowel disease in under-represented minority populations and in patients with unmet medical need.
了解代表性不足的少数群体和医疗需求未得到满足的患者中炎症性肠病的遗传结构和宿主-微生物组相互作用。
  • 批准号:
    10543368
  • 财政年份:
    2022
  • 资助金额:
    $ 56.91万
  • 项目类别:
Genetic and genomic approaches to better understand the clinical heterogeneity in inflammatory bowel diseases
遗传学和基因组方法可以更好地了解炎症性肠病的临床异质性
  • 批准号:
    10178851
  • 财政年份:
    2002
  • 资助金额:
    $ 56.91万
  • 项目类别:
Genetic and genomic approaches to better understand the clinical heterogeneity in inflammatory bowel diseases
遗传学和基因组方法可以更好地了解炎症性肠病的临床异质性
  • 批准号:
    10001454
  • 财政年份:
    2002
  • 资助金额:
    $ 56.91万
  • 项目类别:
Mapping the genes for IBD by admixture linkage disequilibrium in Puerto Ricans
通过混合连锁不平衡绘制波多黎各人 IBD 基因图谱
  • 批准号:
    8146125
  • 财政年份:
    2002
  • 资助金额:
    $ 56.91万
  • 项目类别:
Genetic and genomic approaches to better understand the clinical heterogeneity in inflammatory bowel diseases
遗传学和基因组方法可以更好地了解炎症性肠病的临床异质性
  • 批准号:
    10238132
  • 财政年份:
    2002
  • 资助金额:
    $ 56.91万
  • 项目类别:
Utilizing the Phenomics of IBD to Enhance Gene Discovery
利用 IBD 的表型组学来增强基因发现
  • 批准号:
    8733652
  • 财政年份:
    2002
  • 资助金额:
    $ 56.91万
  • 项目类别:
Utilizing the Phenomics of IBD to Enhance Gene Discovery
利用 IBD 的表型组学来增强基因发现
  • 批准号:
    8549193
  • 财政年份:
    2002
  • 资助金额:
    $ 56.91万
  • 项目类别:
Genetic and genomic approaches to better understand the clinical heterogeneity in inflammatory bowel diseases
遗传学和基因组方法可以更好地了解炎症性肠病的临床异质性
  • 批准号:
    9927928
  • 财政年份:
    2002
  • 资助金额:
    $ 56.91万
  • 项目类别:
Mapping the genes for IBD by admixture linkage disequilibrium in Puerto Ricans
通过混合连锁不平衡绘制波多黎各人 IBD 基因图谱
  • 批准号:
    8141537
  • 财政年份:
    2002
  • 资助金额:
    $ 56.91万
  • 项目类别:
Genetic and genomic approaches to better understand the clinical heterogeneity in inflammatory bowel diseases
遗传学和基因组方法可以更好地了解炎症性肠病的临床异质性
  • 批准号:
    10177485
  • 财政年份:
    2002
  • 资助金额:
    $ 56.91万
  • 项目类别:

相似海外基金

Genetic & Social Determinants of Health: Center for Admixture Science and Technology
遗传
  • 批准号:
    10818088
  • 财政年份:
    2023
  • 资助金额:
    $ 56.91万
  • 项目类别:
Admixture Mapping of Coronary Heart Disease and Associated Metabolomic Markers in African Americans
非裔美国人冠心病和相关代谢组标记物的混合图谱
  • 批准号:
    10571022
  • 财政年份:
    2023
  • 资助金额:
    $ 56.91万
  • 项目类别:
Whole Genome Sequencing and Admixture Analyses of Neuropathologic Traits in Diverse Cohorts in USA and Brazil
美国和巴西不同群体神经病理特征的全基因组测序和混合分析
  • 批准号:
    10590405
  • 财政年份:
    2023
  • 资助金额:
    $ 56.91万
  • 项目类别:
NSF Postdoctoral Fellowship in Biology: Coalescent Modeling of Sex Chromosome Evolution with Gene Flow and Analysis of Sexed-versus-Gendered Effects in Human Admixture
NSF 生物学博士后奖学金:性染色体进化与基因流的合并模型以及人类混合中性别与性别效应的分析
  • 批准号:
    2305910
  • 财政年份:
    2023
  • 资助金额:
    $ 56.91万
  • 项目类别:
    Fellowship Award
Admixture mapping of mosaic copy number alterations for identification of cancer drivers
用于识别癌症驱动因素的马赛克拷贝数改变的混合图谱
  • 批准号:
    10608931
  • 财政年份:
    2022
  • 资助金额:
    $ 56.91万
  • 项目类别:
Leveraging the Microbiome, Local Admixture, and Machine Learning to Optimize Anticoagulant Pharmacogenomics in Medically Underserved Patients
利用微生物组、局部混合物和机器学习来优化医疗服务不足的患者的抗凝药物基因组学
  • 批准号:
    10656719
  • 财政年份:
    2022
  • 资助金额:
    $ 56.91万
  • 项目类别:
The role of admixture in human evolution
混合物在人类进化中的作用
  • 批准号:
    10683318
  • 财政年份:
    2022
  • 资助金额:
    $ 56.91万
  • 项目类别:
Genealogical ancestors, admixture, and population history
家谱祖先、混合和人口历史
  • 批准号:
    2116322
  • 财政年份:
    2021
  • 资助金额:
    $ 56.91万
  • 项目类别:
    Standard Grant
Genetic & Social Determinants of Health: Center for Admixture Science and Technology
遗传
  • 批准号:
    10307040
  • 财政年份:
    2021
  • 资助金额:
    $ 56.91万
  • 项目类别:
Admixture analysis of acute lymphoblastic leukemia in African American children: the ADMIRAL Study
非裔美国儿童急性淋巴细胞白血病的混合分析:ADMIRAL 研究
  • 批准号:
    10307680
  • 财政年份:
    2021
  • 资助金额:
    $ 56.91万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了