INNATE IMMUNE PATHWAYS AND THE MICROBIOME IN HISPANICS WITH INFLAMMATORY BOWEL DISEASE

西班牙裔炎症性肠病患者的先天免疫途径和微生物组

• 批准号: 9106760
• 负责人: Maria Teresa Abreu
• 金额: $ 47.72万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-10 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9106760
• 关键词: Affect; Bacteria; Biopsy; Caribbean region; Caucasians; Characteristics; Child; Chronic; Collection; Complex; Crohn' s disease; Data; Defect; Dendritic Cells; Development; Disease; Disease susceptibility; Epidemiologist; Europe; European; Florida; Frequencies; Gene Expression; Generations; Genes; Genetic; Genetic Structures; Genetic Variation; Genomics; Genotype; Germ-Free; Goals; Grant; Hereditary Disease; Hispanic Americans; Hispanics; Immigrant; Immigration; Immune; Immune response; Immune system; Immunologics; Immunologist; Immunology; Incidence; Inflammation; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intestines; Lamina Propria; Latin America; Mediating; Meta-Analysis; Methods; Microbe; Minority Groups; Mucous Membrane; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; North America; Not Hispanic or Latino; Outcome; Pathogenesis; Pathway interactions; Patient Care; Patients; Pattern; Phagocytes; Phenotype; Population; Predisposition; Prevalence; Property; Ribosomal RNA; Risk; Risk Factors; Role; Shapes; Signal Transduction; Staging; Susceptibility Gene; Systems Biology; Testing; Time; Variant; admixture mapping; base; caucasian American; cohort; deep sequencing; disorder risk; genetic signature; genome-wide; innovation; macrophage; microbiome; microbiota; novel; pathogen; public health relevance; research study; response; risk variant; transcriptomics

 DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD) is a common and devastating immune-mediated disease in which the mucosal immune system abnormally recognizes the intestinal bacterial flora leading to chronic inflammation. The causes of IBD may lie in the interplay between host response genes and a microbiome with pathogenic properties. Most IBD studies have focused on Caucasian populations in North America and Europe. In the US, the population of Hispanics is rising rapidly as is the incidence of IBD in this group-yet litte is known about the genes that may confer susceptibility or factors such as the microbiome that may be promoting disease expression. The most recent meta-analysis of IBD susceptibility, using genome-wide data, identified 140 CD specific loci in studies of European descent populations. We have a unique opportunity to study the interface of genetics, immunology, and the microbiome in South Florida Hispanic patients with CD. A preliminary analysis shows that although the genetic burden is similar between Hispanics and NHWs, the frequency of specific IBD variants is not. We have found that the microbiota of foreign-born Hispanic patients differs from US-born Hispanic IBD patients. Based on these observations, we hypothesize that distinct innate immune pathways are altered in Hispanics with IBD shaped by their underlying admixed genetic ancestry. We further hypothesize that the mucosal microbiome of Hispanic immigrants compared with US-born Hispanics or NHWs will demonstrate a shift towards increasingly dysbiotic microbiota that will be reflected in gene expression changes in the mucosa. To test this hypothesis, we will pursue three related but independently-relevant Specifc Aims. In Aim 1, we will Explore IBD risk alleles and genetic structure in Hispanic patients with CD and its relationship to phenotypic outcomes. We plan to increase our collection to 1000 Hispanic patients with IBD which has never been done before. We will look at the relationship of known and novel Hispanic-specific genes and phenotype. Aim 2 will examine microbiome changes in Hispanic immigrants compared with first-generation Hispanic-Americans or non-Hispanic whites with CD. We have developed an innovative strategy involving deep sequencing of the microbiota in lamina propria phagocytes. Aim 3, will analyze innate immune responses in the mucosa of Hispanic immigrants compared with first-generation Hispanic-Americans and non-Hispanic whites with CD. We will collaborate with Dr. Eric Schadt to integrate the data gathered in the three aims to identify pathways that have not been previously explored in such a comprehensive, layered fashion. By focusing on targeted genomic, transcriptomic, and microbiome differences between immigrant and first-generation Hispanic-Americans with CD, we hope to edify how genes and microbes interact to result in diverse phenotypic manifestations of CD. We will use this as a platform to leverage the ongoing efforts of the NIDDK IBD Genetics Consortium (IBDGC) in Caucasian-Americans.

 描述（由申请人提供）：炎症性肠病（IBD）是一种常见的破坏性免疫介导疾病，其中粘膜免疫系统异常识别肠道细菌植物群，导致慢性炎症。IBD的原因可能在于宿主反应基因和具有致病特性的微生物组之间的相互作用。大多数IBD研究集中在北美和欧洲的高加索人群。在美国，西班牙裔人口正在迅速增加，这一群体中IBD的发病率也在迅速增加，但对可能赋予易感性的基因或可能促进疾病表达的微生物组等因素知之甚少。最新的IBD易感性荟萃分析，使用全基因组数据，确定了140个CD特异性位点的欧洲血统人群的研究。我们有一个独特的机会来研究南佛罗里达西班牙裔CD患者的遗传学、免疫学和微生物组的相互作用。初步分析表明，尽管西班牙裔和NHWs之间的遗传负担相似，但特定IBD变体的频率却不同。我们发现，外国出生的西班牙裔患者的微生物群与美国出生的西班牙裔IBD患者不同。基于这些观察结果，我们假设，不同的先天免疫途径被改变，在西班牙裔IBD形成其潜在的混合遗传祖先。我们进一步假设，与美国出生的西班牙裔或NHW相比，西班牙裔移民的粘膜微生物群将表现出向日益生态失调的微生物群的转变，这将反映在粘膜的基因表达变化中。为了检验这一假设，我们将追求三个相关但独立相关的具体目标。在目标1中，我们将探索西班牙裔CD患者的IBD风险等位基因和遗传结构及其与表型结局的关系。我们计划将我们的收集增加到1000名西班牙裔IBD患者，这是以前从未做过的。我们将着眼于已知的和新的西班牙裔特异性基因和表型的关系。目标2将检查西班牙裔移民与第一代西班牙裔美国人或非西班牙裔白人CD相比的微生物组变化。我们已经开发了一种创新策略，涉及固有层吞噬细胞中微生物的深度测序。目的3，将分析与第一代西班牙裔美国人和非西班牙裔白人CD相比，西班牙裔移民粘膜中的先天免疫应答。我们将与Eric Schadt博士合作，整合三个目标中收集的数据，以确定以前没有以如此全面，分层的方式探索的途径。通过关注移民和第一代西班牙裔美国人CD之间的靶向基因组，转录组和微生物组差异，我们希望启发基因和微生物如何相互作用，导致CD的不同表型表现。我们将以此为平台，利用NIDDK IBD遗传学联盟（IBDGC）在高加索裔美国人中的持续努力。