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（申请人提供）：炎症性肠病（IBD）是一种常见的、破坏性的免疫介导疾病，其中粘膜免疫系统异常识别肠道菌群，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 研究都集中在北美和欧洲的白种人群体。在美国，西班牙裔人口正在迅速增加，该群体的 IBD 发病率也在迅速增加，但人们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。最近的 IBD 易感性荟萃分析利用全基因组数据，在欧洲血统人群的研究中确定了 140 个 CD 特异性位点。我们有一个独特的机会来研究南佛罗里达州西班牙裔 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 NHW 之间的遗传负担相似，但特定 IBD 变异的频率却不同。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，我们假设患有 IBD 的西班牙裔人的独特先天免疫途径发生了改变，这是由他们潜在的混合遗传血统决定的。我们进一步假设，与美国出生的西班牙裔或非健康妇女相比，西班牙裔移民的粘膜微生物群将呈现出日益失调的微生物群的转变，这将反映在粘膜基因表达的变化上。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果的关系。我们计划将收集的 IBD 西班牙裔患者增加到 1000 名，这是以前从未做过的。我们将研究已知和新的西班牙裔特定基因和表型的关系。目标 2 将检查西班牙裔移民与患有 CD 的第一代西班牙裔美国人或非西班牙裔白人相比微生物组的变化。我们开发了一种创新策略，涉及对固有层吞噬细胞中的微生物群进行深度测序。目标 3 将分析西班牙裔移民粘膜的先天免疫反应，与第一代西班牙裔美国人和患有 CD 的非西班牙裔白人进行比较。我们将与 Eric Sc​​hadt 博士合作，整合在三个目标中收集的数据，以确定以前从未以如此全面、分层的方式探索过的途径。通过关注移民和第一代患有 CD 的西班牙裔美国人之间的基因组、转录组和微生物组差异，我们希望了解基因和微生物如何相互作用，从而导致 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) 在白种裔美国人中正在进行的努力。