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（由适用提供）：炎症性肠病（IBD）是一种常见且毁灭性的免疫介导的疾病，其中粘膜免疫系统异常识别肠道细菌菌群，导致慢性炎症。 IBD的原因可能在于宿主反应基因与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高加索人群上。在美国，西班牙裔人群正在迅速上升，而IBD在此组尚未了解的基因可能会导致易感性或可能促进疾病表达的微生物组等因素的基因中知道。使用全基因组数据的IBD易感性的最新荟萃分析在欧洲血统种群的研究中确定了140个CD局部。我们有一个独特的机会来研究南佛罗里达州西班牙裔CD的遗传学，免疫学和微生物组的界面。初步分析表明，尽管西班牙裔和NHW之间的遗传燃烧相似，但特定的IBD变体的频率却不相似。我们发现，外国出生的西班牙裔患者的菌群与美国出生的西班牙裔IBD患者不同。基于这些观察结果，我们假设在西班牙裔中，与IBD的基本混合遗传血统所塑造了不同的先天免疫途径。我们进一步假设，与我们出生的西班牙裔或NHW相比，西班牙裔移民的粘膜微生物组将证明向日益不足的疾病微生物群转变，这将反映在粘膜中的基因表达变化中。为了检验这一假设，我们将追求三个相关但独立的特定目的。在AIM 1中，我们将探索具有CD的西班牙裔患者的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藏品提高到1000名IBD的西班牙裔患者，这从未做过。我们将研究已知和新颖的西班牙裔特异性基因和表型的关系。 AIM 2将检查西班牙裔移民的微生物组变化，与使用CD的第一代西班牙裔美国人或非西班牙裔白人相比。我们已经制定了一种创新策略，涉及对椎板吞噬细胞中微生物群进行深度测序。 AIM 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CD非西班牙裔白人相比。我们将与Eric Sc​​hadt博士合作，将收集的数据集成到三个目标中，以识别以前未以如此全面的分层方式探索的途径。通过关注移民和第一代西班牙裔美国人与CD之间的靶向基因组，转录组和微生物组差异，我们希望能够培养基因和微生物如何相互作用，从而导致CD的潜水表型表现。我们将使用它作为一个平台，以利用高加索裔美国人的NIDDK IBD遗传联盟（IBDGC）的持续努力。