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

研究背景：炎症性肠病（Inflammatory Bowel Diseases，IBD）是一种胃肠道慢性炎症性疾病 与生活质量差相关的道。IBD没有治愈方法，大多数人需要终身 免疫抑制药物，还经常需要手术。克罗恩病（CD）的病因， 溃疡性结肠炎（UC）是IBD的两种最常见的形式，目前尚不清楚，但广泛认为它们 在遗传易感个体中发展，以应对环境因素， 证据就是微生物组传统上被认为是北方欧洲人（EUA）和德系犹太人的疾病 犹太血统IBD的患病率在西班牙裔和非洲裔等少数民族人群中迅速上升 在研究中代表性不足的美国人口。我们研究的目的包括： 描述西班牙裔人群中IBD的遗传结构;描述基因-微生物组 西班牙裔的相互作用;对缺乏对大多数疾病反应的潜在分子原因的理解 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 这些基因变异的。我们将通过实现以下具体目标来实现这些目标。在aim 1中 我们将破译IBD的遗传结构，并使用生物标志物研究宿主-微生物组相互作用- 基于推理的方法在aim 2中，我们将使用先进的技术研究基因和蛋白质的表达 在肠道内层的单个细胞中，以识别与药物反应相关的特征。在aim 3中 我们将使用人肠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：通过合作，我们将建立最大的西班牙裔IBD受试者集合， 使用最先进的遗传学方法来鉴定与IBD发展相关的遗传信号。我们 我预计，这些信号中的一些将与我们在EUA受试者中观察到的信号重叠，而另一些将与我们在EUA受试者中观察到的信号重叠。 是西班牙人特有的由于在北方有大量的美洲原住民血统 美国人群中，我们预计我们还将识别出一些原住民“特有”的遗传信号 美国人很少有研究调查非EUA人群中的宿主-微生物组相互作用 我们将通过调查血清标志物来解决这个问题，这些标志物是微生物组的替代物， 这是我们第一次调查西班牙裔人群中遗传变异和微生物组之间的相互作用。 人口。与此同时，我们将研究肠道活检中的基因表达特征，以确定 这是一个非常重要的临床问题，即对我们最有效的药物无反应， 药物治疗最后，我们使用模型系统来确定遗传变异的功能后果 我们已经确定了。我们将使用我们已经收集到的非常大的细胞系库来完成这一任务 并使用创新的方法将其转化为肠道样上皮类器官。细胞系将被优先考虑 基于我们在包括西班牙裔研究在内的大型遗传研究中发现的遗传变异。

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.