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

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。

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.