Genetic and genomic approaches to better understand the clinical heterogeneity in inflammatory bowel diseases

遗传学和基因组方法可以更好地了解炎症性肠病的临床异质性

基本信息

批准号：
10177485
负责人：
Dermot Patrick McGovern
金额：
$ 34.69万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-30 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10177485
关键词：
2019-nCoV Adult Affect Age Aging Air American Anti-Cytokine Therapy Area Back Big Data Biology Body mass index COVID-19 Cells Colon Crohn&apos s disease Data Data Set Disease Disease Progression Disease susceptibility Enterocytes Epithelial Epithelial Cells Epithelium Financial Hardship Gene Expression Genes Genetic Genetic study Genomic approach Genomics Glycoproteins Human Immune In Vitro Individual Infection Inflammation Inflammatory Inflammatory Bowel Diseases Institutional Review Boards Interleukin-12 Intestines Investigation Large Intestine Libraries Life Liquid substance Location Luciferases Mediating Messenger RNA Metabolic Diseases Methods Molecular Molecular Profiling Morbidity - disease rate National Institute of Diabetes and Digestive and Kidney Diseases Natural History Nature Obesity Operative Surgical Procedures Organoids Outcome Pathway interactions Patients Pattern Peptidyl-Dipeptidase A Pharmaceutical Preparations Pharmacotherapy Pluripotent Stem Cells Postoperative Period Property Proteins Publishing Quality of life Randomized Recombinants Relative Risks Reporting Research Resistance Resources Risk Role Safety Sampling Schedule Severities Site Small Intestines Societies Specimen System TNF gene Testing Tissues Ulcerative Colitis Variant Viral Viral Proteins Virus Work X Chromosome base behavioral response cell injury clinical effect clinical heterogeneity cohort comorbidity cytokine disorder subtype experimental study genetic approach genetic association genetic signature genetic variant genome wide association study genome-wide ileum in vivo induced pluripotent stem cell inflammatory disease of the intestine insight interest intestinal epithelium luminescence male member mortality mouse model new technology next generation sequencing novel pandemic disease polygenic risk score receptor receptor expression response single-cell RNA sequencing statistics transcriptomics

项目摘要

The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), are significant causes of morbidity with recent estimates suggesting there are more than 3 million Americans with IBD with very significant financial burden to the US economy. The world is currently in the middle of a global pandemic caused by SARS-CoV2 which is the cause of COVID- 19. Preliminary studies have identified shared molecular signatures between IBD and COVID-19. Of interest is that the receptor for SARS-COV2 is angiotensin converting enzyme 2 (ACE2) which is most highly expressed in the gut. Our preliminary data suggests that expression of this receptor is influenced by age and obesity as well as in IBD. Differing patterns suggest differences by disease location. Interestingly our preliminary data suggest that anti-cytokine therapy alters ACE2 expression in inflamed tissue. We propose to study the overlap between these 2 conditions using a large-scale and comprehensive genetic approach. We will study genetic variants in ACE2 and related genes for their effect on IBD susceptibility and disease progression as well as response to therapy. We will study, in depth, large numbers of gene expression samples from IBD cases to investigate this overlap further. We will use a newer technology called single cell RNAseq to determine which cells are leading to the changes in gene expression that we have seen with our initial studies. We will also use a statistical approach called Mendelian Randomization (which can be viewed as nature’s equivalent of a randomized study) to determine whether the therapies used in IBD are likely to be beneficial or harmful in COVID-19 infection. We will use these data to identify subjects in whom to generate pluripotent stem cells for functional work. For the functional studies we will use gut organoids and the IPSCs to test the effect of cytokines that reflect the different inflammatory states that we have observed (ageing, obesity, ileal inflammation, colonic inflammation) on ACE2 expression. The results from these analyses will also help us refine our ‘big data’ approach described earlier. We anticipate that these studies will give us insights into the molecular overlap of IBD and COVID-19 and what are the likely effects of anti-cytokine and other treatments used in IBD likely to be in COVID-19.

炎症性肠病（IBD）、克罗恩病（CD）和溃疡性结肠炎（UC）是发病的重要原因，最近估计表明有超过 300 万患有 IBD 的美国人给美国经济带来了非常沉重的经济负担。目前正处于由 SARS-CoV2 引起的全球大流行之中，SARS-CoV2 是导致新冠肺炎 (COVID-19) 的原因 19. 初步研究已确定 IBD 和 COVID-19 之间共有的分子特征。有趣的是，SARS-COV2 的受体是血管紧张素转换酶 2 (ACE2)，我们的初步数据表明该受体的表达在肠道中最高。受年龄和肥胖以及 IBD 的影响，不同的模式表明存在差异。我们的初步数据表明抗细胞因子治疗会改变 ACE2。我们建议使用这两种条件之间的重叠来研究。我们将研究 ACE2 和 ACE2 的遗传变异。相关基因对 IBD 易感性、疾病进展以及反应的影响我们将深入研究来自 IBD 病例的大量基因表达样本。我们将使用一种称为单细胞 RNAseq 的新技术来研究这种进一步的重叠。确定哪些细胞导致了我们用我们的方法观察到的基因表达的变化我们还将使用一种称为孟德尔随机化的统计方法。被视为自然的随机研究）以确定所使用的疗法是否 IBD 可能对 COVID-19 感染有益或有害，我们将使用这些数据来确定。确定可生成多能干细胞以进行功能性工作的受试者。研究中，我们将使用肠道类器官和 IPSC 来测试反映细胞因子的作用我们观察到的不同炎症状态（衰老、肥胖、回肠炎症、结肠炎症）这些分析的结果也将帮助我们完善我们的研究。我们预计这些研究将使我们深入了解前面描述的“大数据”方法。 IBD 和 COVID-19 的分子重叠以及抗细胞因子和药物的可能影响是什么用于 IBD 的其他治疗方法可能适用于 COVID-19。