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）是造成发病率的重大原因，最近的估计表明有超过300万与IBD的美国人对美国经济有着非常重要的金融燃烧。世界是目前处于由SARS-COV2引起的全球大流行中间 19。初步研究已经确定了IBD和Covid-19之间的共享分子特征。有趣的是，SARS-COV2的接收器是血管紧张素转化酶2（ACE2），该酶在肠道中表现最高。我们的初步数据表明该接收器的表达受年龄和肥胖以及IBD的影响。不同的模式暗示了差异疾病位置。有趣的是，我们的初步数据表明，抗循环疗法改变了ACE2 在发炎组织中的表达。我们建议使用这两个条件之间的重叠一种大规模和全面的遗传方法。我们将研究ACE2和相关基因对IBD易感性和疾病进展的影响以及反应接受治疗。我们将深入研究IBD病例的大量基因表达样品进一步研究此重叠。我们将使用一种称为单元rnaseq的较新技术确定哪些细胞导致我们在我们的基因表达中发生变化最初的研究。我们还将使用称为Mendelian随机化的统计方法（可以被视为自然等同于一项随机研究），以确定是否使用的疗法在IBD中，IBD可能在Covid-19感染中有益或有害。我们将使用这些数据来识别出生成多能干细胞进行功能工作的受试者。用于功能研究我们将使用肠道类器官和IPSC测试反映的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）在ACE2表达上。这些分析的结果也将帮助我们完善我们的前面描述的“大数据”方法。我们预计这些研究将使我们深入了解 IBD和COVID-19的分子重叠以及抗周期因子和 IBD中使用的其他治疗方法可能是在Covid-19。