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

• 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
• 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' 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

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，最近的估计表明，有超过300万 患有IBD的美国人对美国经济造成非常严重的经济负担。世界是 目前正处于由SARS-CoV 2引起的全球大流行之中，SARS-CoV 2是COVID的病因， 19.初步研究已经确定了IBD和COVID-19之间共有的分子特征。 令人感兴趣的是，SARS-COV 2的受体是血管紧张素转换酶2（ACE 2）， 在肠道中表达最高我们的初步数据表明，这种受体的表达 受年龄和肥胖以及IBD的影响。不同的模式表明差异， 疾病位置有趣的是，我们的初步数据表明，抗细胞因子治疗改变了ACE 2 在发炎组织中表达。我们建议研究这两个条件之间的重叠，使用 一个大规模和全面的遗传方法。我们将研究ACE 2的遗传变异， 影响IBD易感性和疾病进展以及应答的相关基因 接受治疗我们将深入研究来自IBD病例的大量基因表达样本， 进一步调查这种重叠。我们将使用一种称为单细胞RNAseq的新技术， 确定哪些细胞导致基因表达的变化，我们已经看到，与我们的 初步研究。我们还将使用一种称为孟德尔随机化的统计方法（它可以 被视为自然界的随机研究），以确定是否使用的治疗方法 在IBD中可能对COVID-19感染有益或有害。我们将使用这些数据来 鉴定在其中产生用于功能性工作的多能干细胞的受试者。用于功能 研究中，我们将使用肠道类器官和IPSC来测试细胞因子的作用， 我们观察到的不同炎症状态（衰老、肥胖、回肠炎症、结肠炎和结肠炎）， 炎症）对ACE 2表达的影响。这些分析的结果也将帮助我们改进我们的 前面提到的“大数据”。我们希望这些研究能让我们了解 IBD和COVID-19的分子重叠，以及抗细胞因子和 IBD中使用的其他治疗方法可能与COVID-19有关。