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：
10178851
负责人：
Dermot Patrick McGovern
金额：
$ 16.7万
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/10178851
关键词：
Academia Address Adopted Adult African American American Animals Anti-Tumor Necrosis Factor Therapy Architecture Area Asians Automobile Driving Bioinformatics Biological Assay Biological Markers Biological Response Modifier Therapy Cellular Morphology Collaborations Communities Coupled Crohn&apos s disease Defect Development Disease Disease Resistance Drug Kinetics Enhancers Environment Ethnic Origin European Financial Hardship Gastrointestinal tract structure Genes Genetic Genetic Determinism Genetic Diseases Genetic Risk Genetic Transcription Genetic Variation Genomic approach Genomics Geographic Locations Geography High Prevalence Hispanics Human Industry Inflammatory Bowel Diseases Junk DNA Life Medical Methods Molecular Morbidity - disease rate Oncology Paneth Cells Pathology Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Phenotype Population Population Study Predisposition Process Quality of life Quantitative Trait Loci Regulatory Element Research Research Personnel Sampling Societies Susceptibility Gene TNF gene Technology Testing Therapeutic Tissues Ulcerative Colitis Untranslated RNA Variant Work causal variant chromosome conformation capture clinical biomarkers clinical care clinical heterogeneity clinical practice clinically relevant cohort disease phenotype disorder risk falls functional genomics gene discovery gene environment interaction genetic approach genetic association genetic variant genomic locus immunogenic immunogenicity improved outcome innovation insight novel novel therapeutics recruit risk variant transcriptomics treatment response

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. More than 200 genetic loci that increase susceptibility to IBD have been identified with the anticipation that an understanding of the molecular architecture of IBD will lead to improved outcomes for patients. However, there are significant challenges remaining to achieve this and this proposal seeks to address some of these key issues. 1) The majority of advances have been made in European ancestry populations and we aim to continue our efforts to recruit and study non-European populations to extend the benefits of these advances to all parts of society. 2) We will address unmet medical needs by focusing on genetic discovery in two areas: peri-anal fistulizing CD is associated with poor quality of life, significant morbidity, and poor response to treatment; and non-response to anti-TNF therapy which happens in the majority of subjects with IBD. This latter phenotype is increasingly important to define as new therapeutic options become available for treating IBD. 3) Many of the IBD associated loci fall in intergenic ('junk' DNA) regions and their functional consequences remain unclear. Using innovative genomic approaches together with state-of-the-art bioinformatics strategies we propose to identify the processes that are influenced by the susceptibility loci we have identified. 4) And finally we will extend our previous observations that Paneth cell phenotypes are an important readout of gene-environment interactions, as well as an important clinical biomarker, in CD to populations from a variety of ethnicities and geographical locations. Collectively, these approaches will shed additional insights into the underlying causes of IBD as well as identify additional biomarkers for use in clinical practice and highlight novel potential therapeutic pathways for IBD.

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 IBD的美国人给美国经济带来了非常重大的经济负担。超过200 已经确定了增加对IBD敏感性的遗传基因座了解IBD的分子体系结构将导致患者的预后改善。但是，要实现这一目标还有巨大的挑战，该提议试图解决其中一些关键问题。 1）大多数进步是在欧洲的祖先人口，我们旨在继续努力招募和研究非欧洲人口将这些进步的好处扩展到社会的各个地区。 2）我们将解决通过关注两个领域的遗传发现，未满足的医疗需求：旁边的瘘管CD是与生活质量差，发病率明显和对治疗的反应不佳有关；和对抗TNF疗法的无反应发生在大多数IBD受试者中。这后一种表型越来越重要，因为新的治疗选择成为可用于治疗IBD。 3）许多IBD相关的基因座落在基因中（“垃圾” DNA）地区及其功能后果尚不清楚。使用创新的基因组与最先进的生物信息学策略一起进行的方法，我们建议确定受我们确定的易感基因座影响的过程。 4）最后我们会扩展了我们以前的观察结果，即paneth细胞表型是重要的读数 CD与种群中的基因环境相互作用以及重要的临床生物标志物来自各种种族和地理位置。总的来说，这些方法将脱落对IBD的根本原因的其他见解，并确定其他生物标志物在临床实践中使用，并突出IBD的新型潜在治疗途径。