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：
10238132
负责人：
Dermot Patrick McGovern
金额：
$ 44.75万
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/10238132
关键词：
Academia Address Adopted Adult African American American Animals Anti-Tumor Necrosis Factor Therapy Anus 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。超过200个增加 IBD 易感性的基因位点已被确定，预计了解 IBD 的分子结构将改善患者的治疗结果。然而，要实现这一目标还存在重大挑战，本提案旨在解决其中一些关键问题。 1）大部分进展是在欧洲取得的我们的目标是继续努力招募和研究非欧洲人人民将这些进步的好处扩大到社会各阶层。 2）我们将解决通过关注两个领域的基因发现来满足未满足的医疗需求：与生活质量差、发病率高和治疗反应差有关；和大多数 IBD 患者对抗 TNF 治疗无反应。这随着新的治疗选择的出现，后一种表型的定义变得越来越重要可用于治疗IBD。 3) 许多 IBD 相关位点落在基因间（“垃圾”DNA）中区域及其功能后果仍不清楚。使用创新基因组我们建议将方法与最先进的生物信息学策略一起确定受我们已确定的易感性位点影响的过程。 4）最后我们会扩展我们之前的观察，即潘氏细胞表型是重要的读数基因环境相互作用，以及重要的临床生物标志物，在 CD 中对人群来自不同的种族和地理位置。总的来说，这些方法将摆脱对 IBD 根本原因的更多见解以及确定 IBD 的其他生物标志物在临床实践中的应用并强调 IBD 的新的潜在治疗途径。