The Interplay of Host Genetic Variation and the Gut Microbiome in Crohn's Disease

克罗恩病宿主遗传变异与肠道微生物组的相互作用

• 批准号: 10751276
• 负责人: Shreya Nirmalan
• 金额: $ 4.74万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-17 至 2027-08-16
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751276
• 关键词: Affect; Alleles; Allelic Imbalance; Architecture; Autoimmune Diseases; Binomial Model; Caring; Chemicals; Chronic; Cicatrix; Coculture Techniques; Communities; Complex; Computational Biology; Computing Methodologies; Crohn' s disease; Data; Databases; Diet; Digestive System Disorders; Disease; Environmental Risk Factor; Functional disorder; Gastrointestinal tract structure; Gene Expression; Gene Modified; Genes; Genetic; Genetic Risk; Genetic Transcription; Genetic Variation; Genomic approach; Genotype; Human; Human Microbiome; Immune; Immune response; Immunosuppressive Agents; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestines; Maps; Metabolic; Methods; Microbe; Morbidity - disease rate; Newly Diagnosed; Operative Surgical Procedures; Opioid; Organoids; Outcome; Pathogenesis; Pathologic; Patient Isolation; Patients; Persons; Pharmaceutical Preparations; Phenotype; Physiological; Quality of life; Regulator Genes; Research; Route; Shotguns; Stimulus; Taxonomy; Testing; Treatment Cost; Variant; cost; differential expression; disability; disorder risk; dysbiosis; experience; functional genomics; genetic risk factor; genetic variant; genome wide association study; gut microbiome; host microbiome; host-microbe interactions; insight; metagenomic sequencing; microbial; microbial community; microbial composition; microbiome; microbiome composition; microbiota; microorganism; new therapeutic target; novel; novel therapeutics; pathogen; personalized therapeutic; response; risk variant; therapeutic target; transcriptome; transcriptome sequencing

ABSTRACT Crohn’s Disease (CD) is an autoimmune disease which leads to chronic inflammation and scarring of the digestive tract. The available treatments involve immunosuppressants and surgery which are costly, with many individuals still experiencing a decreased quality of life. The cause of CD is unknown, but is believed to occur due to both genetic and environmental factors, including diet. The gut microbiome is altered in individuals with CD, leading to dysregulation of the host and microbial transcriptional and metabolic landscape. Furthermore, many genetic risk variants associated with CD are in host genes known to function in host response to the microbiome. Thus, characterizing host-microbiome interactions in CD is imperative for understanding the pathogenesis of CD and identifying potential new therapeutic routes. In this proposed research, I aim to characterize the interactions between host genetic variation and the gut microbiome that regulate host gene expression in CD. I will use two complementary approaches. I will use a microbiome/intestinal organoids co-culturing approach to identify host gene expression changes in response to CD-derived microbiomes, and host genetic variants that modulate these changes using allele-specific expression analysis. I will also utilize data available through the Human Microbiome Project Inflammatory Bowel Disease Multi’omics Database to perform eQTL mapping, and integrate all of my findings with GWAS and TWAS to validate the significance of GxM for CD risk. These studies will provide insight into host-microbiome interactions that modify genetic risk for Crohn’s Disease. Furthermore, I will identify specific microbes that could become potential therapeutic targets for CD.

摘要 克罗恩病（CD）是一种自身免疫性疾病，其导致慢性炎症和瘢痕形成， 消化道现有的治疗方法包括免疫抑制剂和手术，这些都是昂贵的，许多人都有可能。 生活质量下降的人。CD的原因尚不清楚，但据信会发生 由于遗传和环境因素，包括饮食。肠道微生物组在患有以下疾病的个体中发生改变 CD，导致宿主和微生物转录和代谢景观的失调。此外，委员会认为， 许多与CD相关的遗传风险变异存在于已知在宿主对CD应答中起作用的宿主基因中， 微生物组因此，表征CD中的宿主-微生物组相互作用对于理解CD中的宿主-微生物组相互作用至关重要。 CD的发病机制，并确定潜在的新的治疗途径。在这项研究中，我的目标是 表征宿主遗传变异与调节宿主基因的肠道微生物组之间的相互作用 CD中的表达。我将使用两种互补的方法。我将使用微生物组/肠道类器官 - 共培养方法，以鉴定响应于CD来源的微生物组的宿主基因表达变化，以及 使用等位基因特异性表达分析调节这些变化的宿主遗传变异。我也会利用 通过人类微生物组项目炎症性肠病多组学数据库获得的数据， 进行eQTL定位，并将我的所有发现与GWAS和TWAS整合，以验证 CD风险的GxM。这些研究将为改变遗传风险的宿主-微生物组相互作用提供见解 治疗克罗恩病此外，我将鉴定出可能成为潜在治疗药物的特定微生物， CD的目标。