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.

抽象的 克罗恩病 (CD) 是一种自身免疫性疾病，会导致慢性炎症和皮肤疤痕 消化道。可用的治疗方法包括免疫抑制剂和手术，费用昂贵， 个人的生活质量仍然下降。 CD 的病因尚不清楚，但据信会发生 由于遗传和环境因素，包括饮食。患有以下疾病的个体肠道微生物群发生改变 CD，导致宿主和微生物转录和代谢景观失调。此外， 许多与CD相关的遗传风险变异存在于已知在宿主对CD的反应中起作用的宿主基因中。 微生物组。因此，表征 CD 中宿主-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治疗途径。在这项拟议的研究中，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 共培养方法来识别宿主基因表达变化以响应 CD 衍生的微生物组，以及 使用等位基因特异性表达分析来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 执行 eQTL 映射，并将我的所有发现与 GWAS 和 TWAS 相结合，以验证 GxM 针对 CD 风险。这些研究将深入了解改变遗传风险的宿主-微生物组相互作用 用于克罗恩病。此外，我将确定可能成为潜在治疗药物的特定微生物 CD 的目标。