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; 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，导致长期感染和疤痕 消化道。可用的治疗涉及免疫抑制剂和手术，这是昂贵的，许多 个人仍然经历生活质量下降。 CD的原因尚不清楚，但据信发生 由于遗传和环境因素，包括饮食。肠道微生物组在患有 CD，导致宿主和微生物转录和代谢景观的失调。此外， 与CD相关的许多遗传风险变异都在已知在宿主对宿主反应中起作用的宿主基因 微生物组。这是在CD中表征宿主 - 微生物组相互作用的 CD的发病机理并确定潜在的新疗法途径。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 在CD中的表达。我将使用两种完整的方法。我将使用微生物组/肠癌 共培养方法以鉴定响应CD衍生的微生物组的宿主基因表达变化，并且 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'杂种数据库可用的数据 执行EQTL映射，并将我的所有发现与GWAS和TWA进行集成以验证的重要性 GXM用于CD风险。这些研究将提供对宿主微生物组相互作用的洞察力，以改变遗传风险 为了克罗恩病。此外，我将确定可能成为潜在治疗的特定微生物。 CD的目标。