Genomic Analysis of Perianal Fistulizing Crohn's Disease across Ancestries

跨血统肛周瘘管克罗恩病的基因组分析

• 批准号: 10033895
• 负责人: SUBRA KUGATHASAN
• 金额: $ 40.53万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-16 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10033895
• 关键词: Affect; African; African American; American; Architecture; Atlases; Bioinformatics; Biological; Biological Markers; Biological Models; Biopsy; Blood; Blood specimen; Cells; Communication; Complex; Complication; Crohn' s disease; Data; Disease; Disease Outcome; Disease Progression; Disease model; Disease remission; Dissection; Enrollment; Epithelial; Epithelial Cells; Epithelium; European; Feces; Fistula; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genomics; Growth Factor; High Prevalence; Hospitals; Immune; Immune system; In Vitro; Individual; Inflammatory; Intestines; Lamina Propria; Legal patent; Link; Maps; Matched Group; Medical; Metabolic; Microbe; Modeling; Molecular; Mucous Membrane; Nature; Operative Surgical Procedures; Organoids; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Population; Quality of life; Rectum; Refractory; Reporting; Resistance; Resolution; Risk; Role; Sampling; Severity of illness; Signal Transduction; Skin; Source; Staging; Suspensions; TNF gene; Testing; Therapeutic Intervention; Time; base; bioinformatics pipeline; causal variant; cell type; clinical phenotype; comparative; comparison intervention; cost; cytokine; design; disability; dysbiosis; follow-up; genome wide association study; genomic profiles; healing; health disparity; insight; microbiome; multiple omics; novel; patient response; peripheral blood; personalized intervention; predictive modeling; recruit; rectal; response; single-cell RNA sequencing; transcriptome; transcriptomics; treatment response

Project Summary Perianal fistulizing Crohn’s disease is a debilitating phenotype of Crohn’s disease (CD) involving the rectum. It is often refractory to treatment and is associated with severe disability and poor quality of life. Fistulizing CD disproportionately affects African Americans (AA), presenting with much higher prevalence, and more severe with destructive pathology. Besides fistulizing CD often requires a more aggressive combination of medical and surgical intervention than does luminal disease. Several lines of evidence suggest that interactions between the rectal epithelium, the microbiome, and the immune system, drive patent-specific pathogenesis of perianal fistula, but there is very little known about these at the molecular and cellular level, particularly with ancestral differences. The complexity of perianal fistula involving communication between microbes and multiple immune and non- immune cell types provides a strong rationale for a need for deep molecular characterization of the disease. One hypothesis is that different biological mechanisms due in part to divergent genomic architecture between African- and European-ancestry patients contributes to the disparity in health outcomes. Consequently, integrative genomic comparisons utilizing state-of-the-art single cell gene expression profiling of rectal biopsies and of peripheral blood immune cells, will be used to investigate the nature of pathological mechanisms of perianal fistulizing CD including specific comparison of African and European ancestry patient groups. Building on preliminary transcriptome profiling of the whole mucosa between these ancestry groups that implicates differences in metabolic and inflammatory signaling, and taking advantage of the emerging Gut Cell Atlas, our profiling of 120 cases will establish which cellular and gene expression features associate with remission, stabilization, or progression of disease. Aim 1 is to biopsy rectum and take blood samples from 120 patients at presentation, and again at follow-up, also with microbiome sampling (rectal wash as well as stool), supported by deep clinical phenotyping. Two ancestral populations (European and AA) are equally powered for comparison studies. Aim 2 is to use single cell RNA sequencing to profile changes in the relative abundance of each of dozens of key cell types, and to identify key genes that are consistent biomarkers of the three therapeutic response states within each cell type. Advanced bioinformatics approaches will be used to characterize the network of cellular interactions, and to link the genetic regulation of gene expression to genome-wide association studies of CD by identifying cell-type specific eQTL. Subsequently, in Aim 3, mechanistic dissection of specific pathways will be pursued with in vitro cultures of patient-derived intestinal organoids to assess patient specific responses when stimulated by relevant molecules. The findings will both illuminate cellular and molecular mechanisms that contribute to a major source of health disparity in fistulizing CD, and support the transition to personalized genomic medical profiling in support of therapeutic intervention.

项目概要 肛周瘘管克罗恩病是累及直肠的克罗恩病 (CD) 的一种衰弱表型。 瘘管性 CD 通常难以治疗，并与严重残疾和生活质量差有关。 对非裔美国人 (AA) 的影响尤为严重，其患病率更高，而且更严重 除了具有破坏性病理学外，CD通常还需要更积极的医疗和治疗相结合。 一些证据表明，手术干预比管腔疾病更有效。 直肠上皮、微生物组和免疫系统驱动肛周瘘的专利特异性发病机制， 但在分子和细胞水平上，人们对这些方面知之甚少，尤其是祖先差异。 肛周瘘的复杂性涉及微生物与多重免疫和非免疫细胞之间的交流 免疫细胞类型为需要对疾病进行深入的分子表征提供了强有力的理由。 假设是，不同的生物学机制部分归因于非洲人之间不同的基因组结构 欧洲血统的患者导致了健康结果的差异。 利用直肠活检和直肠活检的最先进的单细胞基因表达谱进行基因组比较 外周血免疫细胞，将用于研究肛周病理机制的性质 瘘管性 CD，包括非洲和欧洲血统患者群体的具体比较。 对这些祖先群体之间整个粘膜的初步转录组分析表明 代谢和炎症信号传导的差异，并利用新兴的肠道细胞图谱，我们 对 120 例病例的分析将确定哪些细胞和基因表达特征与缓解相关， 目标 1 是对 120 名患者进行直肠活检并采集血液样本。 演示，并在随访中再次进行微生物组采样（直肠冲洗液和粪便），并得到以下支持 两个祖先群体（欧洲人和 AA）的深度临床表型分析具有同等功效。 研究目标 2 是使用单细胞 RNA 测序来分析每种细胞相对丰度的变化。 数十种关键细胞类型，并识别与三种治疗方法一致的生物标志物的关键基因 将使用先进的生物信息学方法来表征每种细胞类型的反应状态。 细胞相互作用网络，并将基因表达的遗传调控与全基因组关联联系起来 随后，在目标 3 中，通过识别细胞类型特异性 eQTL 来研究 CD。 将通过患者来源的肠道类器官的体外培养物来探索途径，以评估患者的特异性 相关分子刺激时的反应，这些发现将阐明细胞和分子。 造成瘘管型 CD 健康差距的一个主要根源的机制，并支持向 支持治疗干预的个性化基因组医学分析。