Mount Sinai NYC Genetics Research Center: Multi-omic integration across data-types, cell niches and populations

纽约西奈山遗传学研究中心：跨数据类型、细胞生态位和群体的多组学整合

• 批准号: 10543288
• 负责人: JUDY H. CHO
• 金额: $ 9.57万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543288
• 关键词: ATAC-seq; Acute; Affect; African American; African American population; Alleles; Automobile Driving; Biological Assay; Blood; Blood Cells; Blood Platelets; Cell Maintenance; Cells; Chronic; Clinical; Collagen; Complement; Crohn' s disease; Data; Data Set; Development; Dinoprostone; Disease; Disease remission; Distal; Endoscopy; Epithelial; Epithelial Cells; European; Excision; Fibroblasts; Fistula; Flare; Funding; Gene Frequency; Genes; Genetic; Genetic Diseases; Genetic Research; Genomics; Genotype; Goals; High Prevalence; Hispanic; IL6ST gene; Immunologic Surveillance; Immunology; In Vitro; Inflammation; Inflammatory Bowel Diseases; Leukocytes; Medical; Mesenchymal; Modeling; Molecular; Morbidity - disease rate; Multiomic Data; Mutation; Myelogenous; Myeloid Cells; National Institute of Diabetes and Digestive and Kidney Diseases; New York; Outcome; PDGFRA gene; Pathway interactions; Patients; Platelet-Derived Growth Factor Receptor; Play; Population; Reactive Oxygen Species; Recording of previous events; Reduce health disparities; Reporting; Research; Research Personnel; Resolution; Role; Sampling; Services; Stromal Cells; System; Systemic disease; TNF gene; TNFSF15 gene; Technology; Thrombosis; Time; Tissues; Transcription Factor AP-1; Ulcerative Colitis; WNT2 gene; Work; XCL1 gene; base; case control; cell type; cohort; comparative; cost effective; data integration; early onset; epithelial stem cell; genetic variant; genome wide association study; imprint; improved; insight; interest; intestinal epithelium; loss of function mutation; macrophage; medical schools; monocyte; multiple omics; new technology; novel strategies; polygenic risk score; recruit; rectal; response; risk variant; single cell analysis; stem; stem cells; therapy resistant; transcriptome; transcriptome sequencing; transcriptomics

PROJECT ABSTRACT This proposal is submitted in response to FOA RFA-DK-21-022, to serve as a Genetics Research Center (GRC), within the NIDDK Inflammatory Bowel Disease (IBD) Genetics Consortium (IBDGC), at the Icahn School of Medicine at Mount Sinai, New York. During the present period, we made substantive progress in defining mechanisms of anti-TNF non-response in ileal Crohn’s disease and defined the role of NOD2 mutations in altering blood monocyte differentiation to result in an aberrant myeloid-stromal niche. In this proposal, we seek to expand on the role of blood monocyte differentiation, but newly-focused on perianal fistulae, a major unmet medical need in Crohn’s disease, disproportionately affecting African-Americans. Single cell transcriptomics has provided enormous insight into molecular mechanisms in IBD; our lab has substantial expertise in this and will leverage new approaches including multiome ATAC + transcriptome and higher resolution spatial transcriptomics platforms available soon. Aim 1 will focus on direct ex-vivo single cell analyses involving perianal fistulae including African-American and European ancestry Crohn’s disease patients. Aim 2 will expand in vitro analyses focusing on rectal-derived enteroids and serial blood leukocyte and platelet analyses. Both epithelial cells and monocytes can differentiate into mesenchymal-type cells. The extent to which stem- and other pluripotent cells are imprinted with chronic inflammation and during acute flares vs. remission will be evaluated via multiome ATAC + transcriptome and serial blood leukocyte and platelet analyses. Comparative analyses of these multi-omic data across European vs. African-American cohorts focused on GWAS loci will be performed, focusing on WNT, AP-1 and reactive oxygen species’ effects. Iterating between direct ex-vivo data (Aim 1) and in vitro systems (Aim 2) will provide maximal insight. Aim 3 describes our proposed contributions to the IBDGC broadly. We have been major contributors to Consortium-wide clinical recruitment efforts (ileal resection, ulcerative colitis demarcation), and more recently, recruitment of African-American and Hispanic IBD patients. We have reported on the particular value of African-American case-control reference data for both common (improving polygenic risk scores) and rare (overlap with very-early onset IBD genes) genetic variants. Beyond perianal Crohn’s disease, new recruitment of ulcerative colitis patients hospitalized with acute flares is proposed; serial blood analyses are feasible, with key short-term outcomes. A complete explication of mechanisms underlying IBD locus associations will require deeper genomic interrogation across populations, as well as data integration across space (cellular niches, disease extent), key clinical scenarios and time.

项目摘要 本提案是根据FOA RFA-DK-21-022提交的，作为遗传学研究中心（GRC）， 在伊坎医学院的NIDDK炎症性肠病（IBD）遗传学联盟（IBDGC）中， 医学在西奈山，纽约。在本报告所述期间，我们在确定 回肠克罗恩病中抗TNF无应答的机制，并确定NOD 2突变在 改变血液单核细胞分化以导致异常的骨髓基质小生境。在这一建议中，我们寻求 扩大血液单核细胞分化的作用，但新的重点是肛周瘘，一个主要的未满足 克罗恩病的医疗需求，不成比例地影响非洲裔美国人。单细胞转录组学 为IBD的分子机制提供了巨大的洞察力;我们的实验室在这方面拥有丰富的专业知识，并将 利用新方法，包括多组ATAC +转录组和更高分辨率的空间 转录组学平台即将推出。目的1将集中于直接离体单细胞分析，涉及肛周 瘘管包括非洲裔美国人和欧洲血统的克罗恩病患者。AIM 2将在体外扩增 分析重点是直肠源性肠上皮细胞和系列血液白细胞和血小板分析。上皮细胞 细胞和单核细胞可以分化成间充质型细胞。在多大程度上干-和其他 多能性细胞被标记有慢性炎症，并将在急性发作与缓解期间进行评价 通过多组ATAC +转录组和系列血液白细胞和血小板分析。比较分析 将进行集中于GWAS基因座的欧洲人与非洲裔美国人群组的这些多组学数据， 重点研究了WNT、AP-1和活性氧的作用。直接离体数据（目标1）和 体外系统（目标2）将提供最大的洞察力。目标3描述了我们对IBDGC的拟议贡献 大致上我们一直是联盟范围内临床招募工作的主要贡献者（回肠切除， 溃疡性结肠炎分界），以及最近招募的非裔美国人和西班牙裔IBD患者。 我们已经报道了非裔美国人病例对照参考数据的特殊价值， （改善多基因风险评分）和罕见（与极早发病IBD基因重叠）遗传变异。超出 肛周克罗恩病，新招募溃疡性结肠炎急性发作住院患者建议; 系列血液分析是可行的，具有关键的短期结果。机制的完整解释 潜在的IBD基因座关联将需要更深入的跨人群基因组调查，以及数据 跨空间（细胞小生境、疾病程度）、关键临床情景和时间的整合。