Modulation of the biliary immune niche by the microbiome

微生物组对胆道免疫生态位的调节

• 批准号: 10349405
• 负责人: CLAIRE E O'LEARY
• 金额: $ 16.2万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-20 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10349405
• 关键词: Acute; Adult; Biliary; Biliary Atresia; Biliary Tract Cancer; Biliary Tract Diseases; Biology; Cell Shape; Cells; Childhood; Cholangiocarcinoma; Cholecystitis; Cholelithiasis; Cholesterol; Chronic; Clinical; Collaborations; Data; Dendritic Cells; Development; Development Plans; Diet; Disease; Disease Progression; Environmental Risk Factor; Epithelial Cells; Epithelium; Event; Extrahepatic; Extrahepatic Bile Ducts; Frequencies; Gallbladder; Germ-Free; Health; Homeostasis; Hospitalization; Human; Immune; Immune system; Immunologics; Immunology; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Integration Host Factors; Left; Ligands; Link; Liver; Liver Failure; Lymphocyte; Lymphoid Cell; Macrophage; Malignant Neoplasms; Methods; Mucous Membrane; Mus; Neutrophil Infiltration; Normal tissue morphology; Operative Surgical Procedures; Pathologic; Pathology; Phenotype; Play; Population; Process; Property; Recording of previous events; Reproducibility; Research; Resolution; Risk; Risk Factors; Role; Secretory Cell; Sensory; Severities; Severity of illness; Shapes; Signal Transduction; Stromal Cells; Surface; Testing; Therapeutic Intervention; Tissue atlas; Tissues; Training; Volatile Fatty Acids; Work; biliary tract; career development; cell type; design; gallstone disease; granulocyte; host microbiome; immune cell infiltrate; immunoregulation; liver transplantation; microbial; microbiome; microbiota; mortality; neutrophil; post-doctoral training; primary sclerosing cholangitis; receptor; repository; single cell sequencing; single-cell RNA sequencing; therapeutic target

PROJECT SUMMARY/ABSTRACT Biliary tract disease and inflammation, including pediatric biliary atresia and primary sclerosing cholangitis, are leading causes of liver failure. Chronic biliary inflammation, which can be associated with the presence of gallstones, is a risk factor for development of cholangiocarcinoma, a rare but deadly malignancy. Acute inflammation of the gallbladder, or cholecystitis, accounts for 20% of all biliary tract disease hospitalizations, usually requires surgical intervention and has significant mortality if left untreated. Together, biliary tract disease, including common gallstones, represents an enormous human health burden. Biliary tract inflammation plays clear roles in progression of various common and rare biliary diseases, however our understanding of inflammation and immune processes within the biliary tract are exceedingly limited. The resident immune cell populations in the extrahepatic biliary tree at homeostasis have never been characterized, and whether host or environmental factors can influence the development of the biliary niche has never been explored. It is unknown if resident biliary immune cells could impact development and progression of biliary disease. During my postdoctoral training, I developed a reproducible tissue digest method that yields highly viable immune, epithelial, and stromal cell populations. Single cell RNA sequencing revealed that there is a diversity of resident immune cells present at homeostasis in the mouse gallbladder/extrahepatic bile ducts, including innate lymphoid cells, adaptive lymphocytes, neutrophils, macrophages, and dendritic cells. In the course of studying biliary tuft cells—rare, chemosensory epithelial cells with known immunomodulating properties—I found that the biliary immune niche is altered in the absence of tuft cells, and is also sensitive to the microbiome-status of the host. My data suggest that the microbiome and biliary epithelial cells (including tuft cells) regulate the establishment of the biliary immune niche. In this proposal, I will test the role of the microbiome and microbial metabolites in setting biliary immune “tone,” and will define a role for tuft cells in regulating the biliary immune cell make-up. I will test whether alterations in the biliary immune niche at homeostasis, specifically the presence or absence of neutrophils, can impact the progression of cholesterol gallstone disease. To accomplish these aims, I have formed collaborations with experts in liver/biliary biology and microbiome manipulations, and have established a career development plan that will facilitate increasing computational independence. These studies will reveal new links between host factors and biliary inflammation, with the potential for therapeutic targeting of biliary epithelial cells and the microbiome to impact biliary health and disease.

项目摘要/摘要 胆道疾病和炎症，包括儿童胆道闭锁和原发性硬化性胆管炎， 导致肝功能衰竭的主要原因。慢性胆管炎，这可能与存在 胆结石是胆管癌变的危险因素，胆管癌是一种罕见的致命恶性肿瘤。急性 胆囊炎或胆囊炎占所有胆道疾病住院病例的20%， 通常需要手术干预，如果不治疗，会有显著的死亡率。加起来，胆道疾病， 包括常见的胆结石在内，是人类健康的巨大负担。胆道炎的作用 明确在各种常见和罕见胆道疾病的进展中的作用，但我们对 胆道内的炎症和免疫过程极其有限。 处于动态平衡状态的肝外胆管树中的常驻免疫细胞群从未 以及宿主或环境因素是否会影响胆汁生态位的发展 从未被探索过。目前尚不清楚常驻胆汁免疫细胞是否会影响发育和进展 胆道疾病。在我的博士后培训期间，我开发了一种可重复的组织消化法，这种方法产生了 高度活跃的免疫细胞、上皮细胞和基质细胞群体。单细胞RNA测序显示有 在小鼠的胆囊管/肝外胆管中存在多种稳定的常驻免疫细胞， 包括先天淋巴样细胞、适应性淋巴细胞、中性粒细胞、巨噬细胞和树突状细胞。在 胆管绒毛细胞的研究历程--罕见的、具有免疫调节功能的化学敏感上皮细胞 特性-我发现胆汁免疫小生境在没有簇状细胞的情况下会发生变化，而且对 微生物群--宿主的状态。我的数据表明，微生物群和胆管上皮细胞(包括簇状细胞) 细胞)调节胆道免疫生态位的建立。在这项提案中，我将测试微生物组的作用 和微生物代谢产物在设定胆汁免疫“基调”中的作用，并将确定丛生细胞在调节 胆汁免疫细胞组成。我将测试胆汁免疫小生境在动态平衡时的变化，特别是 中性粒细胞的存在或不存在会影响胆固醇结石疾病的进展。至 为了实现这些目标，我与肝脏/胆道生物学和微生物组方面的专家进行了合作 操作，并建立了职业发展计划，将促进增加计算量 独立。这些研究将揭示宿主因素和胆道炎之间的新联系， 治疗靶向胆管上皮细胞和微生物群的可能性影响胆道健康和 疾病。