Macrophage Regulation of Immune Pathogenesis of Biliary Atresia

巨噬细胞对胆道闭锁免疫发病机制的调节

• 批准号: 10320943
• 负责人: Sarah Ann Taylor
• 金额: $ 16.3万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320943
• 关键词: Advisory Committees; Alagille Syndrome; Award; Basic Science; Biliary; Biliary Atresia; Bioinformatics; Biology; CCL4 gene; CD3D gene; CD7 gene; CD8-Positive T-Lymphocytes; Cell Surface Proteins; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Characteristics; Child; Childhood; Cholestasis; Cirrhosis; Clinical Data; Collaborations; Collection; Computer Analysis; Data; Diagnosis; Dichloromethylene Diphosphonate; Disease; Disease Outcome; Disease Progression; Educational process of instructing; Ensure; Etiology; Foundations; Funding; Future; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Goals; Hepatic; Heterogeneity; Human; IL7R gene; Immune; Immune Tolerance; Immune response; Immunization; Immunologist; Immunology; Individual; Inflammation; Inflammatory; Inflammatory Infiltrate; Injury; Intraperitoneal Injections; Kupffer Cells; Laboratories; Ligation; Lipids; Liposomes; Lymphocyte Activation; Maintenance; Manuscripts; Mentors; Mus; Nature; Neonatal; Newborn Infant; Obstruction; PTPRC gene; Pathogenesis; Pathogenicity; Patients; Pediatrics; Physicians; Play; Population; Productivity; RANTES; Regulation; Regulator Genes; Research; Research Personnel; Rhesus; Rheumatology; Role; Rotavirus; S100A8 gene; S100A9 gene; Saline; Scientist; Severity of illness; T-Lymphocyte; Techniques; Time; Training; Translational Research; Transplantation; Universities; Work; adaptive immunity; antagonist; big-data science; bile duct; career; career development; differential expression; immunoregulation; improved; infancy; innovation; interest; lipid metabolism; liver injury; liver transplantation; macrophage; monocyte; mouse model; new therapeutic target; novel; professor; protein expression; recruit; single-cell RNA sequencing; skills; success; transcriptome sequencing; translational study; treatment strategy; validation studies

PROJECT SUMMARY: Candidate and Career Development: Dr. Taylor is a pediatric hepatologist and Assistant Professor of Pediatrics at Northwestern University. She has maintained a strong interest in basic science and translational research throughout her early career. Her long-term career goal is to become an independently funded physician-scientist with a focus on the immunology of pediatric cholestatic liver disease. This K08 proposal will help achieve this goal through the following specific objectives: 1) develop Dr. Taylor’s scientific and professional skills in advanced immunology and bioinformatics, and 2) define the pathogenic macrophage (M) subsets in biliary atresia (BA) to ultimately develop cell subset-specific treatment strategies. Dr. Taylor and her co-mentors, Dr. Perlman and Dr. Green, have developed a detailed strategy to achieve these objectives through carefully planned course work, didactics, laboratory techniques, and collaborations at Northwestern. The current proposal will lay the foundation for future R01-level proposals on M-driven regulation of adaptive immunity in BA. Research Plan: BA is a cholestatic liver disease of infancy that is the leading cause of pediatric liver transplantation. BA is thought to arise from an aberrant immune response to an environmental trigger, however, the exact mechanism of disease progression remains unknown. Evidence points to a central role for M in BA pathogenesis, however, M are a heterogeneous and plastic cell population, and prior studies have not distinguished between subsets. We are the first to demonstrate the M heterogeneity in pediatric cholestatic liver disease through single-cell RNA sequencing and identified 3 distinct cholestatic liver M subsets: lipid associated M, monocyte-like M, and adaptive M. Among these, adaptive M demonstrated increased expression of genes involved in lymphocyte activation and greater disease-specific differences between BA and a non-immune etiology of cholestasis. These findings suggest that adaptive M may be the pathogenic subset in BA through stimulation of the T cell immune response known to play a role in BA. In the current proposal we will build upon this Preliminary Data and investigate the hypothesis that adaptive M drive the pathogenicity of BA through recruitment of inflammatory M and T cells. To evaluate this hypothesis we have formulated the following two interrelated Specific Aims: 1) determine whether the novel lipid-associated, monocyte-like, and adaptive M in human BA correlate with transplant-free survival, and 2) determine whether the adaptive M in human BA are essential for the disease mechanism of murine BA. Through parallel studies in human and murine BA, as well as comparison to an innovative non-immune murine model of neonatal bile duct ligation, we will identify the BA-specific M subsets that drive immune injury. Results obtained upon completion of these aims may identify new therapeutic targets for M immune modulation in BA to prolong transplant-free survival.

项目总结： 候选人和职业发展：泰勒医生是儿科肝病专家和儿科学助理教授 在西北大学。她一直对基础科学和翻译研究保持着浓厚的兴趣 在她早期的职业生涯中。她的长期职业目标是成为一名独立资助的内科科学家 重点研究儿童胆汁淤积性肝病的免疫学。K08提案将有助于实现这一目标 通过以下具体目标实现目标：1)发展泰勒博士在以下领域的科学和专业技能 先进的免疫学和生物信息学，以及2)定义胆汁中的致病巨噬细胞(M)亚群 闭锁(BA)最终发展出针对细胞亚群的治疗策略。泰勒博士和她的共同导师。 帕尔曼和格林博士已经制定了一项详细的战略，通过谨慎地实现这些目标 西北大学有计划的课程作业、教学、实验室技术和合作。目前的提案 将为未来关于M驱动的BA获得性免疫调节的R01级提案奠定基础。 研究计划：BA是一种婴儿胆汁淤积性肝病，是导致儿童肝脏疾病的主要原因 移植。然而，BA被认为是由于对环境触发的异常免疫反应而产生的， 疾病进展的确切机制仍不清楚。有证据表明M在BA中扮演着核心角色 然而，在发病机制上，M-是一个异质的可塑性细胞群，以前的研究没有 在子集之间区分的。我们首次证明了儿童胆汁淤积症中M-的异质性 通过单细胞核糖核酸测序和鉴定出3个不同的胆汁淤积型肝脏M亚群：脂质 关联性M、单核细胞样M和适应性M。其中，适应性M-表现为增加 BA和BA患者淋巴细胞活化相关基因的表达及疾病特异性差异 胆汁淤积症的非免疫性病因。这些发现表明，适应性M-可能是致病亚群 在BA中，已知通过刺激T细胞免疫反应在BA中发挥作用。在目前的提案中，我们 将建立在这些初步数据的基础上，并调查适应性M-驱动致病性的假设 BA通过募集炎性M、和T细胞。为了评估这一假设，我们已经制定了 以下两个相互关联的特定目标：1)确定新的脂质相关的、单核细胞样的和 人基底动脉的适应性M-与无移植生存相关，2)决定适应性M-是否在 人BA在小鼠BA的发病机制中起重要作用。通过对人类和小鼠的平行研究 BA，以及与一种创新的非免疫小鼠新生儿胆管结扎模型的比较，我们将 确定导致免疫损伤的BA特异性M-亚群。完成这些目标后所取得的成果 可能为BA的M-免疫调节寻找新的治疗靶点，以延长无移植生存期。