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: 10761123
• 负责人: Sarah Ann Taylor
• 金额: $ 16.29万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 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/10761123
• 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; Immunologic Stimulation; Immunologist; Immunology; Individual; Inflammation; Inflammatory; Inflammatory Infiltrate; Injury; Intraperitoneal Injections; Kupffer Cells; Laboratories; Ligation; Lipids; Liposomes; Lymphocyte Activation; Macrophage; Maintenance; Manuscripts; Mentors; Mus; Nature; Neonatal; Newborn Infant; Obstruction; PTPRC gene; Pathogenesis; Pathogenicity; Patients; Pediatrics; Physicians; 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; comparison control; differential expression; immunoregulation; improved; infancy; innovation; interest; lipid metabolism; liver injury; liver transplantation; 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.

项目概要： 候选人和职业发展：泰勒博士是一名儿科肝病学家和儿科助理教授 在西北大学。她对基础科学和转化研究保持着浓厚的兴趣 贯穿她早期的职业生涯。她的长期职业目标是成为一名独立资助的医师科学家 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 通过以下具体目标来实现这一目标： 1) 培养泰勒博士在以下领域的科学和专业技能： 高级免疫学和生物信息学，2) 定义胆道中的致病性巨噬细胞 (M) 亚群 闭锁（BA）最终开发细胞亚群特异性治疗策略。泰勒博士和她的合作导师，博士。 帕尔曼和格林博士制定了详细的战略，通过仔细地实现这些目标 规划了西北大学的课程作业、教学、实验室技术和合作。目前的提案 将为未来关于 BA 中 M 驱动的适应性免疫调节的 R01 级提案奠定基础。 研究计划：BA是一种婴儿期胆汁淤积性肝病，是小儿肝脏的主要原因 移植。 BA被认为是由对环境触发因素的异常免疫反应引起的，然而， 疾病进展的确切机制仍不清楚。证据表明 M 在 BA 中发挥核心作用 然而，M 的发病机制是异质且可塑的细胞群，之前的研究尚未发现 区分子集。我们是第一个证明儿童胆汁淤积症的 M 异质性的人 通过单细胞 RNA 测序对肝脏疾病进行研究，并确定了 3 个不同的胆汁淤积性肝脏 M 子集：脂质 相关 M、单核细胞样 M 和适应性 M。其中，自适应 M 表现出增加的 BA 和 BA 之间参与淋巴细胞激活的基因表达以及更大的疾病特异性差异 胆汁淤积的非免疫病因。这些发现表明适应性 M 可能是致病子集 BA 中已知通过刺激 T 细胞免疫反应在 BA 中发挥作用。在当前的提案中，我们 将在此初步数据的基础上研究适应性 M 驱动致病性的假设 BA 通过募集炎症 M 和 T 细胞来实现。为了评估这个假设，我们制定了 以下两个相互关联的具体目标：1）确定新型脂质相关的、单核细胞样的和 人类 BA 中的适应性 M 与无移植生存相关，并且 2) 确定人类 BA 中的适应性 M 是否与无移植生存相关。 人类 BA 对于小鼠 BA 的疾病机制至关重要。通过对人类和小鼠的平行研究 BA，以及与新生儿胆管结扎的创新非免疫小鼠模型的比较，我们将 识别导致免疫损伤的 BA 特异性 M 子集。完成这些目标后取得的成果 可能会确定 BA 中 M 免疫调节的新治疗靶点，以延长无移植生存期。