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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要：候选人和职业发展：泰勒博士是儿科肝病学家兼儿科助理教授在西北大学。她对基础科学和翻译研究保持了浓厚的兴趣在她的早期职业生涯中。她的长期职业目标是成为一名独立资助的身体科学家重点是小儿胆固醇肝病的免疫学。该K08提案将有助于实现这一目标通过以下特定目标进行目标：1）发展泰勒博士的科学和专业技能晚期免疫学和生物信息学，以及2）定义胆道中的致病性巨噬细胞（M）子集闭锁（BA）最终开发细胞亚集特异性治疗策略。泰勒博士和她的联合给予者博士佩尔曼（Perlman）和格林博士计划的课程工作，教学，实验室技术和西北地区的合作。当前的建议将为未来R01级的建议奠定基础，该提案对BA中的M驱动的适应性免疫调节。研究计划：BA是婴儿期的胆汁淤积性肝病，是小儿肝的主要原因移植。 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然未知。证据表明M在BA中的核心作用然而，发病机理是一种异质和塑料细胞种群，先前的研究尚未区分子集。我们是第一个证明小儿胆汁淤积的M异质性的人通过单细胞RNA测序的肝病，并鉴定出3种不同的胆汁淤积性肝M子集：脂质相关的M，单核细胞状的M和自适应M。其中，自适应m证明了 Ba和Ba之间涉及淋巴细胞激活和疾病特异性差异的基因的表达胆汁淤积的非免疫病因。这些发现表明自适应m可能是致病性子集在BA中，通过刺激T细胞免疫反应已知在BA中起作用。在当前的建议中将建立在此初步数据的基础上，并研究适应性m驱动致病性的假设通过募集炎症性M和T细胞的招募BA。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的：1）确定新型脂质相关，单核细胞样和是否是否人类BA中的自适应m与无移植生存相关，2）确定自适应m是否在人BA对于鼠ba的疾病机制至关重要。通过人类和鼠的平行研究 BA，以及与新生儿胆管连接的创新的非免疫鼠模型的比较，我们将确定驱动免疫损伤的BA特异性M子集。完成这些目标后获得的结果可以确定BA中M免疫调节的新治疗靶标，以延长无移植生存。