Macrophage Regulation of Immune Pathogenesis of Biliary Atresia

点击翻译按钮获取中文摘要

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.