Tuesday, January 14, 2025
1/14/2025
Cholestatic liver diseases, including biliary atresia (BA), are the leading indication for pediatric liver transplant and there are no effective medical therapies for patients that decrease the need for transplantation. This is due, in part, to the lack of understanding of how the liver reacts to bile acid induced injury in children, including the hepatocyte activation of the unfolded protein response (UPR). The UPR is a protective molecular response that decreases endoplasmic reticulum (ER) stress which can occur in the setting of cholestasis, in part through induction of ER-associated degradation (ERAD) pathways. Our laboratory’s previously published and present preliminary data using several models of ER stress demonstrate that young mice have inadequate UPR activation (specifically within the XBP1 pathway) compared to adult mice, and this is associated with increased liver injury. The same pattern of impaired XBP1 pathway activation occurs in explanted livers from pediatric patients with cholestatic liver diseases compared to both normal and disease controls. The goal of my current investigations is to increase the understanding of the pathophysiologic hepatic responses of the XBP1 pathway to cholestatic liver injury and identify changes during postnatal development that influence UPR activation. This will allow us to target specific UPR pathways for the development of novel treatments for pediatric cholestatic liver diseases. Therefore, I have formulated the following Specific Aims: 1) To define age-dependent changes in XBP1 transcription factor function using murine models of ER stress 2) To define the protective mechanism of XBP1 regulation of ERAD in chronic cholestasis and 3) To determine the changes in mechanism of XBP1 signaling which occur in murine and human biliary atresia (BA). Using murine models of ER stress and cholestasis and human liver tissue from BA patients we will identify the mechanism of XBP1 specific pathway changes that occur during post-natal development, and how these changes influence disease progression in response to cholestasis-induced ER stress. Candidate and Career Development: I am a pediatric hepatologist at Northwestern University who has a demonstrated commitment to basic/translational research throughout my early career. My long-term career goal is to become an independent, extramurally funded physician-scientist with a focus on the hepatocellular UPR response in pediatric cholestatic liver diseases. This K08 proposal will help achieve this goal by advancing my scientific skills and knowledge in gene regulation, cellular signaling pathway analysis and high-throughput data analysis, as well as defining the role of the unfolded protein response in murine cholestatic liver disease models and correlative human diseases. Along with my co-mentors, Drs. Green and Barish, I have developed a career development plan to achieve these goals through didactic lectures, mentoring, and hands-on laboratory training. This proposal will provide the protected time and research training for future R01-level proposals extending mechanistic XBP1 pathway studies within pediatric cholestatic liver diseases and investigating UPR-related therapeutics.
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