Mechanisms of Metabolic Dysregulation in ZZ Alpha-1 Antitrypsin Deficiency Associated Liver Disease

Boston University Medical Campus, Boston MA

Investigators

Abstract

This proposal details a 5-year career development training program focused on studying the basic mechanistic underpinnings of alpha-1 antitrypsin deficiency (AATD) associated liver disease with the goal of developing new treatments for these patients while simultaneously providing the necessary training required for Dr. Kaserman to become a future independent investigator. Individuals homozygous for the “Z” mutation, the most common liver disease-causing variant in AATD, accumulate polymerized Z alpha-1 antitrypsin (ZAAT) protein within the endoplasmic reticulum of hepatocytes resulting in cellular injury. Patient induced pluripotent stem cell (iPSC)- hepatocytes (iHeps) derived from ZZ individuals have recently been shown to exhibit dysregulated metabolic function as well as branch-specific activation of the unfolded protein response (UPR) among distinct hepatocyte subsets. Activation of the UPR, comprising three distinct signaling pathways (ATF6, PERK and IRE1), has been shown to induce hepatic steatosis and fibrosis in multiple other causes of liver disease, and the activation of PERK within ZZ iHep subsets was associated with a pro-fibrotic/ER stress transcriptomic profile while activation of ATF6 was associated with preservation of a homeostatic metabolic transcriptional profile. These observations have informed this proposal’s central hypothesis that the branch specific activation of ATF6 signaling in ZZ hepatocyte subsets preserves homeostatic metabolic function through increased metabolic transcription factor expression, oxidative phosphorylation, and an associated reduction in steatosis. This hypothesis will be tested in three specific aims: 1) Test whether ATF6 activation observed in sorted ZZ iHeps is associated with increased metabolic function and reduced steatosis relative to ATF6 low iHeps. 2) Directly test the contributions of ATF6 and PERK activation to ZZ protein accumulation, cellular homeostasis, and dysfunction through pathway modulation. 3) Test the therapeutic potential of novel drug candidates to ameliorate AATD-associated metabolic dysfunction in-vitro and in-vivo. The scientific component of this proposal is accompanied by a detailed training program that combines expert mentorship, selected coursework, and new analytical and technical expertise focused on hepatocyte metabolism, CRISPR interference (CRISPRi) gene modulation, and the “PiZ” mouse model of AATD associated liver disease. The assembled Advisory Committee members have been carefully chosen based on established track records for productivity and junior faculty mentorship. The mentorship team headed by Dr. Andrew Wilson (primary mentor) and Dr. Anthony Hollenberg (co-mentor) have complementary expertise in the areas of AATD, stem cell biology and metabolism making them ideally suited for this candidate’s career development award. The mentorship team is further strengthened by the expertise of Dr. Wolfram Goessling and Dr. Valerie Gouon-Evans, both experts in liver development, regeneration, and mouse models of liver disease. At the completion of this proposal Dr. Kaserman will have developed the necessary expertise to successfully transition into a career as an independent physician-scientist and future academic leader.