Jessica Maiers, PhD

My research program focuses on understanding the molecular mechanisms of liver fibrosis. The primary fibrogenic cells in the liver are Hepatic Stellate Cells (HSCs). Chronic liver injury promotes differentiation of quiescent HSCs into myofibroblasts which drive fibrogenesis through producing and secreting extracellular matrix (ECM) proteins including procollagen I. ECM secretion creates two problems for HSCs: 1) procollagen I is too large to traffic through the secretory pathway using canonical mechanisms, and 2) increased ECM production activates stress responses which impact cellular homeostasis. Fibrotic HSCs exhibit persistent ECM production and secretion without succumbing to apoptosis; however, the mechanisms regulating this are unclear. We identified the ER protein TANGO1 as a critical moderator of procollagen I ER export in HSCs in vitro and moderator of fibrogenesis in vivo. Loss of TANGO1 in HSCs led to procollagen I retention, HSC apoptosis, and reduced fibrogenesis; suggesting that TANGO1 and ECM trafficking machinery could serve as therapeutic targets. We also interrogated how the unfolded protein response (UPR) and fibrogenesis in HSCs. UPR signaling promotes protein secretion, but also impacts cellular homeostasis. ECM production promotes UPR signaling through ATF6α andIRE1α. Interestingly, both ATF6α and IRE1α signaling are critical for fibrogenesis in vitro and in vivo, though the crosstalk between these pathways and how they influence fibrogenesis is unclear. Building upon this work my lab focuses on two major goals.

1. Understand the mechanisms of procollagen I trafficking:  We developed an immunofluorescence-based screening platform. HSCs were transfected with an siRNA library targeting genes involved in membrane trafficking. This screening platform identified several proteins whose knockdown led to intracellular procollagen I retention. These proteins have diverse functions and roles in membrane trafficking, including endocytosis, suggesting that procollagen I export involves coordination of multiple processes. We have validated these targets and are working to discern their role/mechanism of action in procollagen I trafficking. This screen not only moved forward our work studying ECM trafficking, but also provides a platform to identify compounds that disrupt procollagen I trafficking and fibrogenesis.

2. Elucidating how activated HSCs maintain cellular despite persistent secretory stress: The mechanisms through which HSCs exhibit persistent ECM secretion without succumbing to stress-induced apoptosis are unknown. We propose that understanding how HSCs regulate the UPR to avoid apoptosis would provide unique insight into how we could target activated HSCs for apoptosis. To address this, we are using in vitro and in vivo models to interrogate UPR signaling influence fibrogenesis, as well as HSC homeostasis and survival.