Principal Investigator Matthew Shoulders
Collagen is the molecular scaffold for multicellular life and by far the most abundant protein in the human body. Collagen presents a uniquely complex and still poorly elucidated proteostasis challenge to cells. Imbalances in collagen proteostasis are related to diverse, currently incurable diseases ranging from osteogenesis imperfecta (brittle bone disease) to fibrosis. Our approach focuses on illuminating molecular details of intracellular collagen folding and quality control, followed by using what we learn to identify potential new therapeutic strategies for the collagenopathies. We have built an array of biochemically amenable platforms to explore the collagen proteostasis problem. With new methods in hand, we have now: (1) Developed a customized proteomics workflow to map the proteostasis mechanisms that engage nascent collagen type-I, leading to the discovery of an unprecedented collagen-I post-translational modification (aspartyl hydroxylation) and providing key insights into collagen-I quality control pathways. (2) Pioneered a high-throughput, cell-based screen for modulators of collagen-I secretion that resulted in the identification of several drug classes that impact collagen-I proteostasis. (3) Demonstrated that the endoplasmic reticulum proteostasis network can be remodeled to resolve collagen-I production defects, a finding that may have translational implications for osteogenesis imperfecta, a skeletal disease that is prototypical of the collagenopathies.