Enzyme engineering for crosslinked collagen turnover in the extracellular matrix

The project postulates extracellular matrix (ECM) stiffening as the upstream cause of the hallmarks of aging and proposes leveraging generative AI to engineer matrix metalloproteinases (MMPs) capable of degrading sugar-modified, or glycated, collagen that resists normal remodeling. The initial experimental framework encompasses in vitro studies using hydrogels with tunable stiffnesses to probe cellular responses to different mechanoenvironments, and further in vivo validation in a murine liver regeneration model to build evidence for the proximal role of ECM stiffening in aging. The work aims to overcome hitherto irreparable forms of damage through engineered ECM rejuvenation, offering its first therapeutic application in diabetic nephropathy using enhanced glyoxalase I and MMPs-3, -9, targeting both intracellular and extracellular glycation damage in kidneys.