We investigate keratoconus, a corneal disease associated with ECM degeneration, scarring and vision loss. Affecting ~1 in 1000 people, it is the second-most-common cause for corneal transplants worldwide. While the etiology of keratoconus is not fully understood, interactions of genetic factors with environmental stressors are suspected. We are using proteomic, transcriptomic and genomic approaches to identify genetic variants and disease mechanisms in keratoconus patients. Our proteomic and transcriptomic studies of corneal tissues from keratoconus patients identified increased stress response, poor NRF2-regulated antioxidant response and reduced ECM levels in keratoconus (Shinde 2019, Shinde 2020, Shinde 2021). Our genomic studies of keratoconus have identified rare pathogenic variants in genes encoding cytoskeletal, ECM and cellular stress response proteins. We are using human corneal organoid and mouse models to gain functional insights into these pathogenic variants.