Glaucoma is the world’s leading cause of irreversible blindness, with c. 3M patients in the US (~1% of the population). Primary open-angle glaucoma (POAG) is the most common form of glaucoma. It is often linked with elevated intraocular pressure and is characterized by permanent structural changes to the optic nerve head (ONH) and its associated neurological damage. One such change is irreversible deformation (cupping) of the lamina cribrosa, a mesh-like mechanically supportive structure within the ONH. In many tissues, it is well-known that a delicate mechanobiological feedback loop drives pathologic structural remodeling. Although a similar loop appears to operate in the ONH, we do not understand its mechanics and biology. It is known that soft tissue’s mechanical behavior is inelastic and nonlinear; however, there is limited information about the inelastic and nonlinear mechanical behavior of ONH ECM and the biological element of ONH remodeling is also not clearly understood. In our studies, we investigate mechanical properties and mechanobiology of ONH due to mechanical loading induced remodeling of its ECM, activation of the LC cells, and the connection between them.