Abstract Myopia or ‘nearsightedness’ is rapidly approaching pandemic levels worldwide. If left to the current trajectory, it is predicted that half of the world will be myopic by 2050. It is critical we develop novel treatments to prevent and treat the underlying causes of myopia rather than just correcting blurred vision caused by refractive error. To do this, we need to understand refractive development programs at the cell and cell signaling levels. It is known that refractive development intricately intertwines input from environmental visual stimuli, retinoscleral signaling, and scleral remodeling. This proposal specifically focuses on the ultimate consequence of myopia, scleral ECM remodeling by resident fibroblasts. I hypothesize that scleral fibroblasts follow a specific developmental differentiation program that is disrupted following exposure to myopic stimuli, which results in aberrant cellular signaling and responses. In aim one, I will use the mouse model to identify fibroblast characteristics in eyes that successfully undergo refractive development resulting in no refractive error (emmetropia). I will then directly compare the changes that occur in mice that have been exposed to myopic stimuli. These myopigenesis models include lens-induced myopia (LIM), which uses a negatively powered lens placed in the visual pathway to stimulate myopic eye growth. Furthermore, work from the Pardue and Ethier labs has shown that feeding the biologically active metabolite of retinoic acid (RA) signaling, all-trans- retinoic acid (atRA), to mice is sufficient to induce similar myopic changes in the sclera. This, paired with data showing increases in RA metabolites in myopic retinas, suggests a role for RA signaling in driving myopia. In aim two, I will determine the role of retinoic acid signaling in myopia. Independent of whether the hypotheses laid out in the proposal are supported, the results of these studies will provide valuable information to myopia and vision research communities. To perform these studies, I will need to develop skills including measuring refractive error and axial length in vivo, performing imaging techniques such as multiphoton microscopy techniques and RNA scope, and learning the background knowledge needed to do research in an entirely new system, the eye. These skills will be critical as I pursue my long-term goal of becoming an independent researcher at an academic institution.

Project Narrative Myopia is rapidly approaching pandemic levels worldwide. The proposed studies will use wild-type conditions, environmental (LIM), and pharmacological (atRA) myopia models to elucidate the role of scleral fibroblasts during refractive development in mice. In doing so, I will provide valuable insight into mechanisms driving myopia development that are downstream of retinal signaling, which is an ideal window for clinical intervention in myopia prevention and treatment.