Project Summary Retinitis Pigmentosa (RP) is a degenerative retinal disease that affects over 2 million people worldwide. Patients initially suffer from night blindness and gradually lose their peripheral vision as their visual field becomes increasingly restricted. The majority of patients with RP are completely blind by age 40. Although there is no treatment for RP, many cell and gene replacement therapies are currently being explored. The overall goal of this project is to provide an improved understanding of the in vivo manifestations of the pathophysiology of RP, to guide the continued development and translation of the various therapeutic approaches. In order to effectively diagnose and treat RP, there is a need to develop methods to quantify disease progression on a cellular scale. We will accomplish this through the following two aims – Aim 1: Test the hypothesis that cone reflectivity is positively correlated with function in the transition zone in patients with RP; Aim 2: Determine the sensitivity of in vivo retinal imaging tools (AOSLO & OCT) for detecting degenerative changes in cone structure in RP. For aim 1, we will use high-resolution imaging with adaptive optics to directly image the cone photoreceptors in patients with RP. This imaging has previously shown that cones in the RP retina don't reflect light normally, suggesting they are “sick” or malformed. What isn't known is whether these cones are functional – and we will examine this by using microperimetry to test the sensitivity of individual cones in areas of active disease in patients with RP. This work should result in a validated, cellular- resolution method for assessing retinal function. For aim 2, we will use a transgenic pig model of RP to study how understand how specific anatomical changes in cone structure (due to degeneration) affect the visualization of cones in high-resolution images of the living retina. This work addresses the broad knowledge gap surrounding the cellular origins of reflective signals in both AOSLO and OCT images, which will have a positive impact on the acceptance of these methods for noninvasive monitoring of photoreceptor structure and function in RP and other inherited retinal degenerations. Importantly, this project approaches this goal using both human RP patients and an established RP animal model, a truly unique aspect of the fellowship training.