Our lab’s long-term goal is to create a novel gene therapy-based therapeutic to preserve and restore healthy vision for patients suffering from diseases that cause irreversible blindness. In particular, we study a disease called Retinitis Pigmentosa (RP), which is a disease of the retina that affects 1 in 4000 people worldwide. It is characterized by progressive degeneration of photoreceptors, rods and cones, which are necessary for achromatic night vision and daylight color vision, respectively. Although the disease progression is variable, a typical patient with RP loses night vision as an adolescent and subsequently loses central daylight vision by the age of 60. To date, over 65 causative genes for RP have been identified, and most are expressed solely in rods. At the cellular level, mutations in rod-specific genes lead to rod death and night vision impairment. Recently, gene replacement therapy to introduce the wildtype functional copy to restore rod function has become a realistic avenue for diseases of the retina (e.g. Luxturna). Despite the encouraging advancements, given the heterogeneity of patient genotypes that all converge upon the RP phenotype, replacement of single genes in rods may not be feasible to broadly treat every patient, each of whom may harbor different mutations in different genes. Upon rod death, neighboring cones lose their outer segments, the structure necessary for capturing light, and ultimately degenerate, leading to loss of daylight color vision and diminishing quality of life in patients. Unfortunately, the molecular and cellular mechanisms underlying this non-cell autonomous, rod-dependent cone degeneration in RP is poorly understood. Previous studies have suggested different mechanisms to explain this secondary cone death, including toxicity from the degenerating rods, loss of rod-derived survival factors, immune cell activation, and altered metabolism. A strategy to prevent secondary cone death in the event of rod death provides an attractive avenue for a generalized RP therapy to preserve daylight color vision. We believe that a functional, mutation-independent therapy for RP will require a two-step approach – a first step to prolong cone photoreceptor survival and another step to regenerate the outer segments that are required for functional phototransduction.  The immediate goals of my research program are to (1) elucidate the molecular mechanisms underpinning non-cell autonomous cone photoreceptor degeneration in vivo, (2) dissect the mechanisms governing photoreceptor outer segment formation to induce functional regeneration, and (3) develop novel technologies to facilitate such molecular investigations of the disease from both mouse and human postmortem tissues.