Our current research is focused on two main directions:
The molecular basis of photoreceptor-RPE symbiosis
Photoreceptor cells are immediately apposed by the retinal pigment epithelium (RPE), which supports photoreceptor cell health in a variety of processes including normal outer segment renewal and nutrient exchange. Yet, the molecular basis underlying this critical symbiotic relationship between photoreceptors and the RPE remains poorly understood. One exciting lead that we are currently pursuing is related to ADAM9, a member of the A Disintegrin And Metalloproteinase protein family, whose mutations cause inherited retinal disease in both human and dog patients. The etiology of this disease remains unexplored except that animals bearing ADAM9 mutations exhibit a severe disruption of the interface between photoreceptors and the RPE, and our current work shows an accumulation of interphotoreceptor matrix material at this interface. Overall, this direction seeks to guide therapeutic efforts into ADAM9-associated disease and also provide insights into both interphotoreceptor matrix biology and photoreceptor-RPE symbiosis as a whole. This work is currently supported by a R00 grant from the National Eye Institute (EY033763).
Pathophysiological consequences of rhodopsin mislocalization in inherited retinal disease
Inherited retinal disease (IRDs) are a clinically heterogeneous group of pathologies primarily characterized by photoreceptor cell degeneration. Currently, mutations in over 290 different genes have been identified as being associated with IRDs, which complicates the discovery of treatments for these patients. One promising therapeutic strategy for IRDs would be the identification of a gene-independent therapy for treating a broad group of genetically diverse patients. In both human subjects and animal models of these diseases, mislocalization of the visual pigment rhodopsin from the light-sensitive outer segment compartment to the photoreceptor cell body has been observed and is thought to contribute to disease progression. Our recent work provided two exciting leads regarding the pathophysiological significance of rhodopsin mislocalization in IRDs. First, we showed that genetically reducing rhodopsin expression in two IRD mouse models characterized by a gross mislocalization of rhodopsin led to a significant slowing of photoreceptor cell death. Second, we uncovered that photoreceptor cells have the intrinsic ability to concentrate mislocalized rhodopsin for its disposal from the cell in extracellular vesicles. Following these leads, we will now explore mechanisms of regulating rhodopsin levels in photoreceptor cells and whether they could serve as gene-independent treatments for photoreceptor cell death in IRDs.
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