The role of ADAM9 in retinal health and disease

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PROJECT SUMMARY/ABSTRACT The overall goal of this proposal is to identify the pathophysiological mechanisms underlying photoreceptor degeneration caused by mutations in ADAM9 (A Disintegrin And Metalloproteinase 9) in human and canine patients. Previous work in mouse and canine models has revealed that loss of ADAM9 leads to disruptions in the interface between the photoreceptor outer segments and the retinal pigment epithelium (RPE). Preliminary data for this proposal reveal a substantial accumulation of extracellular material from the interphotoreceptor matrix at this interface. Given the well-established roles of ADAM proteins as both proteases and cell adhesion molecules, this project will explore two not mutually exclusive hypotheses: (1) ADAM9 functions as a protease regulating the composition of the interphotoreceptor matrix and (2) ADAM9 functions as a cell adhesion molecule forming contacts between the photoreceptor outer segments and RPE. These hypotheses will be tested using a variety of genetically modified ADAM9 mouse models. In Aim 1 of the mentored phase, the global ADAM9 knockout mouse will be comprehensively characterized using a variety of techniques that will provide new training opportunities to the candidate. In Aim 2 of the mentored phase, the candidate will train in high-end proteomic techniques to analyze the composition of the interphotoreceptor matrix on both qualitative and quantitative levels. In the independent phase, this training will be applied to test two complementary hypotheses on the function of ADAM9 in the retina. Aim 3 will explore the hypothesis that ADAM9 proteolyzes interphotoreceptor matrix components, whereas Aim 4 will explore the hypothesis that ADAM9 functions as a cell adhesion molecule. Given that ADAM9 is expressed by both photoreceptors and the RPE, the experiments in Aim 5 will identify the cell type primarily responsible for ADAM9-associated pathology. Taken together, the proposed studies will guide future therapeutic efforts for cone-rod dystrophy patients bearing ADAM9 mutations. Additionally, given the critical roles of the interphotoreceptor matrix in supporting the integrity of the outer retina and retinal adhesion to the RPE, this proposal will provide broader insights into retinal diseases such as retinal detachment and some forms of retinitis pigmentosa. The training in experimental approaches provided by the proposed research will be supplemented with career development training at Duke University, including formal coursework, in both communication skills as well as mentoring and leadership skills. The candidate will be mentored by Dr. Vadim Arshavsky, a leader in the field of retinal cell biology and a highly accomplished mentor who has successfully launched the careers of over a dozen faculty members, most of whom are funded by the NIH. Ultimately, this training will allow the candidate to achieve his long-term goal of becoming an independent investigator studying the biology of the visual system and pathophysiology of retinal disease.