This grant addresses NEI research priorities to identify the genes involved in retinal degenerative diseases and study inflammatory eye disease. The eye is an immune privileged site where the molecular basis of local immunological mechanisms is poorly understood. We characterized a large family with severe intraocular inflammation and no systemic features. Based on a number of unique clinical features and its pattern of inheritance, it was named Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy (ADNIV). In this eye-specific, inflammatory condition, a gene defect triggers the release of intraocular cytokines that recruit inflammatory cells. Progressive disease stages lead to loss of the ERG b-wave, progressive pigmentary retinal degeneration, peripheral field loss, and eventually retinal neovascularization, retinal detachment, and glaucoma.
The specific aims of this grant are to apply advanced molecular genetic techniques to discover the causative gene for ADNIV and proteomic techniques to identify downstream cytokine signals. We will utilize a variety of genetic marker strategies to narrow the linkage interval and then test candidate genes for mutations by DNA sequencing. Eye fluid samples will be used to screen for cytokines at various stages of disease, following immunosuppression, and in comparison to other inflammatory eye diseases. Discovery of the ADNIV gene is highly significant, since there are no known genes that exclusively cause inflammatory eye disease. Moreover, the ADNIV gene and its effector cytokines may be linked to more common inflammatory eye diseases, such as diabetic retinopathy, proliferative vitreoretinopathy, and Relevance. Identifying the specific gene mutation for ADNIV will represent an important step towards understanding the basic mechanisms of eye immunology. This will allow for more targeted therapy for patients with inflammatory eye disease. The ADNIV gene will represent the first known gene with immunological effects exclusive to the eye.
ADNIV is an inherited eye disease that shares a number of features with more common eye diseases such as diabetic retinopathy, intraocular inflammation, and retinal detachment, and retinal detachment. Discovery of the gene and downstream signals in this disease will help to understand and treat these blinding diseases.
|Toral, Marcus A; Velez, Gabriel; Boudreault, Katherine et al. (2017) Structural modeling of a novel SLC38A8 mutation that causes foveal hypoplasia. Mol Genet Genomic Med 5:202-209|
|Roybal, C Nathaniel; Velez, Gabriel; Toral, Marcus A et al. (2017) Personalized Proteomics in Proliferative Vitreoretinopathy Implicate Hematopoietic Cell Recruitment and mTOR as a Therapeutic Target. Am J Ophthalmol :|
|Chin, Eric K; Almeida, David R P; Velez, Gabriel et al. (2017) OCULAR HYPERTENSION AFTER INTRAVITREAL DEXAMETHASONE (OZURDEX) SUSTAINED-RELEASE IMPLANT. Retina 37:1345-1351|
|Velez, Gabriel; Roybal, C Nathaniel; Binkley, Elaine et al. (2017) Proteomic Analysis of Elevated Intraocular Pressure with Retinal Detachment. Am J Ophthalmol Case Rep 5:107-110|
|Schaefer, Kellie A; Wu, Wen-Hsuan; Colgan, Diana F et al. (2017) Unexpected mutations after CRISPR-Cas9 editing in vivo. Nat Methods 14:547-548|
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|Schaefer, Kellie A; Toral, Marcus A; Velez, Gabriel et al. (2016) Calpain-5 Expression in the Retina Localizes to Photoreceptor Synapses. Invest Ophthalmol Vis Sci 57:2509-21|
|Cham, Abdourahman; Bansal, Mayank; Banda, Himanshu K et al. (2016) Secondary glaucoma in CAPN5-associated neovascular inflammatory vitreoretinopathy. Clin Ophthalmol 10:1187-97|
|Velez, Gabriel; Roybal, C Nathaniel; Colgan, Diana et al. (2016) Precision Medicine: Personalized Proteomics for the Diagnosis and Treatment of Idiopathic Inflammatory Disease. JAMA Ophthalmol 134:444-8|
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