Age-related macular degeneration (AMD) is the most common cause of severe visual loss in the developed world, affecting more than 10 million people in the United States alone. Approximately 1 in 3 people over the age of 75 are affected to some degree. A significant fraction of this disease is genetic. In this study, we will take advantage of the fact that experienced clinicians can reliably recognize patterns of abnormal structure and function that have discoverable causes. We will couple this clinical expertise with advanced molecular and histopathologic methods to identify new AMD genes and to better understand the disease mechanisms of AMD genes that have been previously discovered.
In aim 1, we will identify novel AMD loci and locus-specific AMD phenotypes by correlating the genotypes of well-characterized AMD patients and human eye donors with their ophthalmoscopic and/or histopathologic findings.
In aim 2, we will identify new AMD-causing genes and new AMD-causing mutations in known AMD genes by using a novel implementation of pyrophosphate DNA sequencing to screen 13 known AMD genes and 37 candidate AMD genes for disease-causing variations. The entire coding sequence and proximal promoter of these genes will be sequenced in 400 AMD patients and 400 aged control individuals using a novel implementation of pyrophosphate sequencing. Variations found to be significantly skewed in patients or controls will be validated by assaying them in a second cohort of 400 AMD patients and 400 controls.
In aim 3, we will investigate the pathophysiologic mechanisms of AMD by characterizing retinal and RPE/choroid gene expression in human donor eyes with both high risk and low risk AMD genotypes. Specifically, for each of five different AMD loci, we will analyze the retinal and RPE/choroidal RNA of five human eye donors who are homozygous for the high-risk genotype and compare these results to those obtained from five donors who are homozygous for the low-risk genotype. These studies will provide new insight into the pathophysiologic mechanisms of AMD that will be valuable for the development of more specific diagnostic methods and more effective therapies.
Age-related macular degeneration (AMD) is the most common cause of blindness in the developed world and this disease is often caused by mutations in genes. In this research study we will discover new genes and new disease-causing mutations that cause AMD. We will also investigate the mechanism by which genetic mutations cause AMD so that more specific diagnostic methods and better treatments can be developed.
|Wert, Katherine J; Mahajan, Vinit B; Zhang, Lijuan et al. (2016) Neuroretinal hypoxic signaling in a new preclinical murine model for proliferative diabetic retinopathy. Signal Transduct Target Ther 1:|
|Small, Kent W; DeLuca, Adam P; Whitmore, S Scott et al. (2016) North Carolina Macular Dystrophy Is Caused by Dysregulation of the Retinal Transcription Factor PRDM13. Ophthalmology 123:9-18|
|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|
|Zheng, Andrew; Chin, Eric K; Almeida, David R P et al. (2016) COMBINED VITRECTOMY AND INTRAVITREAL DEXAMETHASONE (OZURDEX) SUSTAINED-RELEASE IMPLANT. Retina 36:2087-2092|
|Gakhar, Lokesh; Bassuk, Alexander G; Velez, Gabriel et al. (2016) Small-angle X-ray scattering of calpain-5 reveals a highly open conformation among calpains. J Struct Biol 196:309-318|
|Moshfegh, Yasmin; Velez, Gabriel; Li, Yao et al. (2016) BESTROPHIN1 mutations cause defective chloride conductance in patient stem cell-derived RPE. Hum Mol Genet 25:2672-2680|
|Sohn, Elliott H; Wang, Kai; Thompson, Stewart et al. (2015) Comparison of drusen and modifying genes in autosomal dominant radial drusen and age-related macular degeneration. Retina 35:48-57|
|Sohn, Elliott H; Jiao, Chunhua; Kaalberg, Emily et al. (2015) Allogenic iPSC-derived RPE cell transplants induce immune response in pigs: a pilot study. Sci Rep 5:11791|
|Whitmore, S Scott; Sohn, Elliott H; Chirco, Kathleen R et al. (2015) Complement activation and choriocapillaris loss in early AMD: implications for pathophysiology and therapy. Prog Retin Eye Res 45:1-29|
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