Optic nerve diseases are a major public health problem. The defining feature of several optic nerve diseases, including glaucoma and cavitary optic disc anomaly (CODA), is excavation or cupping of the head of the optic nerve. The biological pathways that lead to excavation of the optic disc in these diseases, however, are incompletely understood. Consequently, there is a critical need to clarify the biological mechanisms that lead to loss of tissue (excavation) of the optic nerve to improve our understanding of disease processes and to develop new treatments for optic nerve diseases including CODA and glaucoma. We recently discovered that mutation of the matrix metallopeptidase 19 (MMP19) gene is associated with CODA. Specifically, we discovered a 6 kb DNA sequence upstream of the MMP19 gene that is triplicated in patients with CODA. Moreover, we have proven that this sequence is an active enhancer and upregulates expression of MMP19. We have also shown that MMP19 is specifically expressed in the optic nerve head, where the abnormalities of CODA occur. Moreover, gene expression data shows that MMP19 expression is greatly increased in the optic nerves of both human patients and animals with glaucoma. Together these findings support our hypothesis that abnormal regulation of MMP19 promotes congenital excavation of the optic disc in CODA. We will test this hypothesis with the following research aims:
Aim 1 : Test glaucoma patients for MMP19 mutations. We will test a cohort of glaucoma patients for copy number variations, regulatory sequence mutations, and coding sequence mutations in MMP19 with next generation sequencing.
Aim 2 : Identify the specific enhancer element and transcription factors that regulate MMP19 expression. We will 1) identify the specific DNA sequence of the MMP19 enhancer element via mutagenesis studies and 2) isolate transcription factor(s) that bind to the MMP19 enhancer using a DNA pull down assay and mass spectrometry. This proposal will clarify mechanisms of disease in CODA and provide insights in the process of optic nerve cupping in glaucoma. These investigations may provide the foundation for future studies to develop new sight-saving therapies.
Recently we identified a defect in the matrix metalloproteinase 19 (MMP19) gene that causes cavitary optic disc anomaly (CODA), a disease of the optic nerve with similarities to glaucoma. We have proposed a series of experiments using large cohorts of glaucoma patients and human donor eye tissue to 1) determine if some fraction of glaucoma is also caused by defects in the MMP19 gene and to 2) elucidate the biological pathway by which defects in the MMP19 lead to CODA. These experiments will provide key insights into the biology of optic nerve diseases and my ultimately lay the foundation for the development of novel sight-saving interventions for CODA and glaucoma.