Structural and Proteomic Insights into the Pathogenesis of Intraocular Inflammation

DNA is the genetic material in all cells of the body. The DNA sequence contains all the information needed to produce proteins, which are the molecules that carry out the functions of the cell. The amino acid sequence of proteins, which is encoded by the DNA sequence, dictates their structure and function. Changes to the DNA sequence (i.e. genetic mutations) can alter how proteins are produced, altering their function, and in some cases, leading to disease.

These genetic mutations can be passed onto subsequent generations, resulting in what is known as a genetic disorder or inherited disease. Proteomics refers to the large-scale detection of proteins, metabolites, and modifications within a biologic sample. The ability to measure multiple proteins can enhance our power to correctly diagnose or determine the ideal therapeutic regimen for a complex disease. Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy (ADNIV) is a rare inherited inflammatory eye disease caused by mutations in the CAPN5 gene. The CAPN5 gene encodes a protease known as Calpain-5 (CAPN5). Proteases are proteins that break down (i.e. cut) other proteins to regulate their function. Mutations in CAPN5 are believed to alter the protease’s function, leading to chronic retinal inflammation that culminates in blindness.

To understand how CAPN5 mutations lead to disease, I conducted studies which focus on the CAPN5 protein structure and how ADNIV mutations alter the protein’s function. Using proteomics, I determined which proteins are changed in ADNIV patient vitreous and identified approved drugs which could be repurposed to manage the disease. The findings in this thesis should inform scientists and clinicians on how to better treat ADNIV patients.