The role of mitochondrial DNA mutations and inflammation in adult blindness caused by diabetic retinopathy

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Diabetic retinopathy (DR) is a major cause of blindness in the working-age population for which there is no treatment. Mitochondria are cellular organelles and the site of energy production in the cell. Mitochondrial dysfunction is involved in the development of DR, we recently published the first human study showing that MtDNA changes can be detected in blood samples from DR patients and have found, using patient blood samples and animal/cell models, that diabetes can lead to elevated circulating MtDNA. As MtDNA resembles bacterial DNA it may elicit an inflammatory response via activation of the TLR9 pathway and activate inflammasomes. Recently we have discovered novel MtDNA mutations and deletions in DR patients. In the current project the student will (a) test the hypothesis that damaged MtDNA is causative of energy deficit in the retina and chronic inflammation in circulation (b) characterise the time course of mitochondrial changes associated with DR using in-vitro models and (c) Identify and test therapeutic and preventative strategies. For the rotation/year 1, the student will use human patient samples to define the incidence of MtDNA mutations in DR. These studies will be expanded further and ARPE 19 cells will be used to mimic the damage seen in the retina in hyperglycemic conditions in order to characterise the mitochondrial changes and then test a range of therapeutic strategies. The student will gain training in a range of cell biology and molecular biology techniques including tissue culture, DNA/RNA work, real time quantitative PCR, functional assays and bioenergetics.