Using Drosophila Genetics and Optical Coherence Tomography to Advance RVCL Research
Retinal vasculopathy with cerebral leukoencephalopathy (RVCL) is a rare genetic disorder that manifests mainly in middle age individuals; in most patients death occurs 5 to 10 years after onset.1 The disease is caused by mutated TREX1 gene; for example a frameshift at val235 (V235fs) results in truncated protein, which may cause misregulation of oligosaccharyltransferase (OST) complex leading to immune system disbalance.2 The underlying mechanisms of disease pathogenesis are still unknown. Our lab would like to join the effort led by the RVCL Research Center at Washington University to investigate the mechanisms of RVCL by developing an innovative and efficient RVCL disease model based on Drosophila melanogaster.
In this program, we will develop and characterize various fly models related to the RVCL disease, including fly TREX1 (CG3165) knock-down and knock-out, and human TREX1 WT and V235fs mutant rescues. Fly models can significantly speed up the research in mammalian systems and help to eliminate false positive leads. These fly models are suitable for the advanced research of the RVCL disease throughout the fly lifecycle, and will provide a valuable toolbox for genetic screening of drug targets to combat the RVCL disease.
Leveraging the unmatched set of genetic and biochemical tools offered by the Drosophila models and the non-invasive in vivo OCT imaging tools developed in our group, we will establish an innovative interdisciplinary research platform to perform a series of new experiments, providing insights into conserved mechanisms on the RVCL disease and explore potential therapeutic strategies that is not feasible before. Of course, modelling human diseases in flies has its limitations; but research coordination between Drosophila and mammalian systems can intensify the RVCL cure development.