Research Projects

Rational: Regenerating new neurons from endogenous stem cells is a novel effort to cure blindness resulting from death of retinal neurons either from injury or diseases such as macular degeneration, glaucoma, retinitis pigmentosa, and diabetic retinopathy1,2. As zebrafish retina exhibits remarkable regeneration3, 4 as opposed to mammals, studying the mechanisms in zebrafish can potentially suggest strategies for stimulating similar processes in mammals. Muller glia (MG), in fish and mammals, function to maintain retinal homeostasis and structural integrity5, 6. Although in response to retinal injury mammalian MG rarely proliferate5, zebrafish MG dedifferentiate and proliferate extensively to generate new neurons3, 4. Besides a plethora of MG-intrinsic factors in zebrafish7-15, recent studies have revealed that a threshold level of cell death and microglia accumulation at the site of injury is also necessary for a regenerative response to ensue16-19. Interestingly, mammalian microglia have been shown to inhibit MG-mediated neurogenesis20. However, the molecular mechanisms regulating the communication between dying neurons to MG or microglia to MG are not yet known. Novelty: Although a few previous studies has identified dying neurons and microglia to contribute to the proliferative ability of MG, those studies are merely correlative and do not provide any detailed mechanisms. The successful completion of this project would identify many novel contributors that would be indispensable for future studies in the field and also might pave the way for a successful induction of robust mammalian retina regeneration as a novel strategy to cure blindness. Objectives: 1. Identify cell death pathway components necessary for retina regeneration. 2. Investigate the impact of immune cells accumulation on MG reprogramming in the injured retina. Methods and expected outcome: By employing techniques such as scRNAseq analysis, bulk-RNAseq, pharmacological inhibition, gene knockdown, CRISPR-cas9 based gene editing and overexpression studies, here we propose to characterize the unique contributions that dying neurons and microglia make to regulate the regenerative response of MG in the injured zebrafish retina. Findings from this study might pave the way for a successful therapeutic intervention to restore vision in mammalian retina.