Investigating the retinal proteome in myopia signaling pathways using experimentally induced mouse myopia

Abstract

Myopia (short-sightedness) has become the leading cause of vision impairment, with epidemic prevalence, particularly in Asia. Its severity can progress to high myopia, the second most common cause of blindness. This thesis developed and optimized techniques for precise biometric measurements of refraction, vitreous chamber deepening, and axial elongation in minus lens-induced mice eyes, mimicking established animal models such as chicks and guinea pigs. We investigated the role of the proteome in the myopia signaling pathway using experimentally induced myopia mouse models, focusing on the involvement of proteins in tight junction, HIF-1, cAMP, AMPK signaling pathways, and dopaminergic synapses. Various advanced mass spectrometry techniques optimized for retinal tissues were employed, including isobaric tags, data-dependent acquisition, data-independent acquisition, and multiple reaction monitoring acquisition. This thesis presents the largest retinal-specific spectral library, consisting of 9401 proteins. Our findings revealed dysregulation of retinal Glut1 protein expression during myopia progression and identified the PPAR gamma agonist rosiglitazone as a novel therapeutic agent that regulates insulin sensitivity to slow myopia progression. Additionally, we examined optical defocus-mediated differential protein phosphorylation in early myopia and hyperopia development in chick retinas. The post-translational modifications (PTMs) revealed key bidirectional changes in retinal rhodopsin, violet-sensitive opsin, and blue-sensitive opsin in response to myopic and hyperopic defocus. Kinase enrichment analysis highlighted the dysregulation of protein kinases PDHK1, PDHK4, CDK, CDK10, CLK3, and MTOR, emphasizing their unexplored roles in PTMs related to myopia pathogenesis. In summary, this thesis presents a comprehensive investigation into the proteomic mechanisms of myopia, offering novel insights into the molecular pathways involved in myopia development and identifying potential therapeutic targets. The findings on animal models of myopia, retinal proteome, protein phosphorylation, and drug discovery warrant further research into myopia and emmetropization.