Decifrando o papel da cinase Ndr2 na vascularização induzida pela microglia na retinopatia diabética

This project is based on promising preliminary data showing that Ndr2 KO mice present vascularization defects, oxidative stress and inflammation markers and that Ndr2 kinase is expressed by endothelial and microglial cells. We also demonstrated that microglial Ndr2 expression is affected by hyperglycemic conditions, and that Ndr2 deletion facilitates inflammation mediated by microglia (FCT, PTDC 2022). Therefore, the goal of this project is to elucidate further the role of Ndr2 kinase as a new key player in microglial cells on oxidative stress-induced inflammation and neovascularization in the context of DR. This is in consonance with promoting healthy lives for all, as DR affects the quality of life (Goal 3) of working-age populations. This project will pave the way for the development of new markers able to identify patients at risk of developing DR and open innovative paths for future studies to expand the therapeutic arsenal for DR patients. By addressing the silent progression of DR and proposing innovative treatment avenues, we aim to mitigate the economic burden (Goal 8) associated with vision impairment. To validate our hypothesis, we will apply a multidisciplinary approach using cell culture (Ndr2 mutants microglial cells and endothelial cells) combined with gene-editing, biochemistry, in vivo models (subretinal injections) and molecular biology techniques to uncover the functions of Ndr2 kinase in microglia-mediated inflammation and neovascularization. 1) We also plan to decipher deeper the involvement of Ndr2 in the regulation of the metabolism of microglial cells (T1) and endothelial cells (T4) therefore demonstrating that Ndr2 plays a key role in the production of inflammation in DR. 2) We anticipate that we will unveil new and fundamental functions of Ndr2 kinase in the regulation of the cytoskeleton of microglial cells (T2) which is an essential function of microglia in the context of DR and other neurological conditions. 3) We expect to decode the regulation of the paracrine communication of microglial cells and endothelial cells which is crucial for maintaining retinal homeostasis and vascular integrity (T3, T5) Dysregulation of this communication can contribute to the pathogenesis of DR. We are confident that this study will open new avenues for future studies about the Hippo kinase Ndr2 in retinal degenerative diseases. Moreover, the data we will generate will provide a better understanding of the influence of diabetes on retinal inflammation. This project is built on the established expertise of its members in the areas of neuroinflammation, retinal dysfunction and neurodegeneration, as well as existing preliminary data, ensuring its successful outcome. 4) Finally, we will continue to be strongly engaged in outreach activities to raise awareness about the significance of diabetic retinopathy, the role of microglial cells, and the broader implications for retinal and vascular health. By integrating outreach activities into your project, you can not only advance scientific knowledge but also contribute to empowering individuals and communities to take proactive steps toward better eye health and overall well-being.