RG6: Retinal Ageing and Disease
The goal of RG6 is to understand cellular homeostasis in ageing and age-related forms of retinal degeneration in search for causative mechanisms, which can then be targeted by novel therapeutic approaches. We are interested in the mechanisms underlying the most common diseases of the retina, Age-related Macular Degeneration (AMD) and diabetic retinopathy (DR) as well as inherited forms of blindness, such as Choroideremia (CHM). We integrate 3 research teams (M Seabra, P Pereira, G Silva) and the clinical directors (L Santos, R Flores) of two University-linked Hospitals in Lisbon (CHLC).
We hypothesise that dysfunction of the lysosomal and the proteostasis networks are critical for the pathogenesis of AMD. We developed cellular systems of differentiated retinal pigmented epithelium (RPE) and use various mouse models to validate cellular studies. With these, we study how lysosomal and proteostasis dysfunction may contribute to retinal degeneration, mimicking AMD features. We are also exploring fundamental mechanisms of the lysosomal and proteolytic systems in the RPE as well as intercellular communication via extra-cellular vesicles, such as exosomes, as causative factors of retinal disease. Ultimately, we aim to develop novel therapeutic approaches, including lysosomal rejuvenation and the use of engineered exosomes to restore proteostasis for AMD patients.
DR is a complication of Diabetes. We hypothesise that the Renin-Angiotensin system contributes to the aetiology of DR with the ultimate goal of devising gene-based anti-angiogenic therapies. We are also developing new regenerative tools to prevent or delay neurodegeneration that occurs at early stages of DR.
We developed mouse models of CHM and use other models of inherited retinopathies for viral (AAV) and non-viral (polymer-based) gene therapy studies. Finally, we are developing stem cell-based treatments for AMD, such as RPE transplantation.
Keywords: Retinal ageing; Age-related Macular Degeneration; Choroderemia; Proteostasis
Baptista R, Marques C, Catarino S, Enguita FJ, Costa MC, Matafome P, Zuzarte M, Castro G, Reis A, Monteiro P, Pêgo M, Pereira P, Girão H (2018) MicroRNA-424(322) as a new marker of disease progression in pulmonary arterial hypertension and its role in right ventricular hypertrophy by targeting SMURF1. Cardiovascular Research 114(1):53–64
Bitoque DB, Costa AMR, Silva GA (2018) Insights on the intracellular trafficking of PDMAEMA gene therapy vectors. Materials Science and Engineering C 93(1):277-288
Anjo S, Martins-Marques T, Pereira P, Girão H, Manadas B (2018) Elucidation of the dynamic nature of interactome networks: a practical tutorial. Journal of Proteomics 171(16):116-126
Araújo RS, Santos DF, Silva GA (2018) The role of the retinal pigment epithelium and Müller cells secretome in neovascular retinal pathologies. Biochimie (in press)
Bitoque DB, Silva GA (2018) Molecular biology tools for the study and therapy of PDE6b mutations. Journal of Biotechnology 284:1-5