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Identification of proteins involved in Sickle Cell Retinopathy in retinas of humanized mice HbSS-Townes

Grant number: 21/10159-3
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): October 01, 2021
Effective date (End): September 30, 2023
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal researcher:Mônica Barbosa de Melo
Grantee:Ana Carolina Lima Camargo
Home Institution: Centro de Biologia Molecular e Engenharia Genética (CBMEG). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated research grant:19/18886-1 - Pathophysiological mechanisms and treatment of red blood cell abnormalities, AP.TEM

Abstract

Ophthalmologic complications are frequent in Sickle Cell Disease and include conjunctival abnormalities, Orbital Infarcts, Retinopathy, and Retinal Hemorrhage. Retinal alterations are the most important for eye morbidity in Sickle Cell Diseases, especially its proliferative form, which is the major cause of progressive loss of vision in these patients, leading to visual impairment in 10 to 20% of affected eyes. There is an inverse relationship between the severity of systemic disease and the severity of Sickle Cell Retinopathy (SCR) in HbSS homozygotes versus HbSC compound heterozygotes. Patients with sickle cell anemia have more systemic complications with multiple vaso-occlusive events and secondary organ damage. Heterozygous patients have fewer systemic complications, but they have a higher frequency and early onset of retinal neovascularization. The estimated prevalence of proliferative RF is 32.8% in hemoglobin SC disease, 14% in S-beta thalassemia and 2.6% in Sickle Cell Anemia. Proliferative Sickle Cell Retinopathy (PSCR) can occur in children, but the age group most affected by the disease is between 15 and 29 years1. Spontaneous regression of neovascularization has been reported in 20 to 60% of cases. The precise cause of neovessel formation in sickle cell disease is not fully understood, such that Retinopathy in these individuals offers an exciting study model, given its link to a systemically milder genotype, ²S²C, and the common property of regressing spontaneously.Several murine models have been developed to simulate human sickle cell disease in order to understand the complex mechanisms involved in its pathophysiology. For the study of sickle cell Retinopathy, however, the HbSS-Townes model is the most appropriate. Complete studies of in vivo imaging, electroretinogram and postmortem evaluations demonstrated the development and progression of a phenotype similar to human Retinopathy in these animals, which includes intraretinal hemorrhage, venous tortuosity, pigmentary abnormalities, increased inflammation and oxidative stress, and deficits in visual function, making it a suitable model for studying underlying mechanisms and therapies for RF. Recently, our group performed transcriptome analysis of colony-forming Endothelial Cells (EC) isolated from peripheral blood of patients with SS and SC genotypes with and without proliferative Retinopathy. The Differentially Expressed (DE) genes identified in this study play an important role in the process of vascularization and angiogenesis in PRF and also indicate that different pathways may be involved in the etiology of this complication in SS and SC hemoglobinopathies. Among the DE genes in the SS group with and without Retinopathy, the NR5A-2- Nuclear Receptor Subfamily 5 Group A Member 2 (Cr1) and the HTR1D - 5-Hydroxytryptamine Receptor 1D (Cr1) stand out. In the SC group with and without Retinopathy, the ROBO1-Roundabout guidance receptor 1 (Cr3) and SLC38A5-solute carrier family 38, member 5 (CrX) genes stand out.Given the inherent difficulties in obtaining the human retina for experimental assays, we propose the use of the HbSS-Townes mouse as a study model for the characterization of the proteins encoded by the main genes previously identified. In the course of this study, we intend to analyze the expression of the ROBO1, SLC38A5, NR5A2 and HTR1D genes in the retina of the HbSS-Townes mouse through Real-Time Polymerase Chain Reaction (qRT-PCR) and identify the corresponding proteins through immunohistochemistry and Western blot. We believe that the results obtained may contribute to a better understanding of RF pathophysiology as well as to the development of new therapeutic approaches. (AU)

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