Glucocorticoids (GCs) have been widely used as a therapeutic agent for diverse inflammatory ocular diseases. However, a high percentage of patients undergoing this treatment develop high intraocular pressure (IOP), which if left unsupervised may lead to glaucoma. It is believed that the IOP elevation in response to GC treatment has a genetic determinant. In order to test this hypothesis, we analyzed in 52 patients the presence of single nucleotide polymorphisms (SNPs) in the glucocorticoid receptor gene (GR), the principal mediator of GCs uptake by the cells. We studied six GR SNPs previously reported to be associated with sensitivity and resistance to GCs: GluArg22/23GluLys (codon 22-23), Asn363Ser (codon 363), IVS2+646C>G (intron 2/BclI), IVS3-46G>C (intron 3), IVS4-16G>T (intron 4), Asn766Asn (Codon 766). Nevertheless, the results of this preliminary study did not show any specific correlation between SNPs in the GR gene and IOP elevation. Therefore, we proceeded to perform a whole genome SNP screen with the DNA samples of these patients to search for possible target genes responsible for the elevated IOP after GC treatment. As a result, we identified forty-eight SNPs in thirty-three genes that correlate with the high IOP response. The gene showing the strongest association is a poorly known G-protein coupled receptor. In addition, four SNPs hit a single transporter gene. Other candidate genes identified are a translation elongation factor, an F-box protein, an oxysterol binding protein, and a solute carrier family gene. These results support our hypothesis that IOP elevation following GC treatment is a genetically determined response. GCs are a common treatment for innumerable medical conditions; we believe that a genetic association between GC treatment and its physiological response may be important for improving treatment management and drug development for retinal diseases as well as for other medical ailments. However, further studies need to be performed to analyze in depth the association between the candidate genes identified in this study and the steroid response.

Submitted by Marlene Santos (marlene.bc.ufg@gmail.com) on 2018-07-11T17:48:42Z No. of bitstreams: 2 Tese - Luciano de Sousa Pereira - 2017.pdf: 2889362 bytes, checksum: cfbc7fe755a68223cf99e2cd3795be90 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2018-07-12T11:26:01Z (GMT) No. of bitstreams: 2 Tese - Luciano de Sousa Pereira - 2017.pdf: 2889362 bytes, checksum: cfbc7fe755a68223cf99e2cd3795be90 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2018-07-12T11:26:01Z (GMT). No. of bitstreams: 2 Tese - Luciano de Sousa Pereira - 2017.pdf: 2889362 bytes, checksum: cfbc7fe755a68223cf99e2cd3795be90 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2017-03-14 / Non-arteritic anterior ischemic optic neuropathy (NAION) is the most common acute optic neuropathy in patients over fifty years of age. Management centers around prevention of second eye involvement, without uniformly accepted therapeutic intervention for the involved eye. Several researchers have assessed the benefit of steroids with conflicting results. Animal models based on selective photothrombosis of the microcirculation within the optic nerve head have contributed both to a better understanding of pathophysiological mechanisms associated to NAION; also, it has enabled the testing of potential therapeutic approaches. This study was deisigned to evaluate the efficacy of a single intravitreal triamcinolone acetonide injection (IVTA) in preserving retinal ganglion cells (RGCs) in a rodent model of anterior ischemic optic neuropathy (rNAION). Rodent NAION (rNAION) was induced in female Wistar rats. Animals were randomized into three groups: 1) untreated, 2) treated with 56 μg IVTA, and 3) treated with placebo (intravitreal saline). Procedures were performed in the left eye, with the right eye serving as an internal control. After 30 days, animals were sacrificed and eyes were assessed histologically for RGC number. The average number of RGCs was significantly higher in the control group when compared to rNAION subgroups (p < 0.001). No significant difference was seen between rNAION eyes treated with IVTA, placebo, and untreated eyes (P > 0.05%). In this rodent model for NAION, no therapeutic benefit of intravitreal steroid injection was identified. / A neuropatia óptica isquêmica anterior não-arterítica (NOIA-NA) é a neuropatia óptica aguda mais frequente após os 50 anos de idade. Atualmente, a conduta é centrada na prevenção do acometimento do segundo olho, não havendo, ainda, consenso referente à intervenção terapêutica para o olho acometido. Muitos pesquisadores avaliaram o benefício dos corticosteroides na NOIA-NA, com resultados controversos. Modelos animais baseados na fototrombose seletiva da microcirculação da cabeça do nervo óptico têm contribuído tanto para um maior conhecimento dos mecanismos fisiopatológicos associados a NOIA-NA, quanto para a identificação de potenciais abordagens terapêuticas. O objetivo desse estudo foi avaliar a eficácia da triancinolona intravítrea (TAIV) na preservação das células ganglionares da retina (CGRs) em um modelo animal de NOIA-NA em ratos (rNOIA). A rNOIA foi induzida em 30 ratas da linhagem Wistar. Os animais foram aleatoriamente selecionados em 3 grupos: 1) rNOIA não tratado, 2) rNOIA tratado com 5,6 μg de TAIV, 3) rNOIA tratado com placebo (solução salina intravítrea). Os procedimentos foram realizados no olho esquerdo de cada animal; o olho direito serviu como controle interno. Os tratamentos foram realizados dentro dos primeiros 15 minutos após a indução da rNOIA. Trinta dias após o experimento, os animais foram sacrificados e os olhos foram avaliados histologicamente para contagem e comparação do número de CGRs. A média do número de CGRs foi significamente menor nos subgrupos de rNOIA quando comparados ao grupo controle (p < 0,001). Não foi encontrada diferença estatística entre olhos com rNOIA tratados com TAIV, placebo e não tratados (p > 0,05). Neste modelo animal, a triancinolona intravítrea não se mostrou eficaz na preservação do número de células ganglionares da retina.