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"demethylation of specific tumor suppressor in medulloblastoma using dCas9-Tet1 system"

Grant number: 18/05401-7
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): June 01, 2018
Effective date (End): May 31, 2020
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Luiz Gonzaga Tone
Grantee:Karina Bezerra Salomão Xavier
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:14/20341-0 - Interactions between emerging therapeutic targets and developmental pathways associated with tumorigenesis: emphasis on pediatric malignancies, AP.TEM

Abstract

Medulloblastoma is the most commom tumor in the childhood. This tumor originates from cerebellum, and it is classified as an embryonic tumor. Biology of MB is intrinsically associated with deregulation of signaling pathways that control embryonic development of cerebellum. Therefore, the identification of alterations in molecular mechanisms could result in less toxicity and decrease of side effects due to the treatment. Epigenetic mechanisms have been also described as responsible for signaling pathways control. Negative regulators of these pathways are reported as hypermethylated in MB. In this tumor, the application of DNMT inhibitor to demethylate the genome brought on antitumorigenic effects. However, this approach is non-specific and could generate genomic instability and oncogenes activation, leading to adverse consequences for patients. Recently, it was developed the tool dCas9-Tet1, based in the fusion of Tet1 with a catalytically inactive Cas9 (dCas9). This fusion protein directed by single guide RNAs allows investigating function of DNA methylation gene-specific. Thus, a higher degree of specificity could be achieved, resulting in a therapy against cancer-specific modification patterns. The present project proposes to use dCas-9-Tet1 to demethylate specific tumor suppressor related to development pathways in MB, and to verify molecular and functional effects of this DNA epigenetic edition. The target genes will be selected based in association with one or more signaling pathways, using detection of expression module. The control by methylation, prognosis value and therapeutic potencial will be also used as selection criteria.