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Epigenetic and microRNAs analysis in the DNA repair pathway dysregulation in non syndromic cleft lip-palate patients

Grant number: 11/23653-4
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): March 01, 2012
Effective date (End): August 31, 2017
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:Maria Rita dos Santos e Passos Bueno
Grantee:Lucas Alvizi Cruz
Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:98/14254-2 - The Human Genome Research Center, AP.CEPID
Associated scholarship(s):15/02562-1 - Identification of methylation epialleles conferring susceptibility to cleft lip and palate using patient samples and mouse models for cleft palate, BE.EP.DD


Within all congenital craniofacial malformation, Non Syndromic Cleft Lip/Palate (NS CL/P) is the most frequent, accounting for 75% of all these malformations. NS CL/Ps are result of craniofacial development errors, which is a multiple signaling molecule involved process, time and spatially dependent. Studies of NS CL/P risk factors suggest the multifactorial inheritance model for this malformation, which many at risk alleles and environmental factors play a role. Previously, we have demonstrated the deficiency and dysregulation of the DNA damage repair genetic pathway in NS CL/P stem cells in comparison to controls, using global transcriptome analysis, as well as the higher level of DNA damage in patient cells by functional experiments. Once the DNA damage repair genes downregulation is validated in NS CL/P cells, the aim of this project is to investigate the causal mechanisms responsible for the dysregulation of those genes, by epigenetic markers analysis. Our hypothesis is that there is a higher promoter methylation of regulatory genes from the pathway and the involvement of microRNAs, and to test it we will analyze the BRCA1 gene methylation profile, a key central gene in the pathway, and the global expression of microRNAs in 20 NS CL/P stem cell cultures in comparison to 20 controls. Taking the obtained data, we will propose functional validation by in vitro and in vivo models. (AU)

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Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
CRUZ, Lucas Alvizi. Genetic and epigenetic mechanisms in the aetiology of orofacial clefts. 2017. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Biociências (IBIOC/SB) São Paulo.

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