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Assessment of hIPSC- derived hepatocytes as a model to study the responsiveness losartan in vitro

Grant number: 16/20650-8
Support type:Scholarships in Brazil - Master
Effective date (Start): January 01, 2017
Effective date (End): January 20, 2019
Field of knowledge:Biological Sciences - Genetics
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Lygia da Veiga Pereira
Grantee:Raquel Delgado Sarafian
Home Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:13/08135-2 - CTC - Center for Cell-Based Therapy, AP.CEPID
Associated scholarship(s):17/26460-9 - Characterizing NADPH oxidase-dependent ROS production and redox signalling in hiPSC from normotensive and hypertensive subjects, BE.EP.MS

Abstract

A great challenge for new drugs researches is the constitution of consistent biological models which investigate their toxicity and efficiency. It is estimated that around 90% of new drugs tested into clinical trials are not approved and those who are, are effective into only 30% of individuals. This drugs interindividual variability study involves several factors and requires more knowledge of liver metabolizing substances. Hepatocytes are responsible of generating active or toxic metabolites and for substances depuration through an ezymes set from Citocromo P450 (CYPs).Is known that genes polymorphisms which encode CYPs, can influence on the answers variation about the drugs. In this sense, hepatocytes cells (hepatocyte-like cells - HLCs) derived from hiPSC can represent an important tool for drugs triage. In this study, we propose to acquire HLCs from hiPSC (human induced Pluripotent Stem Cell) from respondent patients and non respondent to Losartan, participants of Adult Health Longitudinal Study (ELSA - Brazil), and correlate CYPs genotype which were involved into drugs metabolizing with metabolizing rate by the related HLCs. These cells will be featured and treated with Losartan and its supernatants will be collected for metabolites quantification through HPLC technique. When it comes to CYPs analysis, the DNA cells will be extracted and genotyped in order to search polymorphisms into CYPs 2C9 and 3A4 which may match the observed in vivo phenotype. With this study we intend to be able to develop an in vitro model that allows us to verify the response prediction of different metabolic profiles of drugs. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
SARAFIAN, RAQUEL; MORATO-MARQUES, MARIANA; BORSOI, JULIANA; PEREIRA, LYGIA VEIGA. Monitoring cell line identity in collections of human induced pluripotent stem cells. STEM CELL RESEARCH, v. 28, p. 66-70, APR 2018. Web of Science Citations: 0.

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