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Evaluation of metabolic and gene expression profiles of hepatocytes obtained from induced pluripotent stem cells (iPSC) from human patients with telomeropathies

Grant number: 15/15225-3
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): November 01, 2015
Effective date (End): October 31, 2018
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal researcher:Rodrigo do Tocantins Calado De Saloma Rodrigues
Grantee:Lílian Figueiredo Moreira
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:13/08135-2 - CTC - Center for Cell-Based Therapy, AP.CEPID


Telomeres are nucleotides repetitive sequences (in mammals, TTAGGGn) coated by a specialized protein complex known as shelterins. Usually, the telomere length is maintained by the telomerase, containing the reverse transcriptase enzyme (TERT) and the RNA template (TERC), as well as associating proteins such as the dyskerin (encoded by DKC1 gene). Mutations in genes associated with telomeres maintenance induce several diseases (called telomeropathies), that can affect the bone marrow, lung and liver. Considering the liver disease, these mutations would accelerate the telomere shortening and impair the regenerative capacity of hepatocytes, inducing the cirrhosis. Data from our group demonstrated that mice with mutations in Tert showed hepatic disease as consequence of metabolic alterations. Several studies showed that the physiopathology of human telomeropathies can be understood by reprogramming of somatic cells from patient into induced pluripotent stem cells (iPSC). The self-renewing of these cells provides abundant material for studies of tissue metabolism and molecular mechanisms of diseases. In this context, based on data obtained from our group in murine model, this project aims to translate these findings to human disease and to evaluate and compare the metabolic profile of hepatocytes obtained from iPSC from patients with mutations and from healthy individuals; and to evaluate and compare the gene expression profile and specific pathways involved on hepatic metabolism. This study may provide a better understanding of cellular and molecular mechanisms that the telomerase deficiency or in proteins associated with telomeres and the telomere shortening can promote the hepatic disease.