Mechanisms of development of liver cirrhosis by CCl4 and schistosomiasis in Tert-/- knockout and DKC1m hypomorphic transgenic mice

• Grant number: 11/18313-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: January 01, 2012
• End date: December 31, 2015
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Rodrigo do Tocantins Calado de Saloma Rodrigues
• Grantee: Raquel de Melo Alves Paiva
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated scholarship(s): 12/00449-5 - Mechanisms of development of liver cirrhosis by CCl4 and schistosomiasis in Tert-/- knockout transgenic mice, BE.EP.PD

Abstract

Telomeres are the ends of linear chromosomes end protect them from degradation and recombination. When a cell divides, telomeres are shortened, but to avoid telomere attrtion, germ-line and some somatic cells express telomerase, an enzyme that elongates telomeres. Telomerase complex is composed of a reverse transcriptase enzyme, TERT, an RNA component, encoded by TERC, and associated proteins, including the dyskerin, encoded by DKC1 gene. DKC1 mutations are etiologic in X-linked form of dyskeratosis congenita, causing aplastic anemia associated with ectodermal dysplasia, pulmonary fibrosis, and cirrhosis. Telomere shortening impairs hepatic regeneration in telomerase knockout mice and is associated to hepatic fibrosis development in humans. This work aims to evaluate the susceptibility to the development of cirrhosis in wild type, Tert-/- knock-out and Dkc1m hypomorphic transgenic mice, and the contribution of the different cell types affected by telomerase deficiency to the pathologic process. Liver injury will be induced by two agents: (1) Carbon tetrachloride (CCl4) and (2) Schistosoma mansoni. Inflammation will be evaluated by cytokine quantification in animals blood serum. Hepatic proteins will be assayed from tissue fragments from the different experimental groups. Gene expression of DNA repair pathways, apoptosis, and inflammatory cytokines will be evaluated by microarray. Results may help to clarify how telomere erosion can contribute to liver cirrhosis.

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)

ALVES-PAIVA, RAQUEL M.; KAJIGAYA, SACHIKO; FENG, XINGMIN; CHEN, JICHUN; DESIERTO, MARIE; WONG, SUSAN; TOWNSLEY, DANIELLE M.; DONAIRES, FLAVIA S.; BERTOLA, ADELINE; GAO, BIN; et al. Telomerase enzyme deficiency promotes metabolic dysfunction in murine hepatocytes upon dietary stress. LIVER INTERNATIONAL, v. 38, n. 1, p. 144-154, JAN 2018. (13/08135-2, 11/18313-0, 12/00449-5)

DE ALMEIDA, LUCIANA YAMAMOTO; PEREIRA-MARTINS, DIEGO A.; WEINHAEUSER, ISABEL; ORTIZ, CESAR; CANDIDO, LARISSA A.; LANGE, ANA PAULA; DE ABREU, NAYARA F.; MENDONZA, SILVIA E. S.; DE DEUS WAGATSUMA, VIRGINIA M.; DO NASCIMENTO, MARIANE C.; et al. The Combination of Gefitinib With ATRA and ATO Induces Myeloid Differentiation in Acute Promyelocytic Leukemia Resistant Cells. FRONTIERS IN ONCOLOGY, v. 11, SEP 28 2021. (17/00775-3, 16/17521-1, 10/16966-3, 15/09228-0, 17/23117-1, 13/08135-2, 13/11817-8, 11/18313-0, 11/17111-4, 16/02713-2, 17/08430-5)