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Evaluation of the mitochondrial function in human patient and mice with telomeropathies

Grant number: 16/03620-8
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): September 01, 2016
Effective date (End): June 30, 2018
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Rodrigo do Tocantins Calado de Saloma Rodrigues
Grantee:André Luiz Pinto Santos
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil


Mutations in genes involved in telomere maintenance and repair, causing excessive telomere shortening, are the molecular basis of a heterogeneous group of disorders collectively termed telomeropathies. These diseases may manifest as bone marrow failure (aplastic anemia), pulmonary fibrosis, hepatic cirrhosis, and increased risk for cancer. In order to avoid telomere attrition, certain cells express the telomerase reverse transcriptase that adds telomere repeats to the end of linear chromosomes. In murine telomerase knockout model, telomere shortening is associated with mitochondrial impairment. Telomere dysfunction activates Tp53, which suppresses Pgc1± e Pgc1-², causing mitochondrial dysfunction and impaired tissue function. Telomerase migrates to the inner mitochondria where it binds to genes that encode electron transport chain proteins. However, the mitochondrial function in human patients with telomeropathies is unknown. The aim of this study is to evaluate the mitochondrial function in patients with telomere diseases and in hypomorphic mice for the Dkc1m gene, which is crucial for telomerase activity. In cells from different tissues we will evaluate: (1) the mitochondrial DNA (mtDNA) copy number, (2) the expression of genes related to telomere biology, analysis of mitochondrial dysfunction, oxidative stress, apoptosis, senescence and p53 pathways, (3) ROS production, and (4) the the respiratory chain performance. This study may elucidate the role of dysfunctional mitochondria in the development of telomeropathies. (AU)

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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)
GUTIERREZ-RODRIGUES, FERNANDA; MUNGER, ERIC; MA, XIAOYANG; GROARKE, EMMA M.; TANG, YOUBAO; PATEL, BHAVISHA A.; CATTO, LUIZ FERNANDO B.; V. CLE, DIEGO; NIEWISCH, MARENA R.; ALVES-PAIVA, RAQUEL M.; et al. Differential diagnosis of bone marrow failure syndromes guided by machine learning. Blood, v. 141, n. 17, p. 14-pg., . (16/12799-1, 13/08135-2, 17/09428-4, 14/26379-9, 16/03620-8)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
SANTOS, André Luiz Pinto. Mitochondrial function in mice and human patients with telomere disorders. 2018. Master's Dissertation - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) Ribeirão Preto.

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