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Effect of Smads and microRNAs in TGF-B1 gene expression and its role in angiogenesis in patients with primary myelofibrosis and essential thrombocythemia

Abstract

Angiogenesis plays an important role in primary myelofibrosis (MFP) and essential thrombocythemia (TE), wich is mainly modulated by transforming growth factor (TGF)-B1, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor. The aim of this study is to investigate the effect of the mRNA expression of the Smad family (Smad1 to Smad8/9) and microRNAs (miR-193a-5p, miR-369-5p, miR-542-5p, miR-590-5p e miR-590-3p) in gene expression (mRNA and proteins) of TGF-B1 and its role in the pathophysiology of angiogenesis in MFP and TE patients. We will study 80 patients with MFP and TE treated at Departamento de Hematologia e Oncologia of Universidade Federal de Sao Paulo - UNIFESP, matched with 160 healthy subjects by gender and age. Bone marrow samples will be obtained from 30 of 80 patients with MFP and TE for cytogenetic analysis and research of chromosomal abnormalities, determination of myelogram and bone marrow biopsy, immunohistochemical analysis (microvessel density, expression of latent and active TGF-B1 and c-MPL), analysis of mRNA expression (Smad1 to 8/9, TGFB1, VEGFA and bFGF) and microRNAs (miR-193a-5p, miR-369-5p, miR-542-5p, miR-590-5p e miR-590-3p). Analysis of mRNA expression and miRNA will also be performed in total peripheral blood leukocytes of these individuals, as well as the other 50 of 80 patients with MFP and TE and healthy subjects. We will also determine blood cells counts and ultrasensitive C-reactive protein and measurement of plasma concentrations of TGF-B1, VEGFA, bFGF in patients and healthy individuals. Genomic DNA extraction will be performed from whole blood of patients for JAK2V617F mutation screening and allele burden and evaluation of JAK2 exon 12 mutation and MPL gene W515K/L and S505N mutations. Gene expression of mRNA and microRNAs will be compared with the intensity of angiogenesis, assessed by microvessel density in patients with bone marrow biopsy available, and by plasma concentrations of TGF-B1 and VEGFA in patients with only peripheral blood available. We expect to contribute to a better understanding of the role of TGF-B1 and its interaction with VEGFA and bFGF and microRNAs in angiogenesis in the pathophysiology of MFP and TE. (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)
TEIXEIRA NUNES, DANIELA PRUDENTE; DE LIMA, LUCIENE TEREZINA; CHAUFFAILLE, MARIA DE LOURDES; MITNE-NETO, MIGUEL; DOS SANTOS, MARCOS TADEU; CLIQUET, MARCELO GIL; GUERRA-SHINOHARA, ELVIRA MARIA. CALR mutations screening in wild type JAK2(V617F) and MPLW515K/L Brazilian myeloproliferative neoplasm patients. BLOOD CELLS MOLECULES AND DISEASES, v. 55, n. 3, p. 236-240, OCT 2015. Web of Science Citations: 8.

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