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Investigation of mitochondrial metabolism in the biology of myelodysplastic syndrome

Grant number: 23/09514-9
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): December 01, 2023
Effective date (End): September 30, 2027
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Fabíola Traina
Grantee:Manuela Albuquerque de Melo
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Myelodysplastic syndrome (MDS) is a heterogeneous group of hematological malignancies characterized by ineffective hematopoiesis, cytopenias and risk of progression to acute myeloid leukemia, which mainly affects the elderly population. Mitochondrial dysfunction and stem cell exhaustion are two features of aging commonly found in MDS. Clonal hematopoiesis is perpetuated by inflammation and is involved in the development and progression of MDS. Recently, it was identified that metformin suppresses the growth clonal hematopoiesis. However, the contribution of mitochondrial metabolism to the pathophysiology, cell survival and management of patients with MDS has yet to be investigated. The aims of this study is to investigate and compare the mitochondrial metabolism, the transcriptomic and the protein inflammatory profile, and the presence of mutations in genes related to clonal hematopoiesis, and finally, to evaluate the effect of mitochondrial complex inhibitors on the clonogenicity of myelodysplastic cells. Bone marrow cells from patients with MDS will be submitted to exome to investigate mutations in genes related to clonal hematopoiesis and myeloid neoplasms, RNAseq for transcriptomic evaluation, immunoassay for evaluation of inflammatory cytokines, evaluation of mitochondrial metabolism in total bone marrow cells and in different compartments of hematopoiesis: tumor, innate and adaptive immune microenvironment. The effects of ex vivo treatment with electron transport chain inhibitors on the myelodysplastic cells will be evaluated using clonogenic assay. Bioinformatics analyzes for the omics data and statistical analyzes will be performed as appropriate.

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