Hematopoiesis regulation depends, among other factors, on the action of cytoplasmic adapter proteins, such as insulin receptor substrates (IRS). Previous study conducted by our research group indicated that IRS1 and IRS2 are differentially expressed in hematological malignancies, including myelodysplastic syndromes and acute leukemias. Our group also demonstrated that IRS2 is recruited during the process of erythroid, megakaryocytic and granulocytic differentiation. However, the role of IRS1 and IRS2 in signal transduction of hematopoietic growth factor receptors and their role in hematopoietic cell differentiation and malignant transformation remains poorly explored. Thus, the present study aims to investigate the participation of IRS1 and IRS2 proteins in normal and myelodysplastic hematopoiesis using murine models and human hematopoietic stem cells. Murine Irs1 or Irs2 knockout models and animals undergoing pharmacological inhibition of Irs1/Irs2 will be used for in vivo hematopoiesis evaluation. To evaluate the effects of inhibition of these proteins on normal human hematopoietic progenitors, CD34+ cells silenced for IRS1 or IRS2 will be evaluated through functional assays including differentiation, colony formation, proliferation and apoptosis. In order to investigate the expression profile of genes involved in IRS-mediated signaling in a model of neoplasia with ineffective hematopoiesis, expression of IRS1, IRS2 and related genes will be investigated and compared between CD34+ cells from healthy donors and myelodysplastic syndrome patients, through PCR array.
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