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Study of gamma globin gene expression induced by pomalidomide derivatives

Grant number: 16/11283-1
Support Opportunities:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): October 03, 2016
Effective date (End): April 09, 2017
Field of knowledge:Health Sciences - Pharmacy - Medicines Analysis and Control
Principal Investigator:Jean Leandro dos Santos
Grantee:Thaís Regina Ferreira de Melo
Supervisor: Lionel Blanc
Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
Research place: Feinstein Institute for Medical Research, United States  
Associated to the scholarship:14/06755-6 - Synthesis and pharmacological evaluation of new pomalidomide derivatives to treat sickle cell disease symptoms, BP.DR


Sickle Cell Disease (SCD) is one of the most prevalent inherited blood disorders. This genetic disease is characterized by a single substitution of aminoacids (glutamic acid to valine) at the ²-globin chain leading to hemoglobin polymerization at low oxygen environment. The sickle-shaped cells have exhibited high adherence to the vascular endothelium and contribute to inflammatory panel and vaso-occlusive process. Currently, the only drug approved by Food and Drug Administration (FDA) is the hydroxyurea (HU), however, adverse effects including myelosuppression and lack of responsiveness limit its use during long-term therapy. Therefore, the discovery of new drugs as alternative to HU is urgent. It is well established that fetal hemoglobin (HbF) induction is a promising strategy in order to find new drugs able to reduce clinical severity of SCD. In this aspect, it was demonstrated that pomalidomide induce ³-globin gene expression at levels superior to that of HU without its deleterious effects. Previously, we used molecular modification tools to design new pomalidomide derivatives with ability to release nitric oxide. Beyond ³-globin gene induction, NO has been also reported to contribute with vasodilation and inhibition of platelet aggregation in SCD. Herein, we propose to evaluate the induction of HbF and ³-globin gene expression induced by these compounds and study hypothetical molecular mechanisms involved in its regulation. This study aims to open new frontiers to discovery safe and more effective drugs as alternative to the current therapy with HU. (AU)

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