Pathology and Molecular Pharmacology

Histamine receptors: signal transduction and ligand action mechanisms.
Histamine exerts multiple actions through the interaction with four specific receptors (H1-H4) that belong to the superfamily of G protein-coupled receptors (GPCR). H1 and H2 receptor antagonists/inverse agonists are widely used to treat allergies and gastric acidity, respectively, and are among the twenty most widely used over-the-counter and prescription drugs worldwide. In recent years, our laboratory has contributed on the understanding of the signaling and regulation of the response through H1 and H2 receptors to histamine. We have recently demonstrated the existence of cross-regulation at the level of these receptors induced by both their agonists and their antagonists/inverse agonists. Our next step will be to analyse the mechanisms involved, as well as their therapeutic relevance in different study models. In this way, we will provide new basis for the rational use of histaminergic agonists or antagonists in different pathologies, the development of new drugs and propose new therapeutic strategies in drug repositioning studies.

Therapeutic targets associated with the cAMP cascade in human myeloid leukaemia.
A potentially less toxic approach to improve the treatment of acute myeloid leukaemia is the so-called “differentiating therapy”. This strategy is based on the fact that neoplastic cells frequently exhibit reversible defects in the differentiation process. Therefore, an appropriate treatment may reprogram these cells, reduce their proliferative capacity and induce their maturation or death by apoptosis. We have previously shown that the balance between cAMP production, degradation and exclusion is essential for the proliferation/differentiation of leukemic cells. Different molecules participate in this regulation, such as the histamine H2 receptor, the kinase responsible for desensitizing the histamine H2 receptor GRK2, phosphodiesterases, and the cAMP transporter MRP4, among others. Thus, we are interested in evaluating the joint effect of the histamine H2 receptor activation and the pharmacological inhibition of MRP4 and/or GRK2 on cell proliferation/differentiation, in in vitro and in vivo models of human myeloid leukaemia. Although these molecular targets associated with the cAMP cascade have been deeply studied by our laboratory, and their association with the desired cell differentiation induction process has been demonstrated, to date there are no studies that allow postulating their synergistic action or the possible application of polypharmacological strategies in differentiating therapy.

In addition, we closely collaborate with different laboratories of the Molecular Pharmacology Area in ININFA-UBA-CONICET.