A few years ago we discovered a novel organelle in trypanosomes that we named the acidocalcisome. This organelle is present in several trypanosomatids (T. cruzi, T. brucei, Leishmania spp.) and apicomplexan parasites (T. gondii, P. falciparum). The discovery of novel enzymes in this organelle that are absent from mammalian cells led to the finding of compounds (bisphosphonates) that produced radical cures in animal models of diseases caused by several parasites. We have recently identified the presence of a contractile vacuole complex in T. cruzi and we have demonstrated that acidocalcisomes of T. cruzi are involved, through their association with this contractile vacuole, in osmoregulation. T. cruzi possess a robust regulatory volume decrease mechanism that completely reverses cell swelling when submitted to hypo- osmotic stress. The efflux of amino acids and K+ release could account for only part of this volume reversal. Swelling of acidocalcisomes together with a microtubule and cyclic AMP-mediated translocation of an aquaporin to the contractile vacuole and the resulting water movement are responsible for the volume reversal not accounted for by efflux of osmolytes. Osmoregulation is essential for T. cruzi since the parasite is in contact with a variety of osmotic stresses during its life cycle. We propose that further exploration of the osmo-regulatory mechanisms in T. cruzi, and the role of the acidocalcisome and the contractile vacuole complex in these mechanisms, will lead to the identification of further targets for drug action. In this project we will have the following specific aims:
Specific aim 1 : To identify the signaling pathways involved in sensing osmotic changes in T. cruzi.
Specific aim 2 : To identify the molecular mechanism involved in the traffic T. cruzi aquaporin to the contractile vacuole complex and the role of aquaporin in regulatory volume decrease. ? ? ?
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