The long term goal of our laboratory is that of elucidating the basic biological mechanisms that control the cell cycle of Plasmodia and their capacity to invade mammalian cells aiming to provide support to the development of novel diagnostic and clinical applications in malaria. This disease affects 250-500 million people annually and it is undergoing a devastating resurgence.
The main focus of the laboratory is unravel the mechanisms used by malaria parasites to transduce environmental signals into the control of its cell cycle. In particular we aim at discovering how during the parasite cell cycle, signaling by external signals affects and shapes changes in gene transcription and the activity of the ubiquitin- proteasome system (UPS). We use heterologous transfections to dissect the signaling pathways activated by host-pathogen interactions and to understand the role of different parasite genes in Plasmodium invasiveness. Currently, we still do not know the function of about 2,500 genes (i.e., 50 % of Plasmodium Genome).
Our laboratory has developed a number of tools to study the dynamics of Ca2+ changes in live malaria parasites inside host cells. We have discovered that the IP3/calcium signaling pathway regulates different aspects of parasite biology; a key regulator of Plasmodium IP3-Ca2+ signaling is represented by the host hormone melatonin. We have identified a knock-out strain, Plasmodium kinase 7 (PfPK7), that has lost the ability to respond to melatonin, opening the way to unravel at the molecular level the signalling pathways that control the parasite cell-cycle.
A large number of cellular processes in eukaryotes such as fertilization, contraction, hormone and fluid secretion rely on Ca2+ signaling. The concentration of Ca2+ in the medium surrounding the cells is, in multicellular organisms, about 10,000 times higher (2mM) than in the cytoplasm (100 nM). This large concentration gradient is essential to allow Ca2+ influx through plasma membrane channels and to maintain a high Ca2+ content within intracellular stores (primarily the endoplasmic reticulum). This situation is also similar for plasmodia when they are in the blood stream of the host. We discovered that once the Plasmodium parasite infects the RBC, it creates around itself a microenvironment, rich in Ca2+, that is necessary to fully exploit the Ca2+ signalling pathway. To achieve our goals, we combine work on live cell microscopy in conjunction with molecular biology techniques. Our laboratory is also set up for the screening of chemical compounds focusing on the development of new drugs to treat malaria.
Prof. Célia Regina da Silva Garcia