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Half a billion people will come down with malaria this year. Two people will die of it each minute. Most of these people will be children. The parasite is increasingly resistant to the drugs he have and all of the new drugs available are too expensive to be used by most of the worlds population. Nutrient uptake by the malaria parasite represents one of the greatest potential drug targets. There are two projects currently being worked on in the lab. The first is looking at the uptake of hemoglobin. The second project is looking at all of the Rab family of proteins and their role in regulating endocytosis/exocytosis. All of the pathology caused by the parasite is caused during its life cycle inside of the red blood cells. During this stage the parasite ingests massive amounts of hemoglobin. Digestion of hemoglobin provides the parasite with needed amino acids as well as other undefined functions. To measure hemoglobin uptake by the parasite, we have developed an assay using 3 dimensional reconstructions of serial transmission electron micrographs. Using this tool we have analyzed over 450 parasites and over 50 complete infected-Red Blood Cells. This standard data set makes it possible to investigate the effects of different treatments on the parasite to a degree of precision never before possible. Analysis of 3D reconstructions can differentiate between decreased uptake due to slower growth and decreased uptake due to altered kinetics of a process. By treating with drugs and the addition of dominant negative protein constructs we have begun to dissect the molecular players in the hemoglobin uptake pathway. Contrary to all expectations, we have shown that actin is not involved in the initial endocytic process, but is involved in the transport of the hemoglobin containing vacuoles to the parasite's food vacuole. We have shown that a specific Rab (Rab5a) localizes to the surface of the hemoglobin containing vacuoles, as seen by immuno-EM. A stably expressed dominant negative protein alters the morphology of the uptake process. This finding links the two projects in the lab. The second project in the lab involves an international collaboration to clone and identify the functions of the Rab proteins. As part of this project our Paris collaborator is knocking out and creating mutants of all of the Rabs using a rodent malaria model. Our Alabama collaborator will be doing the X-ray crystal structure of the important and interesting Rabs and we will be identifying the function and interactions of the Rabs and the yet to be discovered interacting proteins. Parasites present two very powerful reasons to study them. The first is the obvious desire to learn about them so that we can kill them. This work has the potential to save millions of people each year. The second reason to study these organisms has to do with their location on the tree of life. These parasites are among the earliest branching eukaryotes. These organisms have, through the ages, stripped themselves of everything that is not needed for their specific lifestyle. This makes them very good at a small number of processes. They have very few proteins involved in processes that are much more complex in 'higher' organisms. Thus in studying these organisms we have a window both into the early development of life, but also a very much simplified system to study the functions of humans.