Apicomplexan parasites have specialized cell cycles that are distinct from their human host. Unlike animal cell division, which results from fission of the mother into two daughters, new Apicomplexa parasites follow flexible, division schemes that assemble numerous daughter parasites in a complex budding process that consumes the mother cell. Understanding the molecular basis of this unusual parasite cell cycle is desirable for the potential new therapies this knowledge will yield. Studies of Toxoplasma gondii tachyzoite replication have defined the major cell cycle divisions and established the basic steps of cytoskeletal assembly required to produce infectious parasites. Tachyzoites are a proven model for cell cycle investigations in the Apicomplexa as they undergo simple binary division with a single round of chromosome replication followed by concurrent mitosis and parasite budding. With the major morphogenic steps of tachyzoite growth defined, we can now unravel the molecular basis of their regulation in the context of basic cell cycle mechanisms. In this application, we will exploit robust Toxoplasma genetic models to characterize centrosome-based regulation of the parasite cell cycle. We hypothesize that the centrosome is the central organelle coordinating conserved features of eukaryotic cell cycle control with the parasite specific process of assembling the specialized invasion competent zoite cell required for transmission. To understand the molecular basis of the centrosome and budding cycles, we propose two aims.
In aim 1 we will decipher centrosome biogenesis and the role of key structural proteins in the initiation of parasite budding.
In aim 2, we will characterize cell cycl kinases that operate through the centrosome and associated structures to control cytokinesis and mitosis. The proposed experiments will expand our knowledge of how the apicomplexan cell cycle is regulated. The two aims represent complimentary approaches where the development of a structural framework for centrosome biogenesis will provide the cell cycle context for understanding protein kinase regulation of the centrosome and internal budding cycles. This project has the potential to discover new factors required for parasite growth that may be exploited in the future to develop new strategies for therapeutic intervention.
Protozoa of the phylum Apicomplexa multiply by diverse processes within a wide variety of animal cells. Repeated cycles of parasite invasion, replication and host cell lysis can lead to significant damage or death if not countered by an effective host defense. A greater understanding of the mechanisms that control parasite growth is important as the most effective treatments of apicomplexan disease are able to reduce parasite infection burden. Current drug treatments are under significant pressure from drug resistance that shortens the lifespan of almost all clinical treatments. Therefore, a robust pipeline of anti-growt targets is vital to replace failing therapies.
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