African trypanosomes (e.g. Trypanosoma brucei) are protozoan parasites that cause African sleeping sickness, a fatal disease with devastating health and economic impact. These parasites are digenetic organisms, spending part of their life cycle in a mammalian host and part in an insect vector (the tsetse fly). Trypanosomes are highly motile in both life cycle stages and motility is central to parasite development and disease pathogenesis. Motility is mediated by a single flagellum that is an essential and multifunctional organelle with critical roles in cell motility, host-parasite interaction, cell morphogenesis and cell division. Surprisingly, we know very little about the flagellar apparatus at the molecular level. In particular, we lack an understanding of how flagellar proteins are assembled into supramolecular structures within the axoneme and how they function individually and collectively to drive cell motility and other flagellum functions. The long-term goal of the proposed research is to advance our understanding of the trypanosome flagellum and to exploit trypanosomes as a model to investigate the eukaryotic cilium. This will be done using a combination of functional and structural approaches. RNAi, site-directed mutagenesis and ultrastructural analyses will be used to investigate the function of trypanin and other components of the dynein regulatory complex (DRC). The DRC is part of a signal transduction pathway that regulates flagellar motility and is essential in bloodstream-form trypanosomes, making it a candidate drug target. The trypanosome flagellum is analogous to cilia and flagella in other eukaryotes, including humans. Flagella are required for motility of several human pathogens and are present on most tissues of the human body. They perform motility, transport and sensory functions. Infectious diseases caused by pathogens that require cilia include African sleeping sickness and Malaria. Together, these diseases are responsible for mortality and morbidity in approximately 0.4 billion people world-wide. Heritable human diseases caused by cilia defects include: hydrocephalus, infertility, epilepsy, left-right axis defects, eye disorders, polycystic kidney disease and obesity. Therefore, in addition to addressing fundamental questions in cell biology, this research directly impacts efforts to understand and treat infectious diseases and genetic diseases in humans.
African trypanosomes are protozoan parasites that cause African sleeping sickness, a fatal disease with devastating health and economic impact. The trypanosome flagellum is essential for viability and is central to parasite development and disease pathogenesis. Therefore, this research will directly impact efforts to understand and treat infectious human disease.
|Shimogawa, Michelle M; Ray, Sunayan S; Kisalu, Neville et al. (2018) Parasite motility is critical for virulence of African trypanosomes. Sci Rep 8:9122|
|Langousis, Gerasimos; Shimogawa, Michelle M; Saada, Edwin A et al. (2016) Loss of the BBSome perturbs endocytic trafficking and disrupts virulence of Trypanosoma brucei. Proc Natl Acad Sci U S A 113:632-7|
|Marti, Matthias; Hill, Kent L (2016) Sensing and signaling in parasitism. Mol Biochem Parasitol 208:1|
|Oberholzer, Michael; Saada, Edwin A; Hill, Kent L (2015) Cyclic AMP Regulates Social Behavior in African Trypanosomes. MBio 6:e01954-14|
|Saada, Edwin A; DeMarco, Stephanie F; Shimogawa, Michelle M et al. (2015) ""With a Little Help from My Friends""-Social Motility in Trypanosoma brucei. PLoS Pathog 11:e1005272|
|Shimogawa, Michelle M; Saada, Edwin A; Vashisht, Ajay A et al. (2015) Cell Surface Proteomics Provides Insight into Stage-Specific Remodeling of the Host-Parasite Interface in Trypanosoma brucei. Mol Cell Proteomics 14:1977-88|
|Lopez, Miguel A; Saada, Edwin A; Hill, Kent L (2015) Insect stage-specific adenylate cyclases regulate social motility in African trypanosomes. Eukaryot Cell 14:104-12|
|Kisalu, Neville K; Langousis, Gerasimos; Bentolila, Laurent A et al. (2014) Mouse infection and pathogenesis by Trypanosoma brucei motility mutants. Cell Microbiol 16:912-24|
|Saada, Edwin A; Kabututu, Z Pius; Lopez, Miguel et al. (2014) Insect stage-specific receptor adenylate cyclases are localized to distinct subdomains of the Trypanosoma brucei Flagellar membrane. Eukaryot Cell 13:1064-76|
|Freire, Eden R; Malvezzi, Amaranta M; Vashisht, Ajay A et al. (2014) Trypanosoma brucei translation initiation factor homolog EIF4E6 forms a tripartite cytosolic complex with EIF4G5 and a capping enzyme homolog. Eukaryot Cell 13:896-908|
Showing the most recent 10 out of 34 publications