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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI052348-10
Application #
8389657
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Mcgugan, Glen C
Project Start
2002-06-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
10
Fiscal Year
2013
Total Cost
$343,961
Indirect Cost
$113,637
Name
University of California Los Angeles
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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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; Vashisht, Ajay A; Malvezzi, Amaranta M et al. (2014) eIF4F-like complexes formed by cap-binding homolog TbEIF4E5 with TbEIF4G1 or TbEIF4G2 are implicated in post-transcriptional regulation in Trypanosoma brucei. RNA 20:1272-86
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
Nguyen, HoangKim T; Sandhu, Jaspreet; Langousis, Gerasimos et al. (2013) CMF22 is a broadly conserved axonemal protein and is required for propulsive motility in Trypanosoma brucei. Eukaryot Cell 12:1202-13
Freund, Jonathan B; Goetz, Jacky G; Hill, Kent L et al. (2012) Fluid flows and forces in development: functions, features and biophysical principles. Development 139:1229-45
Merveille, Anne-Christine; Davis, Erica E; Becker-Heck, Anita et al. (2011) CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs. Nat Genet 43:72-8
Ralston, Katherine S; Kisalu, Neville K; Hill, Kent L (2011) Structure-function analysis of dynein light chain 1 identifies viable motility mutants in bloodstream-form Trypanosoma brucei. Eukaryot Cell 10:884-94
Oberholzer, Michael; Langousis, Gerasimos; Nguyen, HoangKim T et al. (2011) Independent analysis of the flagellum surface and matrix proteomes provides insight into flagellum signaling in mammalian-infectious Trypanosoma brucei. Mol Cell Proteomics 10:M111.010538
Hill, Kent L (2010) Parasites in motion: flagellum-driven cell motility in African trypanosomes. Curr Opin Microbiol 13:459-65

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