Hill Lab
Motility and More: The Trypanosome Flagellum/Cilium
as a Host-Pathogen Interface

 

Office Phone: (310) 267-0546
Office Room: 4801A MSB
Lab Phone: (310) 206-7452
Lab Room: 4566 MSB



 

Figure 1.  African trypanosome in the bloodstream.  (enlarge )
PMT = subpellicular microtubules, PFR = paraflagellar rod, FAZ = flagellum attachment zone.


A) Scanning EM (provided by J.E. Donelson, University of Iowa)
B) Schematic of the trypanosome flagellum (Hill et al. 2000. J. Biol. Chem. 275:39369-39378.)



 

Figure 2.  Tsetse fly taking a bloodmeal.  (enlarge )



Figure provided by J.E. Donelson, University of Iowa


Research Program:  Parasites in Motion, Mechanism and Biology of Flagellar Motility in Trypanosomes

My laboratory is investigating flagellar motility in African trypanosomes (Figure 1). These protozoan parasites cause a disease that is commonly called "African Sleeping Sickness". They are transmitted to the bloodstream of their mammalian hosts through the bite of an insect vector, the tsetse fly (Figure 2). Once in the bloodstream, these highly motile, unicellular parasites burrow through the blood vessel endothelium and eventually invade the central nervous system, where they initiate a cascade of events that ultimately results in fatal sleeping sickness. The two general, long-term objectives of our research are:

1)  Provide a better understanding of the cellular and molecular biology of trypanosomes and related kinetoplastid parasites, thereby facilitating the development of more effective treatments for the diseases caused by these organisms. These parasites are the source of mortality and morbidity in several million people worldwide and current treatment regimens are antiquated, costly and ineffective.

2)  Exploit trypanosomes as a model system to investigate the function of the eukaryotic flagellum. As early diverging eukaryotes, trypanosomes have historically been a rich source for the discovery of novel biological phenomena that are subsequently found to occur in other eukaryotic organisms.


Why Study Trypanosome Flagella?

Cilia and flagella are evolutionarily-conserved organelles that protrude like small appendages from the surface of a cell. They are biological "nanomachines" that are present on most tissues of the human body and on many single-celled microbes. They perform motility, transport and sensory functions.

Flagella are required for motility of human pathogens and defects in human cilia cause a variety of fatal and debilitating diseases.

Infectious Diseases caused by pathogens that require cilia include:

African sleeping sickness,

Malaria,

Epidemic Diarrhea and

Trichomoniasis (the most common non-viral sexually transmitted disease in the world).

These pathogens are responsible for mortality and morbidity in approximately 0.5 billion people world-wide.

Heritable Human Diseases caused by cilia defects include:

Hydrocephalus,

Infertility,

Left-Right Axis Defects,

Eye Disorders,

Polycystic Kidney Disease and

Bardet-Biedle Syndrome (BBS).

Therefore, in addition to addressing fundamental questions in cell biology, our research directly impacts efforts to understand and treat infectious diseases and genetic diseases in humans.


Specific Research Projects include:

I. Cell Motility.  We have used the novel methodology of RNA-interference to generate inducible gene "knockdowns" in trypanosomes. One of the genes that we have "knocked-down" encodes a recently discovered protein that is essential for cell motility.  (See videos.)  Since trypanosomes are named for their hallmark auger-like motility ("trypanon" is Greek for auger), we have named this protein "trypanin". Ongoing studies on this project include:

  i) Determining how cell motility influences parasite development and disease pathogenesis.

 ii) Identification and characterization of other components of the trypanosome's motility apparatus.

iii) Elucidation of the mechanisms by which trypanin controls cell motility.

 iv) Characterization of trypanin-related proteins that are present in other organisms.

II. Protein Trafficking.  Formation of the eukaryotic flagellum is dependent upon an evolutionarily-conserved protein targeting process termed Intraflagellar Transport ("IFT"), in which newly synthesized proteins are delivered from the cytoplasm into the flagellum. Recent work has led to the identification of IFT motors and other components of the IFT pathway. However, a unifying explanation for how flagellar proteins are targeted to the flagellum is unknown. We have identified a set of 30 novel flagellar proteins and are using these proteins to elucidate mechanisms of protein targeting to the flagellum.

III. Additional areas of research include studies on a mammalian trypanin homologue and development of new methodologies for gene transfection and in situ gene tagging in trypanosomes. This latter project will benefit greatly from the recently completed trypanosome genome project.


Hill Lab
Desiree Baron (PhD student)
Sarah Kim (undergraduate research fellow)
Alana Lerner (undergraduate research fellow)
Bryce McLelland (Staff Research Associate)
Katy Ralston (PhD student)
Jessica Russell (PhD student)
Chris Steiger (undergraduate research fellow)
Jennifer Stevens (PhD student)

 


Funding:  Research in my laboratory is supported by the National Institutes of Health, the Beckman Foundation, the Ellison Medical Foundation, and Burroughs Wellcome Fund.



Kent L. Hill, Ph.D.
Professor
UCLA
Department of Microbiology, Immunology and Molecular Genetics
609 Charles E. Young Dr.
Los Angeles, CA 90095

4801A MSB (Office)
4566 MSB (Lab)
PH:  (310) 267–0546
FAX:  (310) 206–5231
Lab PH:  (310) 206–7452
E-mail:  kenthill@mednet.ucla.edu
Honors and Awards:

NIH Research Scholar Development Award, NIH (2000–2002)

New Scholar in Global Infectious Disease, Ellison Medical Foundation (2003–2007)

Beckman Young Investigator, Arnold and Mabel Beckman Foundation (2004–2007)

Burroughs Wellcome Fund: Investigator in the Pathogenesis of Infectious Disease Award (2008–2013)

SELECTED PUBLICATIONS