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Investigators:
Computing Team
Tarynn M. Witten, Project Director
Ford Sleeman
Gurav Rana
Daniela Puiu
Katie Youell
Biology Team
Gregory A. Buck, Director
Luiz S. Ozaki
Patricio A. Manque
Joao M. P. Alves
Myrna Serrano
Trypanosoma cruzi is a flagellate protozoan parasite,
a member of the order Kinetoplastida and of the family Trypanosomatidae.
Despite nearly 100 years of research on the T. cruzi
parasite, we still understand very little about its dynamics.
While there is a treatment for the acute stage (a highly toxic
drug), if recognized in time, there is still no treatment
for chronic Chagas’ Disease, which infects millions
of individuals worldwide. Because of its complex lifecycle,
T. cruzi provides one of the most fascinating and
complex, yet sophisticated model systems for investigating
host-parasite dynamics. These organisms also are of biological
interest since they are able to change their morphology according
to the environment where they live, through a process of reversible
cell transformation.
Therefore, new treatment strategies must be devised, and these
will very likely be derived from application of contemporary
molecular modeling strategies to develop inhibitors of novel
processes in the basic biology and pathogenesis of the parasites.
To do so will require looking at host-parasite dynamics using
new and more sophisticated tools than those that have been
employed over the past century. The experimental research
strength of the VCU microbiology group in this area provides
the necessary biological input to theoretical analysis of
the process.
Our methodology is based upon an integrated mathematical,
in silico modeling approach that is directly coupled
to biological experimentation. The initial goal of this research
is to create an extensible, portable, in silico,
multi-scale, high performance computational model of the T.
cruzi life cycle. The long-term goal is to apply novel
mathematical and computational modeling technologies, well
informed by biological experimentation, to specific host-parasite
systems in order to develop new paradigms for understanding
the infectious disease process, for the purpose of developing
new therapeutic and public health interventions and strategies.
Successful development of this project will allow potential
application of this methodology to viruses, Cryptosporidium
parvum (for which there is no treatment and which is
a potential bioterrorism agent), worms, bacteria and potentially
to larger systems.
Model development incorporates the basic Newtonian equations,
but alters the form of the T. cruzi approximation
to be cylindrical in nature and adjusts all of the fluid dynamics
equations to address the dynamics of the swimming tail, which
is used to pull the T. cruzi parasite forward in
the water rather that to push it forward as in other organisms.
The data generated by the simulation is passed to a visualizing
program that allows the user to view the motion of the T.
cruzi parasite in three dimensions. Computations take
place in a simulated laboratory environment defined by the
experimentalist. In this figure, blue spheres represent the
hypothetical mammalian cells plated on the bottom of the dish.
The T. cruzi parasites are represented by the white
spheres. The green vectors indicate the traveling direction
and the velocity of the T-cruzi. The length of the
vector is proportional to how fast it is swimming. The user
interface keeps track of all basic simulation data. An interface
allows the user to navigate through the actual simulation
and examine the simulation from any given perspective.
We intend the model will ultimately include host-parasite
proximity factors (recognition, reorientation, binding and
attachment), host-parasite transformation for invasion (signal
transduction pathway factors, membrane factors), modeling
of the physical invasion (entry) of the parasite, along with
optimization of the computational methods to adjust for the
increased complexity of the simulation. The dynamics of recognition,
orientation and attachment is little understood but highly
complex.
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