SYSTEMS APPROACH TO STRESS BIOLOGY
The genetic networks that determine how an organism detects and responds to stress form
a dynamic and complex system. Exposure to stress causes a perturbation of this system
as the organism prepares a defense against its changing environment. Recent
developments in systems biology methodologies provide us with powerful tools for
extracting meaning from a variety of stress response networks.
Using C. elegans, we are studying how organisms
and their individual cell and tissue types detect and
respond to diverse stress conditions. Molecular chaperones
are critical for relieving cellular stress. Expression
of different chaperones increases in response to certain
types of environmental and physiological stress. To
define the coordinated activation of chaperone networks
under different conditions, we are using genetic, molecular,
and genomic techniques. Once an organism's genomic response
for different stress treatments is described, we can
define which elements of the chaperone network signature
become important under different situations and which
components are shared despite the imposed stress. We
also compare acute stress conditions (such as heat shock
and oxidative stress) to chronic stressors (the presence
of aggregation prone proteins-- polyglutamine proteins,
mutant SOD1, tau, and yeast prions). A primary focus
of these studies will be on how individual chaperone
network deviate from the population average phenotype
of chronic stressors, as this could have important implications
regarding variation in disease models.
In our analysis of the stress response, we are developing
new procedures to elucidate structural features of the
chaperone network. While techniques such as hierarchical
clustering are useful for identifying groups of genes
that may be associated by regulation or function, we
are also using a network approach as a means of identifying
modules of genes that are similar in their response
to various stress conditions. These studies are in collaboration
with Professor Luis Amaral (Dept. of Chemical and Biological
Engineering, Northwestern University). Professor Amaral's
website is at http://amaral.northwestern.edu.
References
- Rieger TR,
Morimoto RI, and V. Hatzimanikatis. Bistability explains
threshold phenomena in protein aggregation both in vitro
and in vivo. Biophys J. 90: 886-95 (2006).
- Rieger, T.,
R.I. Morimoto, and V. Hatzimanikatis. Mathematical Modeling
of the Eukaryotic Heat Shock Response: Dynamics of the
Hsp70 Promoter. Biophysical Journal 88: 1646-1658 (2005).
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