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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

  1. Prahlad, V., T. Cornelius and R.I. Morimoto, . Regulation of the Cellular Heat Shock Response in Caenorhabditis elegans by Thermosensory Neurons. Science 320: 811-814 (2008).
  2. Prahlad, V., and R.I. Morimoto. Integrating the Stress Response: Lessons for Neurodegenerative Diseases from C. elegans. Trends in Cell Biology 19: 52-61 (2009). PMID: 19112021 [PubMed - as supplied by publisher].
  3. 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).
  4. 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).
Transcriptional regulation of heat shock response
Roles of Molecular Chaperones in Protein Folding, Trafficking, and Stress Sensors in Cell Growth and Death
All Chaperome Project
Misfolded and aggregation prone proteins in neu
C elegans as a model system for analysis of stress response and diseases of protein misfolding
Small molecule screen for the stress response
Systems Approach to Stress Biology