We are biologists that use molecular approaches to investigate basic processes and explore applications of our discoveries. We focus on the heat shock response, a stress response that is critical for normal cell growth and also associated with a number of human diseases. We use the small roundworm, C. elegans, as a discovery tool and cultured human cell lines to validate and extend our findings.
The heat shock response (HSR) is a universal stress response that activates the HSF1 transcription factor and induces a cytoprotective transcriptional program. The HSR is activated by temperatures increases and other stress that cause protein misfolding. The central role of protein folding in the cell explains the requirement for the HSR during normal growth, aging and development.
We have completed a genome-wide screen to identify new regulators of the heat shock response. Unexpectedly, these regulators act in a tissue-specific manner, even when they are broadly expressed. Together, our data reveal that each tissue mounts a unique response to a uniform stress. We are now exploring the basis of this specificity and its connection to organismal physiology and disease.
We are also investigating applications of our basic discoveries. HSF1 is associated with numerous protein misfolding diseases, including Alzheimer's disease. There is strong evidence that artificial activation of HSF1 could be a beneficial therapeutic approach for some of these diseases. We are now investigating the role of our new HSR regulators in various neurodegenerative disease models.
We are also exploring the connection between the HSR and cancer. As many as 80% of women with invasive breast cancer have abnormally high levels of HSF1, and the women with the highest levels have the worst clinical outcomes. Many other types of cancer are also associated with increase levels or activity of HSF1. However, the mechanisms used by cancer cells to dysregulate HSF1 are poorly understood. Excitingly, mice lacking HSF1 are remarkably resistant to carcinogenesis, which raises the possibility that these findings can be applied towards the discovery of new anticancer therapeutics.
The heat shock response (HSR) is a universal stress response that activates the HSF1 transcription factor and induces a cytoprotective transcriptional program. The HSR is activated by temperatures increases and other stress that cause protein misfolding. The central role of protein folding in the cell explains the requirement for the HSR during normal growth, aging and development.
We have completed a genome-wide screen to identify new regulators of the heat shock response. Unexpectedly, these regulators act in a tissue-specific manner, even when they are broadly expressed. Together, our data reveal that each tissue mounts a unique response to a uniform stress. We are now exploring the basis of this specificity and its connection to organismal physiology and disease.
We are also investigating applications of our basic discoveries. HSF1 is associated with numerous protein misfolding diseases, including Alzheimer's disease. There is strong evidence that artificial activation of HSF1 could be a beneficial therapeutic approach for some of these diseases. We are now investigating the role of our new HSR regulators in various neurodegenerative disease models.
We are also exploring the connection between the HSR and cancer. As many as 80% of women with invasive breast cancer have abnormally high levels of HSF1, and the women with the highest levels have the worst clinical outcomes. Many other types of cancer are also associated with increase levels or activity of HSF1. However, the mechanisms used by cancer cells to dysregulate HSF1 are poorly understood. Excitingly, mice lacking HSF1 are remarkably resistant to carcinogenesis, which raises the possibility that these findings can be applied towards the discovery of new anticancer therapeutics.