Study the metabolism of stress regulated genes in health and disease.
The Vera Ugalde lab investigates the molecular mechanisms by which eukaryotic cells survive to adverse circumstances. Cell functionality is threatened by environmental changes that damage proteins. The universal response to the presence of denatured proteins is to repress general gene expression programs and activate a survival mechanism known as the heat shock response. The components of the heat shock response, the heat shock proteins (HSPs), are molecular chaperones with cytoprotective capabilities. They hold and refold misfolded proteins preventing their toxic aggregation and promoting their functional conformation. Once protein homeostasis and cellular functions are recovered, the stress response is specifically attenuated.
Survival of cells to stress depends on their capacity to recognize the HSP mRNAs as the only ones being translated during adverse conditions and degraded upon recovery of functional cell homeostasis. Therefore, the strength of the heat shock response should be precisely tuned by the demand of the damage and the status of the cell. Our goal is to comprehend how eukaryotic cells manage the expression of chaperones upon stress. To resolve this biological process in time and space, we monitor individual HSP mRNAs life-cycle using single molecule fluorescence microscopy technologies in fixed and live cells. We integrate the findings from the single molecule methods with physiological parameters of the cell.
The combination of these approaches will allow us to identify the modulators of the stress response and how they operate in different conditions and cell types. Hence, they will help to better understanding the etiology of diverse diseases caused by the loss of cellular homeostasis. Important examples are the stunted stress response of neurons that leads to age-related neurodegeneration and the uncontrolled production of HSPs by tumor cells that precludes therapy efficacy. Our long-term goal is to determine how this response can be therapeutically manipulated to treat cancer and neurodegenerative diseases.