Stress response networks in organismal proteostasis

Stress response pathways are essential for cellular and organismal survival following exposures to acute environmental and physiological changes, and important for modulating protein quality control systems during development and aging. Failure of stress response and protein quality control systems may underlie the mechanism of aging and pathologies of late-onset neurodegenerative diseases such as Huntington’s and Alzheimer’s diseases in which the mutant proteins are highly prone to aggregation. Evidence from our laboratory and others now indicates that multiple stress transcription factors are involved in sensing and transmitting the stress signal between tissues to restore organismal proteostasis during aging and upon challenges of metastable proteins. Here, I propose to use C elegans to characterize the cell-autonomous and cell-non autonomous properties of the integrated stress transcription network and determine its functions in longevity and organismal proteostasis. We will focus on the four evolutionarily conserved transcription factors, HSF-1, SKN-1/Nrf2, DAF-16/FOXO, PHA-4/FOXA and perform unbiased genome-wide transcription analyses in different tissue types and at different stages of development and aging to elucidate the mechanisms of tissue sensing for proteotoxic protection.