ABSTRACT Cells are constantly subjected to a variety of intrinsic and extrinsic stresses—oxidative, protein misfolding, osmotic—that have deleterious impact on cellular structures and function. In response, eukaryotic cells activate a range of molecular pathways to mitigate and repair damage—oxidative stress response, unfolded protein response, osmotic stress response. While substantial molecular detail is known about individual stress response pathways, and some interventions improve resistance to multiple forms of stress (e.g. dietary restriction), surprisingly little is known about how cells respond differently when challenged with multiple types of stress simultaneously. The molecular architecture underlying multi-stress response is a critical knowledge gap with has broad implications for medicine. Human diseases rarely involve a single form of stress— Alzheimer’s disease is characterized by neuroinflammation, increased oxidative stress, and accumulation of misfolded proteins, while cancer exhibits oxidative stress, DNA damage, and localized hypoxia. By understanding the molecular network underlying stress response, we aim to identify specific intervention points to target distinct stress profiles. Our lab employs a novel platform for high-throughput health and survival analysis in Caenorhabditis elegans. Combining this platform with analytical tools in genetics and molecular tools for stress response (e.g. fluorescence stress response reporters), we will: (1) define the genetic network that modulates multi-stress response; (2) determine which components are activated in response to distinct stress combinations; (3) investigate mechanisms of cross-adaptation—mild exposure to one stress imparting resistance other forms of stress; and (4) identify key intervention targets to mitigate different stress combinations. Selected stress combinations, modes of cellular response, and interventions will be validated in human cell culture and mouse models. Our long-term goal is to answer key questions in the biology of stress response: How is the genetic stress response network organized? Which elements general and which are specific to distinct stress types? How does response to stress alter an organism’s resistance other types? What nodes in the stress response network that can be targeted to improve health or treat specific diseases? Here we propose to purchase a new confocal microscopy system as an Administrative Supplement to support this work.