ABSTRACTThe goal of the work outlined in this proposal is to understand the fundamental biology of cellular response todifferent forms and combinations of stress. Cells are constantly subjected to a variety of intrinsic and extrinsicstressesoxidative protein misfolding osmoticthat have deleterious impact on cellular structures andfunction. In response eukaryotic cells activate a range of molecular pathways to mitigate and repair damageoxidative stress response unfolded protein response osmotic stress response. While substantial moleculardetail is known about individual stress response pathways and some types of intervention improve resistanceto multiple forms of stress (e.g. dietary restriction inhibition of insulin signaling) surprisingly little is knownabout how these responses differ when cells are challenged with multiple types of stress simultaneously. Themolecular architecture underlying multi-stress response represents a critical knowledge gap in the field. Thisgap has broad implications for medicine. Human diseases rarely involve a single form of stressAlzheimer'sdisease is characterized by neuroinflammation increased oxidative stress and accumulation of misfoldedproteins while cancer exhibits oxidative stress DNA damage and localized hypoxia. By understanding thenetwork of molecular pathways that underlie stress response we aim to identify specific intervention points thatcan be targeted to target different stress profiles. Our lab employs a novel platform for high-throughput healthand survival analysis in Caenorhabditis elegans. Combining this platform with tools in systems and classicalgenetics we will: (1) define the genetic network that modulates the response to multiple forms of stress in C.elegans; (2) determine which network components are activated in response to distinct combinations of stress;(3) investigate mechanisms of cross-adaptationmild exposure to one stress imparting resistance to anotherform of stressfor different combinations of stressors; and (4) identify key intervention points that can betargeted to mitigate different combinations of cellular stress. Using this approach we have identified 3-hydroxyanthranilic acid (3HAA) a metabolite in the tryptophan-kynurenine pathway that improves survival andhealth in C. elegans by mitigating both oxidative stress and ER stress. These benefits are realized at least inpart through direct antioxidant and chaperone activity by 3HAA. We are now beginning mouse studies tovalidate our mechanistic model for the action of 3HAA in a mammalian system. The long-term goal of our workis to answer several outstanding questions about the fundamental biology of cellular stress response: (1) Howis the genetic network underlying cellular stress response organized? (2) Which elements of this stressresponse network are general (i.e. responsive to a wide range of types of stress) and which are specific (e.g.responsive to only specific stressors)? (3) How does the cellular response to one type of stress alter anorganism's resistance to another type? (4) What are the key molecular nodes in the stress response networkthat can be targeted to improve health or treat specific forms of disease in humans?