Defining the genetic architecture of multiple stress response

University Of Arizona, Tucson AZ

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Abstract

ABSTRACT The goal of this work is to understand the fundamental biology of cellular response to different forms and combinations of stress. Cells are constantly subjected to intrinsic and extrinsic stresses—reactive oxygen species, protein misfolding, osmotic stress—that negatively impact cellular structure and function. In response, cells activate a range of molecular pathways to mitigate and repair damage—oxidative stress response, unfolded protein response, osmotic stress response. Several interventions that improve health, such as dietary restriction, both activate stress response pathways and promote multi-stress resistance. While individual stress response pathways are reasonably well defined, how stress responses differ when cells are challenged with multiple forms of stress simultaneously is less well understood and represents a critical knowledge gap. This gap 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 network of molecular pathways that define cellular stress response, we aim to identify intervention points that can be targeted to activate distinct stress response profiles that improve health, combat disease, and enhance resilience. The long- term goal of this research program is to answer fundamental questions about the biology of stress response: (1) How is the molecular stress response network organized? (2) Which elements of this network are general (responsive to many types of stress) and which are specific (responsive to specific stressors)? (3) How does the cellular response to one type of stress alter an organism’s resistance to other types? (4) Are there key molecular nodes in the stress response network that can be targeted to improve health or treat specific diseases? Over the past five years we have examined the physiological and molecular response of the round worm Caenorhabditis elegans to a range of stress combinations. In parallel, we studied C. elegans and mice with elevated levels of the tryptophan metabolite 3-hydroxyanthanilic acid (3HAA) as models of multi-stress resistance. Evidence from these projects converged on heavy metal regulation and host-bacteria intercommunication as molecular processes responsive to many types and combinations of stress. We are now focused on answering several questions related to these molecular themes: (1) What role does heavy metal transport and storage play in the response to diverse stressors? (2) How does the response of intestinal bacteria to stress impact host health and stress resistance? (3) Can these processes be targeted to promote animal health and resilience? (4) How do changes in intestinal iron and zinc localization promote broad-spectrum stress resistance in animals with elevated 3HAA? Beyond these questions, we will continue our search for novel stress interactions in pursuit of our broader goal to comprehensively understand the cellular stress response network. Supporting each of these projects, we continue to build innovative, high-content tools for studying stress response in C. elegans.