Molecular and neuronal mechanisms responsible for limiting stress responses

PROJECT SUMMARY Research in my lab focuses on neural regulation of stress responses. Living organisms are constantly challenged by internal and external insults. Over- or underreacting to these insults may compromise health and longevity; thus, deploying appropriate stress responses to counter these attacks is critical. In contrast to our growing understanding of how stress is sensed and responses are initiated, our understanding of how overreactions are sensed and responses are attenuated is limited. This is largely because the regulation of stress responses is usually cell non-autonomous and involves multiple organs, with the nervous system, a highly complex and difficult to dissect system, often being the master regulator. We use Caenorhabditis elegans for our studies because it is one of the simplest organisms with a nervous system, and neural control of many stress responses occurs homologously in this model. With this system, we have discovered and characterized specific neural regulatory circuits that control stress responses to pathogen infection, warm temperatures, and oxidative stress. Pertinent to this R35 application is the neuroimmune regulatory pathway mediated by the neuronal G protein-coupled receptor NPR-8. We have found that the tripeptide proline-glycine- proline (PGP), derived from collagen degradation, binds NPR-8 in AWB, AWC, and ASJ amphid sensory neurons to suppress innate immunity against pathogen infection. Such regulation is achieved by inhibiting the expression of collagens with defense activity, forming a negative feedback loop to limit the intensity of the innate immune response. Based on these findings, we hypothesize that pathogen infection induces collagen degradation in the host to produce PGP that binds to NPR-8, activating the NPR-8 neural circuit that inhibits the immune response to maintain immunological homeostasis. This NPR-8-dependent neuroimmune regulatory pathway can be used by the host to limit or dampen overreaction of immunity or resolve the immune response after infection is cleared. This pathway provides a platform for deciphering the neuronal and molecular mechanisms that limit innate immune responses in a whole animal. Building on this platform, we propose to dissect neural signaling in the NPR-8 pathway and examine the immunomodulatory role of collagens in host defense. Specifically, we will elucidate how neuroimmune regulatory signals are initiated, how the signals are transmitted within the neural network, and how the signals are transduced from the neural network to non-neural tissues, such as the intestine, where the infection and defense often take place. We will also examine how collagens are remodeled and how they function in cell signaling in defense. Our goals are to understand neural signaling in neuroimmune regulation and decipher the neural-collagen regulatory mechanism that modulates pathogen infection outcomes. Since excessive immune responses have been linked to a myriad of human health conditions, our studies will facilitate the development of more effective treatments for innate immune disorders and infectious diseases.