Principal Investigator Dennis Kim
The detection and compensatory response to the accumulation of unfolded proteins in the endoplasmic reticulum (ER), termed the Unfolded Protein Response (UPR), represents a conserved cellular homeostatic mechanism with important roles in normal development and in the pathogenesis of disease. A pivotal mediator of the UPR, the transcription factor XBP-1, is required for the differentiation of the highly secretory plasma cells of the mammalian adaptive immune system, but recent work also points to important receiprocal interactions between the UPR and other aspects of immunity and inflammation. Building on our characterization of the innate immune system in C. elegans, we have been able to define an essential role for XBP-1 in protecting the host during activation of innate immunity (Richardson et al., 2010). Our findings support the idea that the ubiquitous microbiota of multicellular organisms represents a physiologically relevant inducer of ER stress. Our current work is defining how physiological induction of immunity and ER stress influences organismal physiology.
We have also initiated the study of how immunity influences stress responses at the cellular and organismal levels by analyzing the interaction between immunity and aging. The increased susceptibility to infection with advancing age has been observed in diverse species, including humans, but the molecular mechanisms remain poorly understood. We have begun to define the dynamic activities of immune signaling pathways over the course of the aging process, and how infection and innate immunity can influence organismal longevity.