PROJECT SUMMARY/ABSTRACT An important component of the mammalian innate immune system is the NLRP3 inflammasome, an intracellular complex of three proteins that, upon activation, produces the cytokine interleukin-1β. Activation of the NLRP3 complex can occur via internalization of a growing number of endogenous human molecules, referred to as damage-associated molecular patterns (DAMPs). The absolute mechanisms of how DAMPs trigger NLRP3 inflammasome activation is not fully understood. There is convincing evidence that direct interactions between internalized DAMPs and inflammasome proteins may be one of these mechanisms. This high-impact R15 AREA application will seek to characterize direct interactions between the well-known DAMP amyloid-β (Aβ) and inflammasome proteins (1) in vitro and (2) in cellular systems. The last objective will be to link these direct interactions with inflammasome activation. These findings will have implications for the treatment of inflammatory, neurodegenerative, and heart diseases.

PROJECT NARRATIVE An important component of the innate immune system is the NLRP3 inflammasome, an intracellular complex of three proteins that, upon activation, produces critical inflammatory molecules. Activation of the NLRP3 complex can occur by endogenous human molecules, yet how this occurs is still an open question. This project, which will seek to investigate direct interactions of these molecules with NLRP3 inflammasome proteins, will have implications for the treatment of inflammatory, neurodegenerative, and heart diseases.