Toll-like receptors (TLRs) are a family of evolutionary conserved proteins that mediate innate immune responses in mammals. TLRs have the ability to recognize specific molecular patterns associated with microbial components; this property allows the cell to detect potentially harmful bacteria. When activated, TLRs rapidly induce inflammation by recruiting specific adapter proteins to their intracellular TIR domains. Several adapter proteins have been identified which also contain this TIR motif arid can thus interact directly with the receptor to mediate inflammatory pathways. Recently, it has been demonstrated that in addition to inflammation, TLRs can also activate apoptosis. However, little else is known about this aspect of TLR signaling. This proposal aims to characterize pro-apoptotic signaling mediated by TLRs by using TLRs and its ligand flagellin as a model to identify TIR-containing adapter proteins which relay the signal. We will use in vitro biochemical and functional assays as well as genetically modified mice to characterize the roles of these proteins. ? ?
