Platelet dysfunction in pediatric multiple organ dysfunction syndrome: Role of unfolded protein response

PROJECT SUMMARY Multiple organ dysfunction syndrome (MODS), most commonly caused by sepsis, is a hyperinflammatory condition in which ≥2 organ systems are dysfunctional. Disseminated microvascular thrombosis is a hallmark of MODS. When MODS presents with thrombocytopenia, pediatric mortality is as high as 80%. The combination of inflammation, thrombosis and thrombocytopenia suggests that platelet dysfunction plays a central role in pediatric MODS. Our highly promising preliminary data supports a role for endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in producing a heterogeneous dysfunctional platelet response, including apoptosis. Due to inflammation and other stressors, ER stress with accumulating protein aggregates triggers the UPR to restore protein folding homeostasis. When ER stress is severe, the pro-survival protective UPR may be overwhelmed and divert some platelets to dysfunction, specifically apoptosis, contributing to thrombosis, thrombocytopenia, then MODS. We have shown that the UPR may be a master regulator of these pathological pro-thrombotic and pro-bleeding responses. UPR in platelets remains unexplored in children whose platelets are functionally different from adults, and in response to ER stress in MODS. Our central hypothesis states that hyperinflammation causes severe ER stress and overwhelms the UPR leading to platelet dysfunction in children. This platelet dysfunction contributes to thrombosis, thrombocytopenia, then MODS. But the UPR can be modulated to prevent these complications. We propose to determine the effects of ER stress due to inflammation on platelet UPR activation and dysfunction in pediatric MODS (Specific Aim 1), to determine the molecular mechanisms of ER stress-induced platelet dysfunction and its complications in in vivo model of pediatric MODS (Specific Aim 2), and to determine the diagnostic and therapeutic implications of platelet UPR activation in pediatric MODS (Specific Aim 3). We will use innovative concepts, cutting-edge techniques, and ex vivo pediatric and in vivo murine models to investigate the role of UPR in platelet dysfunction in MODS in children. At the completion of this research, we expect to define a novel, pediatric-specific role of platelet UPR in platelet dysfunction, thrombosis, thrombocytopenia and MODS. These results are expected to provide a strong foundation for the development of therapies specific to MODS in children that are based on the UPR in platelets.