Severe trauma leads to the activation a systemic inflammatory response that when excessive, contributes to both end-organ dysfunction and immune dysregulation. The goal of this project is to define molecular mechanisms for the initiation and propagation of inflammation following severe injury. We hypothesize that tissue damage and/or ischemia leads to the release of endogenous molecules that then trigger inflammatory signaling through pattern recognition receptors of the innate immune system. We have compelling evidence that two pattern recognition receptors, toll-like receptors 4 and 9 (TLR4 and 9) and the nuclear protein and TLR4 ligand, high mobility group box-1 (HMGB1), play critical roles in initiating inflammation following injury. We will more fully characterize the function of TLR4 and 9 and HMGB1 in the injury response in three Aims.
Under Aim 1, we will define the relative roles of TLR4 and TLR9 to the systemic and organ-specific responses. We will also use a TLR4-loxP mouse recently developed in our lab to define cell-type specific roles for TLR4.
Under Aim II, we will use gene knockout mice to establish the major TLR-dependent signaling pathways involved in trauma-induced inflammatory response.
Under Aim 1 11, we will define the cell types that mobilize and release HMGB1 following systemic injury and the mechanisms leading to HMGB1 release. To accomplish these aims, we will utilize our well-characterized mouse models of hemorrhagic shock and peripheral tissue trauma. It is expected that the completion of this work will both advance our understanding of how the immune system becomes activated after injury and define potential targets for therapeutic intervention to limit the excessive inflammation in severely injured patients.
Trauma is the most common cause of death and morbidity in peopl under the age of 50 in the USA. Much of the morbidity and mortality are due to an excessive inflammatory response. The research described in this proposal is aimed at understanding how trauma induces an inflammatory response at the molecular level with the long-term goal identifying strategies to modify this response and improve survival.
|Zettel, Kent R; Dyer, Mitchell; Raval, Jay S et al. (2016) Aged Human Stored Red Blood Cell Supernatant Inhibits Macrophage Phagocytosis in an HMGB1 Dependent Manner After Trauma in a Murine Model. Shock :|
|Constantine, Gregory; Buliga, Marius; Mi, Qi et al. (2016) Dynamic Profiling: Modeling the Dynamics of Inflammation and Predicting Outcomes in Traumatic Brain Injury Patients. Front Pharmacol 7:383|
|Abboud, Andrew; Namas, Rami A; Ramadan, Mostafa et al. (2016) Computational Analysis Supports an Early, Type 17 Cell-Associated Divergence of Blunt Trauma Survival and Mortality. Crit Care Med 44:e1074-e1081|
|Abboud, Andrew; Mi, Qi; Puccio, Ava et al. (2016) Inflammation Following Traumatic Brain Injury in Humans: Insights from Data-Driven and Mechanistic Models into Survival and Death. Front Pharmacol 7:342|
|Namas, Rami A; Almahmoud, Khalid; Mi, Qi et al. (2016) Individual-specific principal component analysis of circulating inflammatory mediators predicts early organ dysfunction in trauma patients. J Crit Care 36:146-153|
|He, Xingying; Qian, Yongbing; Li, Zhigang et al. (2016) TLR4-Upregulated IL-1Î² and IL-1RI Promote Alveolar Macrophage Pyroptosis and Lung Inflammation through an Autocrine Mechanism. Sci Rep 6:31663|
|Vogel, Sebastian; Rath, Dominik; Borst, Oliver et al. (2016) Platelet-derived high-mobility group box 1 promotes recruitment and suppresses apoptosis of monocytes. Biochem Biophys Res Commun 478:143-8|
|Korff, Sebastian; Loughran, Patricia; Cai, Changchun et al. (2016) Tlr2 on Bone Marrow and Non-Bone Marrow Derived Cells Regulates Inflammation and Organ Injury in Cooperation with Tlr4 During Resuscitated Hemorrhagic Shock. Shock 46:519-526|
|Namas, Rami A; Vodovotz, Yoram; Almahmoud, Khalid et al. (2016) Temporal Patterns of Circulating Inflammation Biomarker Networks Differentiate Susceptibility to Nosocomial Infection Following Blunt Trauma in Humans. Ann Surg 263:191-8|
|Kassab, Ghassan S; An, Gary; Sander, Edward A et al. (2016) Augmenting Surgery via Multi-scale Modeling and Translational Systems Biology in the Era of Precision Medicine: A Multidisciplinary Perspective. Ann Biomed Eng 44:2611-25|
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