Autocrine regulation of neutrophil chemotaxis

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 DESCRIPTION (provided by applicant): In critical care and trauma patients, dysregulated neutrophil (PMN) chemotaxis contributes to sepsis and multi-organ failure. The underlying mechanisms are only partially understood, which is a major hurdle in the search for effective therapeutic interventions that improve the treatment of sepsis and critical care patients. Chemotaxis is a complex process that allows PMNs to locate and eliminate invading bacteria. Dysfunctional chemotaxis impairs not only host defense but can also contribute to collateral host tissue damage. Our previous work has demonstrated that PMN chemotaxis requires autocrine purinergic signaling mechanisms that involve localized release of cellular ATP at the leading edge and complex pull-push mechanisms that involve different purinergic receptor subtypes at the front and back of cells. Recently we found that rapid activation of mitochondrial ATP formation triggers these purinergic signaling mechanisms. In addition, we found that sepsis is accompanied by the release of systemic ATP, which interferes with the autocrine purinergic navigation systems of PMNs. Based on this evidence, we hypothesize that therapeutic strategies that support mitochondrial ATP production or eliminate the interfering effects of systemic ATP will improve PMN chemotaxis and host defense and that clinical strategies based on these concepts may sooner or later diminish morbidity and mortality in critically care, sepsis, and trauma patients. Specific Aim 1. Mechanisms that regulate PMN chemotaxis: We will study the mechanisms that regulate the production of ATP which fuels autocrine purinergic signaling at the front and back of cells. Special emphasis will be placed on mTOR and AMPK and their roles in regulating mitochondrial function. Specific Aim 2. Impaired PMN chemotaxis in patients: We will study how oxygen and glucose supply and systemic ATP affect PMN chemotaxis and we will investigate how these factors contribute to impaired PMN chemotaxis in critically care patients. Specifically, we will test how these variables affect mitochondrial function and PMN chemotaxis in ICU patients. Specific Aim 3. Therapeutic strategies to restore PMN chemotaxis and host defense: Finally, we will use a mouse sepsis model to test novel therapeutic strategies to improve PMN chemotaxis and host defenses. We will focus on approaches that improve mitochondrial ATP production and reduce the disruptive influence of systemic ATP levels on PMN chemotaxis in other functional responses. We anticipate that our findings will advance scientific knowledge of the mechanisms by which PMN chemotaxis is regulated and that this knowledge will reveal novel therapeutic strategies that may ultimately lead to improvements in the care of trauma, sepsis, and critical patients.