Autocrine regulation of neutrophil chemotaxis

 描述（由申请人提供）：在重症监护和创伤患者中，中性粒细胞（PMN）趋化性失调导致脓毒症和多器官衰竭。其潜在机制仅部分了解，这是寻求有效治疗干预措施以改善脓毒症和重症监护患者治疗的主要障碍。趋化性是一个复杂的过程，允许PMNs定位和消除入侵的细菌。功能失调的趋化性不仅损害宿主防御，而且还可能导致附带的宿主组织损伤。我们以前的工作已经证明，中性粒细胞的趋化性需要自分泌嘌呤能信号机制，涉及在前沿和复杂的推拉机制，涉及不同的嘌呤能受体亚型的细胞前部和后部的细胞定位释放的细胞ATP。最近，我们发现线粒体ATP形成的快速激活触发了这些嘌呤能信号机制。此外，我们发现脓毒症伴随着全身ATP的释放，这干扰了中性粒细胞的自分泌嘌呤能导航系统。基于这些证据，我们假设支持线粒体ATP产生或消除全身ATP干扰作用的治疗策略将改善PMN趋化性和宿主防御，基于这些概念的临床策略迟早会降低重症监护、脓毒症和创伤患者的发病率和死亡率。具体目标1。调节中性粒细胞趋化性的机制：我们将研究调节ATP产生的机制，ATP在细胞的前部和后部激发自分泌嘌呤能信号。特别强调mTOR和AMPK及其在调节线粒体功能中的作用。具体目标2。患者中性粒细胞趋化性受损：我们将研究氧气和葡萄糖供应以及全身ATP如何影响中性粒细胞趋化性，并研究这些因素如何导致重症患者中性粒细胞趋化性受损。具体来说，我们将测试这些变量如何影响ICU患者的线粒体功能和PMN趋化性。具体目标3。恢复PMN趋化性和宿主防御的治疗策略：最后，我们将使用小鼠脓毒症模型来测试改善PMN趋化性和宿主防御的新治疗策略。我们将重点关注的方法，提高线粒体ATP的生产和减少系统的ATP水平对中性粒细胞的趋化性在其他功能反应的破坏性影响。我们预计，我们的研究结果将推进PMN趋化性调节机制的科学知识，这些知识将揭示新的治疗策略，最终可能导致创伤，脓毒症和危重患者的护理改善。

 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.