MKK3 is a Mediator of Sepsis and Lung Injury in the Elderly

描述（由申请人提供）：老年人对急性肺损伤和脓毒症的易感性和死亡率增加。脓毒症是对感染的全身性炎症反应，是急性肺损伤的主要原因。预计美国人的平均年龄将上升，这一人群的疾病负担可能会大幅增加。因此，需要开发靶向生物疗法以改善结果。具体目标：本研究拟探讨丝裂原活化蛋白激酶信号分子MKK3作为老年脓毒症肺损伤的治疗靶点。我们首次确定MKK 3是内毒素（LPS）攻击的幼年小鼠急性肺损伤的关键介质，内毒素是一种公认的脓毒症介质。在这个过程中，我们发现MKK3调节与衰老相关的关键途径，如Nrf1，Sirt1，线粒体健康和线粒体自噬。MKK 3在脓毒症老年小鼠模型和人中的作用尚不清楚。我们的假设是MKK 3是衰老过程中急性肺损伤和脓毒症的重要决定因素。我们建议表明，MKK 3活性随着年龄的增长而增加，并与老年脓毒症小鼠和肺损伤患者的不良结局相关。我们将：1.确定MKK 3在脓毒症小鼠模型中年龄相关的肺损伤易感性和死亡率中的作用。2.在重症脓毒症患者中，将MKK 3活性与年龄、脓毒症严重程度和肺损伤易感性相关。实验方法：我们将使用内毒素休克的小鼠模型，并研究来自重症脓毒症患者的外周血单核细胞。目的：我们的总体目标是确定MKK 3作为老年人脓毒症和肺损伤的重要介质。通过使用动物模型和临床样本，我们将证明MKK 3是脓毒症的潜在有效治疗靶点。 公共卫生相关性：我们的研究目标是确定导致脓毒症老年患者肺衰竭和死亡的分子和途径。我们提出的研究将有助于确定MKK 3作为这些患者的治疗靶点。

DESCRIPTION (provided by applicant): The aged have increased susceptibility to and mortality from acute lung injury and sepsis. Sepsis is a systemic inflammatory response to infection and is the leading cause of acute lung injury. The average age of people in the USA is projected to rise, and the disease burden in this population is likely to increase substantially. There is therefore a need to develop targeted biologic therapies to improve outcomes. Specific Aims: We propose to investigate MKK3, a mitogen-activated protein kinase signaling molecule, as a therapeutic target in sepsis-induced lung injury in the aged. For the first time, we identifie MKK3 as a critical mediator of acute lung injury in young mice challenged with endotoxin (LPS), an established mediator of sepsis. In the process, we found that MKK3 modulates key pathways associated with aging such as Nrf1, Sirt1, mitochondrial health and mitophagy. The role of MKK3 in aged mouse models of sepsis and in people is unknown. Our hypothesis is that MKK3 is an important determinant of acute lung injury and sepsis during aging. We propose to show that MKK3 activity increases with aging and correlates with worse outcomes in older septic mice and people with lung injury. We will: 1. Determine the role of MKK3 in age-related susceptibility to lung injury and mortality in a mouse model of sepsis. 2. Correlate MKK3 activity to age, severity of sepsis and susceptibility to lung injury in critically ill septic people. Experimental Approach: We will use a mouse model of endotoxic shock and also study the peripheral blood monocytes from critically ill septic patients. Objective: Our overall goal is to identify MKK3 as a important mediator of sepsis and lung injury in the aged. By using both animal models and clinical samples, we will show that MKK3 is a potentially effective therapeutic target in sepsis. PUBLIC HEALTH RELEVANCE: Our research goal is to identify molecules and pathways responsible for causing lung failure and death in septic, elderly patients. Our proposed studies will help in identifying MKK3 as a target for therapy in these patients.