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败血症的易感性和死亡率增加。败血症是一种对感染的全身炎症反应，是急性肺损伤的主要原因。美国人的平均年龄预计会上升，这一人群的疾病负担可能会大幅增加。因此，有必要开发靶向生物疗法来改善结果。具体目的：研究丝裂原激活的蛋白激酶信号分子MKK3在老年人脓毒症所致肺损伤中的治疗作用。我们首次确定MKK3是内毒素（LPS）攻击的年轻小鼠急性肺损伤的关键介质，内毒素（LPS）是一种已建立的脓毒症介质。在此过程中，我们发现MKK3调节与衰老相关的关键通路，如Nrf1、Sirt1、线粒体健康和线粒体自噬。MKK3在老年脓毒症小鼠模型和人体内的作用尚不清楚。我们的假设是，MKK3是衰老过程中急性肺损伤和败血症的重要决定因素。我们提出证明MKK3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预后相关。我们将：1；确定MKK3在脓毒症小鼠模型中与年龄相关的肺损伤易感性和死亡率中的作用。2. 危重脓毒症患者的MKK3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：我们将使用内源性休克小鼠模型，并研究重症脓毒症患者外周血单核细胞。目的：我们的总体目标是确定MKK3是老年人败血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MKK3是脓毒症的潜在有效治疗靶点。

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.