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

MKK3 是老年人败血症和肺损伤的调节剂

• 批准号: 8522116
• 负责人: Praveen Mannam
• 金额: $ 7.87万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8522116
• 关键词: Acute Lung Injury; Age; Aging; Animal Model; Biogenesis; Biological Response Modifier Therapy; Cells; Cessation of life; Clinical; Critical Illness; Data; Development; Elderly; Endothelial Cells; Endotoxic Shock; Endotoxins; Failure; Figs - dietary; Generations; Goals; Gram-Negative Bacteria; Health; Human; Incidence; Infection; Inflammation Mediators; Inflammatory Response; Injury; Life Expectancy; Link; Lung; MAP2K3 gene; Mediating; Mediator of activation protein; Membrane; Mitochondria; Mitogen-Activated Protein Kinases; Mus; Outcome; Oxidants; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phosphotransferases; Population; Predisposition; Process; Production; Reactive Oxygen Species; Regulation; Research; Resistance; Role; Sampling; Secondary to; Sepsis; Severities; Signal Pathway; Signaling Molecule; Syndrome; Time; United States; Woman; age related; aged; burden of illness; improved; interest; intraperitoneal; lung injury; macrophage; men; mitogen-activated protein kinase p38; monocyte; mortality; mouse model; older patient; peripheral blood; response; septic; therapeutic target

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.

描述（由申请人提供）：老年人对急性肺损伤和败血症的敏感性和死亡率增加。败血症是对感染的全身性炎症反应，是急性肺损伤的主要原因。预计美国人民的平均年龄会上升，并且该人群的疾病负担可能会大大增加。因此，需要开发有针对性的生物疗法以改善预后。具体目的：我们建议研究MKK3（一种促丝分裂原激活的蛋白激酶信号分子），作为老年败血症诱导的肺损伤的治疗靶标。我们第一次将MKK3识别为脓毒症（LPS）挑战的年轻小鼠急性肺损伤的关键介体，这是脓毒症的既定介质。在此过程中，我们发现MKK3调节与衰老相关的关键途径，例如NRF1，SIRT1，线粒体健康和线粒体。 MKK3在老年败血症和人的老鼠模型中的作用尚不清楚。我们的假设是MKK3是急性肺损伤和衰老过程中的重要决定因素。我们建议表明，MKK3活性随老化而增加，并且与老年化粪池小鼠和肺部损伤患者的结局相关。我们将：1。确定MKK3在败血症小鼠模型中与年龄相关的肺损伤和死亡率的作用。 2。将MKK3的活性与年龄，败血症的严重程度以及对疾病患者的肺损伤的易感性相关。实验方法：我们将使用内毒性休克的小鼠模型，并研究重症败血症患者的外周血单核细胞。目的：我们的总体目标是将MKK3识别为老年败血症和肺损伤的重要介体。通过使用动物模型和临床样品，我们将证明MKK3是败血症中潜在的有效治疗靶标。