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Role of Growth Arrest and DNA Damage 45-alpha in Acute Lung Injury Pathogenesis

生长停滞和 DNA 损伤 45-α 在急性肺损伤发病机制中的作用

基本信息

批准号：
7276255
负责人：
Nuala Jennings Meyer
金额：
$ 5.67万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2008-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7276255
关键词：
Acute Acute Lung Injury Alveolus American Animal Model Animals Apoptosis Apoptotic Bilateral Biological Assay Blood capillaries Candidate Disease Gene Cell Cycle Arrest Cells Cultured Cells DNA Damage Development Disease Disruption Electrical Resistance Endothelial Cells Endotoxins Environmental air flow Epithelial Event Floods Frequencies Functional disorder Gadd45a protein Gases Gene Expression Profiling Genes Genetic Growth Heart Atrium Human Hyperoxia Hypertension Hypoxemia IV Fluid Immunohistochemistry In Vitro Inflammatory Injury Interleukin-6 Ischemia Knock-out Lead Learning Left Life Liquid substance Location Lung MAPK14 gene Measures Mechanical ventilation Mechanics Mediating Minority Modeling Molecular Profiling Molecular Target Mus National Research Service Awards Numbers Oryctolagus cuniculus Pathogenesis Pathway interactions Patients Play Pneumonia Population Predisposition Principal Investigator Process Rate Recovery Regulation Resistance Risk Factors Role Sepsis Severities Simulate Small Interfering RNA Stress Stretching Structure Structure of parenchyma of lung Syndrome System Testing Tissue-Specific Gene Expression Transfusion Translational Research Trauma Ultraviolet Rays United States Up-Regulation Ventilator Wild Type Mouse attenuation capillary cell injury cytokine electric impedance gene repair human MAPK14 protein human subject improved injury and repair insight lung injury mitogen-activated protein kinase p38 mortality novel therapeutics response skills therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Acute Lung Injury (All) is a common and devastating disorder, afflicting an estimated 190,000 patients each year in the United States and inflicting a mortality rate of 30 - 50%. Treatment of ALI invariably necessitates mechanical ventilation, which can itself potentiate or even induce lung injury. To date, our only proven therapies for ALI are to employ a non-injurious ventilation strategy and to limit excess intravenous fluid administration. As only a minority of the patients with risk factors for the disease will develop the full-blown syndrome of airspace flooding and profound hypoxemia, a better understanding of ALI susceptibility might lead to improved and more personalized therapy. Our studies focused on expression profiling of animal and human ALI to explore potential genetic contributions to the development of ALI revealed significantly elevated expression of a number of genes potentially implicated in the pathogenesis of ALI. Growth arrest and DNA damage-inducible gene 45 alpha (GADD45a), a constitutively expressed gene activated by cellular injuries resulting in DNA damage or cell cycle arrest, is one such gene with intense upregulation in response to ALI. While it has no known action in the lung to date, we hypothesize that GADD45a is a viable candidate gene which confers protection against ALI. In this application, the principal investigator will study mechanisms by which GADD45a may influence acute lung injury. Specific Aim #1 will employ an animal model of both ventilator-induced and sepsis- induced ALI to test whether a GADD45a knockout strain is more susceptible to lung injury. We will characterize the spatial location of GADD45a expression within murine lung tissue, and assay murine lungs to determine whether GADD45a knockout alters the expression of inflammatory cytokines such as TNF-a, IL-6, or IL-1(3 compared to controls. Specific Aim #2 will test our hypothesis that GADD45a is a protective factor in ALI by silencing GADD45a in a cell culture model exposed to cyclic stretch or endotoxin, and evaluating the effect on endothelial cell barrier function. We will also explore the dominant mechanistic effect of GADD45a in ALI protection, distinguishing between putative roles in apoptosis regulation and p38 MARK inactivation. These studies will elucidate new insights into ALI pathophysiology, which may generate novel therapeutic targets for this devastating disease.

描述(申请人提供)：急性肺损伤(ALL)是一种常见和破坏性的疾病，在美国每年约有19万名患者受到影响，死亡率为30%-50%。ALI的治疗需要机械通气，机械通气本身会加重甚至导致肺损伤。到目前为止，我们唯一被证实的治疗ALI的方法是采用非创伤性的通气策略，并限制过量的静脉输液。由于只有少数具有疾病危险因素的患者会发展为空隙泛滥和严重低氧血症的全面综合征，因此更好地了解ALI的易感性可能会导致改进和更个性化的治疗。我们的研究集中在动物和人类ALI的表达谱上，以探索在ALI发生发展中潜在的遗传贡献，发现一些潜在参与ALI发病机制的基因表达显着上调。生长抑制和DNA损伤诱导基因45α(GADD45a)是一种结构性表达的基因，可被细胞损伤激活，导致DNA损伤或细胞周期停滞，是ALI反应中表达强烈上调的基因之一。虽然到目前为止，GADD45a在肺中的作用尚不清楚，但我们假设GADD45a是一个可行的候选基因，可以提供对ALI的保护。在这项申请中，首席研究员将研究GADD45a可能影响急性肺损伤的机制。具体目标#1将采用呼吸机诱导的ALI和败血症诱导的ALI的动物模型来测试GADD45a基因敲除菌株是否对肺损伤更敏感。我们将确定GADD45a在小鼠肺组织中表达的空间位置，并对小鼠肺组织进行检测，以确定GADD45a基因敲除是否改变了炎症细胞因子如TNF-a、IL-6或IL-1的表达(与对照组相比。具体目标#2将通过在周期性拉伸或内毒素暴露的细胞培养模型中沉默GADD45a，并评估其对内皮细胞屏障功能的影响，来检验我们的假设，即GADD45a是ALI的保护因子。我们还将探索GADD45a在ALI保护中的主导机制作用，区分在细胞凋亡调控和p38 Mark失活中的可能作用。这些研究将阐明对ALI病理生理学的新见解，这可能为这种毁灭性疾病产生新的治疗靶点。