Counter-Regulatory Lipid Mediators in Lung Disease

肺部疾病中的反调节脂质介质

基本信息

批准号：
8079663
负责人：
Bruce D Levy
金额：
$ 30.63万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-12-10 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8079663
关键词：
Acids Acute Acute Lung Injury Address Adult Respiratory Distress Syndrome Aerosols Affect Anabolism Anti-Inflammatory Agents Anti-inflammatory Arachidonic Acids Autacoids Bacterial Pneumonia Biological Process CD59 Antigen Catalytic Domain Cell membrane Cells Charge Chemicals Complication Coupled Critical Illness Data Development Diphosphates Disease Docosahexaenoic Acids Dose Eicosapentaenoic Acid Epithelial Equilibrium Event Fluorescence Funding Gastric Acid Gene Deletion Gene Targeting Generations HIV High Pressure Liquid Chromatography Human In Vitro Infectious Agent Inflammation Inflammatory Inflammatory Response Interphase Cell Lasers Lead Leukocytes Lipids Lipoxins Lung Lung Inflammation Lung diseases Measures Mediating Modeling Molecular Monitor Morbidity - disease rate Mus Mutation Neutrophil Activation Phosphatidylinositols Phospholipase D Phosphoric Monoester Hydrolases Phosphorylation Site Phosphotransferases Polyisoprenyl Phosphates Population Proteomics Receptor Activation Recovery Regulation Resolution Role Secondary to Series Severities Signal Pathway Signal Transduction Site Stimulus Structure-Activity Relationship Surface Plasmon Resonance Survivors System Testing Therapeutic Time Tissues Translating Trauma Work airway epithelium base design detector disability in vivo inhibitor/antagonist injured airway insight killings leukocyte activation lipid mediator loss of function lung injury mimetics mortality neutrophil novel novel therapeutic intervention novel therapeutics presqualene monophosphate presqualene pyrophosphate prevent research study respiratory response

项目摘要

DESCRIPTION (provided by applicant): In this competitive renewal of my first R01, we propose new experiments to test the hypothesis that presqualene diphosphate levels in cells are regulated by polyisoprenyl diphosphate phosphatase 1, which serves as a target for select counter-regulatory lipid mediators that promote resolution of acute lung inflammation and injury. Local airway trauma secondary to accidental aspiration of gastric acid is a frequent cause of acute lung injury and acute respiratory distress syndrome with neutrophil (PMN)-predominant inflammation in the lung. Despite a robust inflammatory response, bacterial pneumonia is a frequent complication. To date, anti- inflammatory agents have not proven effective in reducing the associated critical illness, mortality and prolonged disability in ARDS survivors. Novel therapeutic approaches are needed. During the last funding cycle, we made significant scientific progress towards all of our original specific aims and established polyisoprenyl phosphate (PIPP) remodeling as a new counter-regulatory signaling pathway in PMN. We determined structure-activity relationships for presqualene diphosphate (PSDP) inhibition of phospholipase D, identified endogenous PSDP as a direct inhibitor of phosphatidyl inositol 3- kinase in the regulation of cell activation and uncovered polyisoprenyl diphosphate phosphatase 1 (PDP1) as the first PSDP phosphatase capable of catalyzing the conversion of PSDP to its inactive monophosphate form (PSMP) that is 2 log orders less potent than PSDP as an inhibitor. In addition, we prepared new bioactive PSDP mimetics with in vivo protective actions in acid-initiated acute lung injury. Lipoxins are arachidonic acid-derived autacoids that also display protective actions in acute lung injury and regulate leukocyte actions via inhibition of PSDP remodeling, suggesting a pivotal counter-regulatory signaling role for PDP1 in cell activation. In extrapulmonary tissues, intriguing tissue-protective actions have recently also been assigned to three new classes of autacoid lipid mediators derived from eicosapentaenoic and docosahexaenoic acids. To test our hypothesis, we propose three specific aims: Elucidate factors responsible for cellular PDP1 activation, Define the influence of PDP1-based counter-regulatory lipid mediators on select human PMN and airway epithelial functional responses, and Establish the regulation of acute lung injury resolution by PDP1-based lipid mediators. These specific aims will enable us to (i) uncover new molecular insights into lipid-derived signaling pathways during homeostatic loss and recovery in the lung; and (ii) design novel therapeutic strategies using these lipid signals as templates. PROJECT NARRATIVE: Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a serious and explosive illness with substantial morbidity and mortality that affects as many as 75/100,000 population. No matter the cause, once ALI/ARDS is established the disease has no specific treatment. In this proposal, we seek to develop a better understanding of the biological processes invoked after airway injury that naturally promote resolution in order to develop new, more specific therapeutic approaches to prevent the development or lessen the severity of ARDS.

描述（由申请人提供）：在我的第一个R01的这种竞争性更新中，我们提出了新的实验，以测试细胞中双磷酸presqualene二磷酸的假说，受聚异源型二磷酸磷酸盐磷酸酶1的调节，该磷酸二磷酸磷酸盐酶1，该靶标作为选择的反监管脂肪中介子的靶标，以促进促进急性lung ungung lung ung ung ung ung lung ung ung ung ung ung ung ung ung ung ung ung ung ung ung ung ung ung ung ung。胃酸意外抽吸的局部气道创伤经常引起急性肺损伤和急性呼吸窘迫综合征，伴有肺中性粒细胞（PMN） - 肺中前炎症的炎症。尽管炎症反应有强大，但细菌性肺炎是常见的并发症。迄今为止，抗炎性药物尚未证明有效减少ARDS幸存者的关键疾病，死亡率和长期残疾。需要新颖的治疗方法。在上一个融资周期中，我们朝着所有最初的特定目的和建立的聚异源磷酸盐（PIPP）重塑做出了重大的科学进步，作为PMN中新型的反调节信号通路。我们确定了对磷酸二磷酸（PSDP）抑制磷脂酶D的结构活性关系，将内源性PSDP鉴定为细胞激活调节磷脂酰肌醇3-激酶的直接抑制剂，并在未覆盖的多发性二磷酸磷酸磷酸磷酸磷酸盐酶1（PSD）中，pSD PSD PSD PSD PSD PSD P.对于其非活性单磷酸盐形式（PSMP），它的2 log订单比PSDP作为抑制剂的效力较低。此外，我们在酸炎的急性肺损伤中使用体内保护作用制备了新的生物活性PSDP模拟物。脂蛋白是蛛网膜酸衍生的自闭症，也通过抑制PSDP重塑，在急性肺损伤中表现出保护作用，并调节白细胞的作用，这表明PDP1在细胞活化中具有关键的PDP1的反调节信号传导作用。在肺外组织中，最近还将有趣的组织保护作用分配给了三种新的源自eicosapentaenoic和docosahexaenoic酸的新型自动脂质脂质介质。为了检验我们的假设，我们提出了三个具体目的：阐明负责细胞PDP1激活的因素，定义了基于PDP1的反调节脂质介体对精选人PMN和AIRWAIL上皮功能响应的影响，并确定基于PDP1的Lipid脂质介质器对急性肺部受伤的调节。这些具体目标将使我们能够（i）发现在肺部稳态损失和肺部恢复期间对脂质衍生的信号传导途径的新分子见解；（ii）使用这些脂质信号作为模板设计新颖的治疗策略。项目叙述：急性肺损伤/急性呼吸窘迫综合征（ALI/ARDS）是一种严重且爆炸性的疾病，具有严重的发病率和死亡率，影响多达75/100,000人口。无论原因是什么原因，一旦建立了ALI/ARDS，疾病就没有特定的治疗方法。在该提案中，我们试图更好地了解气道损伤后所援引的生物学过程，这些过程自然会促进解决方案，以开发出新的，更具体的治疗方法，以防止或减轻ARDS的严重性。