Cardiolipin as a Novel Mediator of Acute Lung Injury

心磷脂作为急性肺损伤的新型调节剂

• 批准号: 8608045
• 负责人: Rama K Mallampalli
• 金额: $ 195.84万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-03 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8608045
• 关键词: Acute Lung Injury; Adult Respiratory Distress Syndrome; Anabolism; Animals; Apoptosis; Arts; Bacterial Infections; Biology; Cardiolipins; Cells; Data; Environment; Epithelial; Epithelium; Event; Homeostasis; Human; Immune; Inner mitochondrial membrane; Lipids; Lung; Mammalian Cell; Masks; Mediator of activation protein; Mitochondria; Modeling; Molecular; Molecular Profiling; Myeloid Cells; Pathogenesis; Pattern; Pneumonia; Research Personnel; Role; Seminal; Services; Therapeutic Intervention; Translating; adverse outcome; base; bioimaging; extracellular; human subject; in vivo Model; innate immune function; lung injury; mortality; novel; novel therapeutics; programs; repository; tool

The acute respiratory distress syndrome (ARDS) is most commonly due to severe bacterial infection, including pneumonia. Despite decades of intense study, mortality rates for ARDS are still very high and yet newer therapeutic strategies based on fundamentally novel molecular-pathophysiologic-driven models have not emerged. This PPG application is based on our seminal discovery that a critical mitochondrial-specific lipid, cardiollpin, profoundly produces ARDS-like features when released into the extracellular environment (Nat. Med. 2010). The overall conceptual model underlying this Program is that cardiollpin is a new "lipidomic associated molecular pattern" encoding bacterial-like molecular signatures that is normally masked by its compartmentalization within the inner mitochondrial membrane of mammalian cells. However, in our preliminary data suggest that in pneumonia models there occur seminal events whereby cardiollpin is exposed into the extracellular environment through its dysregulated biosynthesis (Project 1) or oxidative transmigration (Project 2) from mitochondria in epithelia resulting in severe adverse consequences for immune suppressor activities of myeloid cells (Project 3). Thus, the overall hypothesis is that cardiollpin elicits differential efects on pulmonary homeostasis in ARDS that are cell specific and highly compartmentalized. To execute this Program, we have assembled a team of world-class leaders with complementary expertise to synergistically investigate mechanisms that modulate availability cardiollpin and its role in mitochondrial integrity, epithelial apoptosis, and innate immune function. To evaluate the hypothesis, investigators will employ state-of-art molecular, cell-based, and lipidomic tools that will be translated to complementary in vivo models of lung injury and analysis in human subjects with ARDS. The Program will be supported by highly interactive Cores with expertise in oxidative lipidomics, animal and human repository services, and bioimaging. Execution of these studies will provide a paradigm-changing conceptual model for ARDS pathogenesis that serves as a basis for therapeutic intervention and providing a new and sustained field of scientific inquiry in lung biology.

急性呼吸窘迫综合征 (ARDS) 最常见的原因是严重细菌感染，包括肺炎。尽管经过数十年的深入研究，ARDS 的死亡率仍然非常高，而且基于全新的分子病理生理学驱动模型的新治疗策略尚未出现。该 PPG 应用基于我们的开创性发现，即一种关键的线粒体特异性脂质心磷脂在释放到细胞外环境中时会产生类似 ARDS 的特征 (Nat. Med. 2010)。该计划的总体概念模型是心磷脂是一种新的“脂质组学相关分子模式”，编码类似细菌的分子特征，该特征通常被其在哺乳动物细胞线粒体内膜内的区室化所掩盖。然而，我们的初步数据表明，在肺炎模型中，发生了重大事件，心磷脂通过上皮细胞线粒体的生物合成失调（项目 1）或氧化迁移（项目 2）暴露到细胞外环境中，从而对免疫抑制剂产生严重的不良后果骨髓细胞的活性（项目 3）。因此，总体假设是心磷脂对 ARDS 中的肺稳态产生不同的影响，这些影响是细胞特异性的和高度分化的。为了执行该计划，我们组建了一支由具有互补专业知识的世界级领导者组成的团队，以协同研究调节心磷脂可用性及其在线粒体完整性、上皮细胞凋亡和先天免疫功能中的作用的机制。为了评估这一假设，研究人员将采用最先进的分子、细胞和脂质组学工具，将其转化为肺损伤的补充体内模型，并在患有 ARDS 的人类受试者中进行分析。该计划将得到高度互动的核心的支持，这些核心拥有氧化脂质组学、动物和人类储存库服务以及生物成像方面的专业知识。这些研究的执行将为 ARDS 发病机制提供一个范式改变的概念模型，作为治疗干预的基础，并为肺生物学提供一个新的、持续的科学探究领域。