Cardiolipin as a Novel Mediator of Acute Lung Injury

急性呼吸窘迫综合征（ARDS）最常见的原因是严重的细菌感染，包括肺炎。尽管经过数十年的深入研究，ARDS的死亡率仍然很高，但基于新颖分子病理生理驱动模型的新治疗策略尚未出现。PPG的应用是基于我们开创性的发现，即一种关键的线粒体特异性脂质，心磷脂，当释放到细胞外环境时，会产生类似ards的特征（Nat. Med. 2010）。该计划的总体概念模型是，cardiollpin是一种新的“脂质组相关分子模式”，编码细菌样的分子特征，通常被哺乳动物细胞线粒体内膜内的区隔化所掩盖。然而，我们的初步数据表明，在肺炎模型中，心肌素通过其失调的生物合成（项目1）或上皮线粒体的氧化转运（项目2）暴露于细胞外环境中，从而导致骨髓细胞免疫抑制活性的严重不良后果（项目3）。因此，总的假设是，cardiollpin对ARDS患者肺内平衡的不同影响是细胞特异性和高度区隔的。为了执行这个项目，我们组建了一个世界级的领导团队，他们具有互补的专业知识，协同研究调节cardiollpin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，这些工具将转化为补充的ARDS患者肺损伤体内模型和分析。该项目将由具有氧化脂质组学、动物和人类存储库服务以及生物成像专业知识的高交互性核心提供支持。这些研究的开展将为ARDS发病机制提供一个改变范式的概念模型，作为治疗干预的基础，并为肺生物学提供一个新的和持续的科学探索领域。

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.