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）最常见的是包括严重的细菌感染，包括肺炎。尽管进行了数十年的深入研究，但ARD的死亡率仍然很高，但基于从根本上新颖的分子 - 病态生理驱动模型的新治疗策略尚未出现。该PPG应用是基于我们的开创性发现，即关键的线粒体特异性脂质Cardiollpin在释放到细胞外环境中时会产生类似ARDS的特征（Nat。Med。2010）。该程序的总体概念模型是，Cardiollpin是一种编码细菌样分子特征的新型“脂质组相关的分子模式”，通常通过其内部线粒体内膜内的哺乳动物细胞内部的分隔掩盖。 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).因此，总体假设是，心脏单胞蛋白会引起对细胞特异性且高度分室化的ARDS肺稳态的差异性。为了执行该计划，我们召集了一个拥有互补专业知识的世界一流领导者团队，以协同研究调节可用性Cardiollpin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。为了评估该假设，研究人员将采用最先进的分子，基于细胞的和脂质细胞组的工具，这些工具将转化为ARDS人类受试者的肺损伤体内肺损伤和分析的互补模型。该计划将由具有氧化脂质症，动物和人类存储库服务以及生物成像的高度互动核心支持。这些研究的执行将为ARDS发病机理提供改变范式的概念模型，该模型是治疗干预的基础，并在肺部生物学中提供了新的，持续的科学询问领域。