Impact of Diet Induced Obesity on Acute Lung Injury

饮食引起的肥胖对急性肺损伤的影响

• 批准号: 10371363
• 负责人: Maria Plataki
• 金额: $ 16.79万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10371363
• 关键词: Acetyl Coenzyme A; Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Address; Adult; Advisory Committees; Amines; Bacterial Pneumonia; Bioenergetics; Biological; Biology; Body mass index; Carnitine Palmitoyltransferase I; Cells; Chimeric Proteins; Clinical; Communities; Complex; Critical Illness; Cytosol; Databases; Development Plans; Diffuse; Down-Regulation; Environment; Enzymes; Etiology; Fatty Acids; Fatty-acid synthase; Functional disorder; Generations; Genetic; Goals; Health; High Fat Diet; Hyperoxia; Impairment; Inflammatory; Injury; Interdisciplinary Study; Lead; Levocarnitine; Light; Link; Lipids; Lung; Measures; Medicine; Mentors; Mentorship; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Morphology; Multiple Trauma; Nonesterified Fatty Acids; Obese Mice; Obesity; Pathogenesis; Pathway interactions; Patients; Pharmacology; Physiological; Plasma; Play; Pneumonia; Predisposition; Process; Regulation; Research; Research Personnel; Resources; Respiration; Risk; Role; Shapes; Sterility; Stress; Testing; Toxic effect; Training; United States; Ventilator-induced lung injury; Viral Pneumonia; Weight; acylcarnitine; alveolar epithelium; authority; base; biobank; career; career development; cell type; diet-induced obesity; fatty acid metabolism; fatty acid oxidation; genetic approach; insight; lipid metabolism; lung injury; metabolomics; mitochondrial dysfunction; mitochondrial metabolism; mortality; mouse model; obese patients; obese person; oxidation; skills; therapy development

PROJECT SUMMARY Obesity afflicts 42% of the adults in the United States and is associated with significant deleterious health effects. Acute respiratory distress syndrome (ARDS) represents a final pathway of acute lung injury (ALI) arising from infectious, such as pneumonia, or sterile, such as ventilator induced lung injury, etiologies, and is associated with high mortality. Obese patients are at increased risk of developing ARDS. This proposal addresses the critical need to better understand the mechanisms that underlie the increased susceptibility of obese patients to ARDS. We have shown in a murine model of high fat diet that obesity results in more severe ALI in sterile and infectious models of ARDS. Obesity is characterized by increased fatty acid (FA) release that exceeds metabolic demands. Although FA are important for the physiologic regulation of a number of processes, high levels are deleterious. We have found increased free FA in the lung of obese mice after infectious and sterile ALI. FA are broken down by means of oxidation for energy generation inside the mitochondria, whereas endogenous FA are synthesized de novo from acetyl coenzyme A. High fat diet was associated with increased lung expression of carnitine palmitoyltransferase 1a (CPT1a), an essential rate limiting enzyme for oxidation, and decreased expression of fatty acid synthase (FASN), the enzyme catalyzing de novo FA synthesis, and of the mitochondrial fusion protein mitofusin 2 (MFN2) after ALI. Mitochondria alter size and shape via fission and fusion to meet cellular metabolic demands. Mitochondrial alterations in the alveolar epithelium have been implicated in ALI pathogenesis. We demonstrated that depletion of FASN in alveolar epithelial type 2 cells was associated with more severe ALI and impaired mitochondrial bioenergetics. In this proposal, we hypothesize high fat diet induced downregulation of mitochondrial fusion and lipid synthesis lead to impaired mitochondrial metabolisml after injury. Mitochondrial overload through excessive oxidation further exacerbates mitochondrial dysfunction. Aim 1 will investigate the role of FA utilization in the pathogenesis of experimental obesity induced ALI by using genetic and pharmacologic approaches to inhibit and enhance oxidation. Aim 2 will delineate the association between FASN regulation, mitochondrial dynamics and alveolar epithelial cell type 2 dysfunction in ALI with high fat diet using genetic approaches to inhibit FASN and MFN1/2 in a sterile and infectious model of ALI. Aim 3 will characterize dysregulated metabolic pathways based on body mass index (BMI) in patients with ARDS using plasma metabolomic profiling. These studies will provide insight into the interplay between obesity and ARDS and may uncover an unappreciated role for lipid metabolism in ALI. This proposal plays a central role in a career development plan for becoming a successful independent investigator focused on lung biology and lipid metabolism. Weill Cornell Medicine is an ideal environment in which to execute this training plan not only because of its excellent physical resources, but also because of its intellectual community of researchers with a track record of strong mentorship of early stage investigators.

项目摘要 肥胖症遭受了美国42％的成年人的影响，并且与重大有害健康作用有关。 急性呼吸窘迫综合征（ARDS）代表由急性肺损伤（ALI）的最终途径 传染性，例如肺炎或无菌，例如呼吸机诱导的肺损伤，病因，并且与 死亡率很高。肥胖患者患ARDS的风险增加。该提议解决了关键 需要更好地了解肥胖患者对ARDS敏感性增加的机制。 我们已经在高脂饮食的鼠模型中显示，肥胖导致无菌和传染性的ALI更为严重 ARDS的模型。肥胖症的特征是脂肪酸（FA）释放增加，超过了代谢需求。 尽管FA对于许多过程的生理调节很重要，但高水平是有害的。 我们发现在传染性和无菌ALI后，肥胖小鼠肺中的自由FA增加。 FA被分解 通过线粒体内部能量产生的氧化，而内源性FA是 来自乙酰辅酶A的合成。 肉碱棕榈转移酶1A（CPT1A），这是一种限制酶氧化酶的基本速率，并改善了 脂肪酸合酶（FASN）的表达，酶催化从头fa合成和线粒体的表达 ALI之后的融合蛋白丝线2（MFN2）。线粒体通过裂变和融合改变大小和形状以满足 细胞代谢需求。牙槽上皮的线粒体改变已与Ali有关 发病。我们证明了FASN在肺泡上皮2型细胞中的耗竭与 更严重的ALI和线粒体生物能力受损。在此提案中，我们假设高脂饮食引起 线粒体融合和脂质合成的下调导致损伤后线粒体代谢受损。 线粒体通过过量的氧化氧化进一步加剧了线粒体功能障碍。目标1意志 研究FA利用在实验性肥胖诱导ALI的发病机理中的作用，使用遗传 以及抑制和增强的药理学方法。 AIM 2将描述 FASN调节，线粒体动力学和肺泡上皮细胞2型ALI的功能障碍，高脂饮食 使用遗传方法在ALI的无菌和感染模型中抑制FASN和MFN1/2。目标3意志 根据体重指数（BMI）的ARDS患者的体重指数（BMI）的表征，使用非代谢途径 血浆代谢组分析。这些研究将洞悉肥胖与ARDS之间的相互作用 并且可能会发现Ali中脂质代谢的不欣赏作用。该建议在职业中起着核心作用 成为成功的独立研究者的发展计划，专注于肺部生物学和脂质 代谢。威尔·康奈尔（Weill Cornell）医学是执行该培训计划的理想环境 由于其出色的物理资源，而且还因为其知识分子社区的研究人员 早期研究人员强烈心态的记录。