Impact of Diet Induced Obesity on Acute Lung Injury

项目摘要 肥胖困扰着美国42%的成年人，并且与显著的有害健康影响相关。 急性呼吸窘迫综合征（ARDS）是由急性肺损伤（ALI）引起的终末途径， 感染性，如肺炎，或无菌性，如呼吸机引起的肺损伤，病因，并与 死亡率很高。肥胖患者发生ARDS的风险增加。该提案涉及关键的 需要更好地理解肥胖患者对ARDS易感性增加的机制。 我们已经在高脂肪饮食的小鼠模型中表明，在无菌和感染性小鼠中，肥胖导致更严重的ALI。 ARDS模型肥胖症的特征是脂肪酸（FA）释放增加，超过代谢需求。 虽然FA对于许多过程的生理调节是重要的，但是高水平是有害的。 我们发现感染性和无菌性ALI后肥胖小鼠肺中游离FA增加。FA被分解 通过线粒体内的脂肪酸氧化产生能量，而内源性FA 由乙酰辅酶A从头合成。高脂饮食与肺组织中 肉毒碱棕榈酰转移酶1a（CPT 1a），一种重要的限速酶，为肉毒碱氧化，并减少 脂肪酸合成酶（FATCH）（催化FA从头合成的酶）和线粒体的表达 融合蛋白线粒体融合蛋白2（MFN 2）。线粒体通过分裂和融合改变大小和形状， 细胞代谢的需求。肺泡上皮细胞的线粒体改变与ALI有关 发病机制我们证明肺泡上皮2型细胞中FXR的耗竭与 更严重的ALI和受损的线粒体生物能量学。在这个建议中，我们假设高脂肪饮食诱导 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。 通过过度的谷胱甘肽氧化导致的线粒体过载进一步加剧了线粒体功能障碍。目标1将 应用遗传学方法探讨脂肪酸利用在实验性肥胖性ALI发病机制中的作用。 和药理学方法来抑制和增强谷胱甘肽氧化。目标2将描述 高脂饮食致急性肺损伤的线粒体动力学和肺泡上皮细胞2型功能障碍 在无菌和感染性ALI模型中使用遗传方法抑制FEV 1和MFN 1/2。目标3将 使用体重指数（BMI）表征ARDS患者中失调的代谢途径 血浆代谢组学分析。这些研究将提供深入了解肥胖和ARDS之间的相互作用 并可能揭示了脂质代谢在ALI中未被重视的作用。这个建议在职业生涯中起着核心作用 成为一名成功的独立研究者的发展计划，专注于肺生物学和脂质 新陈代谢.威尔康奈尔医学是一个理想的环境，在其中执行这一培训计划，不仅 因为它拥有优良的物质资源，但也因为它的研究人员的智力社区， 对早期调查人员的良好指导记录。

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.