Impact of Diet Induced Obesity on Acute Lung Injury

项目总结 在美国，42%的成年人患有肥胖症，并与严重的有害健康影响有关。 急性呼吸窘迫综合征(ARDS)是急性肺损伤(ALI)的最终途径，由以下原因引起 感染性的，如肺炎，或无菌的，如呼吸机引起的肺损伤，病因，与 死亡率很高。肥胖患者患ARDS的风险增加。这项建议解决了关键的 需要更好地了解肥胖患者对ARDS易感性增加的机制。 我们已经在高脂饮食的小鼠模型中表明，肥胖会导致更严重的不孕不育和传染性ALI。 ARDS的模型。肥胖的特征是脂肪酸(FA)的释放增加，超过代谢需求。 虽然FA对许多过程的生理调节很重要，但高水平是有害的。 我们发现，在感染和无菌ALI后，肥胖小鼠肺中游离FA增加。FA被分解了 通过氧化在线粒体内产生能量，而内源FA是 从乙酰辅酶A合成从头开始，高脂饮食与肺组织表达增加有关 肉毒碱棕榈酰基转移酶1a(CPT1a)是氧化的重要限速酶，其活性降低 脂肪酸合成酶(FASN)和线粒体的表达 ALI后的融合蛋白Mfn2(Mfn2)。线粒体通过分裂和融合改变大小和形状，以满足 细胞代谢需求。肺泡上皮细胞线粒体改变与ALI有关 发病机制。我们证明肺泡上皮2型细胞中FASN的耗竭与 更严重的ALI和线粒体生物能量学受损。在这项建议中，我们假设高脂肪饮食导致 损伤后线粒体融合和脂质合成的下调导致线粒体代谢受损。 过度的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 从遗传学角度探讨FA利用在实验性肥胖诱导ALI发病机制中的作用 以及抑制和增强氧化的药理方法。目标2将描述两者之间的关联 高脂饮食ALI患者FASN调节、线粒体动力学及肺泡上皮细胞2型功能障碍 在ALI不育和感染模型中使用基因方法抑制FASN和Mfn1/2。目标3将 基于体重指数(BMI)的ARDS患者代谢异常特征的研究 血浆代谢组谱。这些研究将为肥胖和ARDS之间的相互作用提供洞察力 并可能揭示ALI中脂代谢的一个未被认识的角色。这个提议在职业生涯中起着核心作用。 成为一名成功的专注于肺部生物学和血脂的独立调查者的发展计划 新陈代谢。威尔·康奈尔医学院是执行该培训计划的理想环境，不仅 因为它优越的物质资源，也因为它的智力社区的研究人员与 对早期调查人员有很强的指导作用。

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.