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

基本信息

批准号：
10548843
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
项目类别：
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/10548843
关键词：
Acetyl Coenzyme A Acute Acute Lung Injury Acute Respiratory Distress Syndrome Address Adult Advisory Committees Amines Authorization documentation 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 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 Patient Admission Patients 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 biobank career career development cell type comparison control 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 pharmacologic skills therapy development

项目摘要

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.

项目概要肥胖困扰着美国 42% 的成年人，并且对健康造成严重的有害影响。急性呼吸窘迫综合征（ARDS）代表急性肺损伤（ALI）的最终途径传染性的，例如肺炎，或无菌性的，例如呼吸机引起的肺损伤，病因，以及相关的肥胖患者患 ARDS 的风险增加。需要更好地了解肥胖患者对 ARDS 易感性增加的机制。我们在高脂肪饮食的小鼠模型中表明，肥胖会导致无菌性和传染性疾病中更严重的急性肺损伤 (ALI) ARDS 模型的特点是脂肪酸 (FA) 释放量增加超过代谢需求。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，感染性和无菌 FA 被分解后，肥胖小鼠肺部的游离 FA 增加。通过  氧化在线粒体内产生能量，而内源 FA 是由乙酰辅酶 A 从头合成。高脂肪饮食与肺表达增加有关肉碱棕榈酰转移酶 1a (CPT1a)，一种  氧化的必需限速酶，并且降低脂肪酸合酶 (FASN)、催化 FA 从头合成的酶以及线粒体的表达 ALI 后，融合蛋白线粒体融合蛋白 2 (MFN2) 通过裂变和融合改变大小和形状以满足需要。肺泡上皮细胞代谢需求的改变与 ALI 相关。我们证明 2 型肺泡上皮细胞中 FASN 的消耗与更严重的 ALI 和线粒体生物能量学受损在这项提案中，我们解决了高脂肪饮食引起的问题。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。过度的氧化导致的线粒体超载会进一步加剧线粒体功能障碍。利用遗传手段研究 FA 利用在实验性肥胖诱导的 ALI 发病机制中的作用目标 2 将描述抑制和增强 β 氧化的药理学方法之间的关联。高脂饮食引起的 ALI 中 FASN 调节、线粒体动力学和肺泡上皮细胞 2 型功能障碍在 ALI 的无菌和感染模型中使用遗传方法抑制 FASN 和 MFN1/2。根据 ARDS 患者的体重指数 (BMI) 描述失调的代谢途径这些研究将深入了解肥胖与 ARDS 之间的相互作用。并可能揭示脂质代谢在 ALI 中未被重视的作用。该提议在职业生涯中发挥着核心作用。成为专注于肺生物学和脂质的成功独立研究者的发展计划威尔康奈尔医学中心不仅是执行该训练计划的理想环境。因为它优良的物质资源，也因为它的研究人员的知识群体对早期研究人员的强有力指导的记录。