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:10371363
- 负责人:
- 金额:$ 16.79万
- 依托单位:
- 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:
- 关键词:Acetyl Coenzyme AAcuteAcute Lung InjuryAcute Respiratory Distress SyndromeAddressAdultAdvisory CommitteesAminesBacterial PneumoniaBioenergeticsBiologicalBiologyBody mass indexCarnitine Palmitoyltransferase ICellsChimeric ProteinsClinicalCommunitiesComplexCritical IllnessCytosolDatabasesDevelopment PlansDiffuseDown-RegulationEnvironmentEnzymesEtiologyFatty AcidsFatty-acid synthaseFunctional disorderGenerationsGeneticGoalsHealthHigh Fat DietHyperoxiaImpairmentInflammatoryInjuryInterdisciplinary StudyLeadLevocarnitineLightLinkLipidsLungMeasuresMedicineMentorsMentorshipMetabolicMetabolic PathwayMetabolismMitochondriaModelingMorphologyMultiple TraumaNonesterified Fatty AcidsObese MiceObesityPathogenesisPathway interactionsPatientsPharmacologyPhysiologicalPlasmaPlayPneumoniaPredispositionProcessRegulationResearchResearch PersonnelResourcesRespirationRiskRoleShapesSterilityStressTestingToxic effectTrainingUnited StatesVentilator-induced lung injuryViral PneumoniaWeightacylcarnitinealveolar epitheliumauthoritybasebiobankcareercareer developmentcell typediet-induced obesityfatty acid metabolismfatty acid oxidationgenetic approachinsightlipid metabolismlung injurymetabolomicsmitochondrial dysfunctionmitochondrial metabolismmortalitymouse modelobese patientsobese personoxidationskillstherapy 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.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Maria Plataki其他文献
Maria Plataki的其他文献
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{{ truncateString('Maria Plataki', 18)}}的其他基金
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:
10548843 - 财政年份:2022
- 资助金额:
$ 16.79万 - 项目类别:
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:
10632732 - 财政年份:2022
- 资助金额:
$ 16.79万 - 项目类别:
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