The Role of PON2 in the Development of Non-Allergic Asthma in Obesity
PON2 在肥胖引起的非过敏性哮喘发展中的作用
基本信息
- 批准号:10734050
- 负责人:
- 金额:$ 8.53万
- 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:2022-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:3-nitrotyrosineAcuteAddressAffectAgonistAirway DiseaseAirway FibrosisAsthmaBronchoalveolar Lavage FluidCell CountChronicCollagenCollagen Type IVCoronary arteryDataDepositionDevelopmentDietDiseaseEpithelial CellsEpitheliumExhalationExhibitsExposure toFatty acid glycerol estersFibrosisFructoseGlutathione DisulfideHomeostasisHumanIndividualInflammatoryInhalationIsoprostanesLeftLinkLipid PeroxidationLungMeasuresMediatorModelingMusNitratesNitritesNon obeseNuclearObese MiceObesityOxidative StressOzonePPAR gammaParaoxonase-2Pathway interactionsPatientsPhenotypePhysical condensationPhysiologyPioglitazonePredispositionProcessQuality of lifeReactive Oxygen SpeciesResearch ProposalsReverse Transcriptase Polymerase Chain ReactionRodentRoleSignal TransductionSignaling MoleculeStressStructure of parenchyma of lungSymptomsTherapeuticThinnessTissuesTreatment EfficacyTrichrome stainVentilatorair filterairway epitheliumairway hyperresponsivenessairway inflammationantioxidant enzymeasthmaticasthmatic patientcell typecomorbiditycytokinediet-induced obesitydietary controleosinophilic inflammationexperiencefeedinggastrointestinal epitheliumimproved outcomeinterestknock-downmouse modelnitrosative stressobese patientsoxidant stressozone exposureprofiles in patientsresponserosiglitazonestressorsugar
项目摘要
Project Abstract
Asthma is a common disease characterized by airway hyperresponsiveness (AHR) and a heterogenous
inflammatory profile. In patients with asthma, comorbid obesity is associated with worse asthma control and
decreased efficacy of therapy. The inflammatory profile in patients with comorbid obesity and asthma is typified
by less eosinophilic inflammation and more oxidative and nitrosative (oxo-nitrosative) stress than lean patients
with asthma. The mechanism of this observation is not known. However, patients with comorbid obesity and
asthma have lower levels of paraoxonase 2 (PON2) in their airway epithelium than lean patients with asthma.
Furthermore, PON2 levels are modulated by peroxisome proliferator-activated receptor gamma (PPAR) in
multiple tissues. This proposal examines the role of changes in PON2 and PPAR in contributing to oxo-
nitrosative stress in patients with comorbid obesity and asthma. Using a murine model of diet induced obesity
and ozone exposure as a model of inhaled oxidative stress, this proposal will address three questions. First,
what is the relationship between Pon2 expression and oxo-nitrosative stress under the condition of obesity? This
question will be answered by using a high fat, high sugar diet to induce obesity and an acute ozone exposure as
an exogenous oxidative insult. Pon2 expression, markers of oxo-nitrosative stress, and airway physiology will
be assessed in lean and obese mice to determine if there is an association between Pon2 levels and airway
oxo-nitrosative stress. These findings will be compared to Pon2-/- mice under the same conditions to isolate the
effect of PON2. To isolate the precise role of the pulmonary epithelium in this process, cultured human airway
epithelial cells will be exposed to ozone and assessed for oxo-nitrosative stress. Second, how does Pon2
expression changes affect the development of airway fibrosis after chronic exposure to an oxidative stressor?
This question will be addressed by feeding mice either a high fat, high sugar or a control diet and then chronically
exposing them to ozone for 6 weeks. At the end of six weeks, airway physiology will be measured and lung tissue
will be assessed for the development of fibrosis. Third, does PPAR activation abrogate the effect of obesity on
PON2 expression, AHR and markers of oxo-nitrosative stress? This question will be addressed by treating mice
with the PPAR agonist, pioglitazone, and repeating the high fat, high sugar diet and acute ozone exposures
from our first question. Airway physiology, PON2 levels and oxo-nitrosative stress will then be assessed.
项目摘要
哮喘是一种以呼吸道高反应性(AHR)为特征的常见病
炎性侧写。在哮喘患者中,合并肥胖与较差的哮喘控制和
治疗效果下降。同时患有肥胖症和哮喘的患者的炎症特征是典型的。
与瘦患者相比,嗜酸性炎症较少,氧化和亚硝化(氧化-亚硝化)应激更多
患有哮喘。这种观察的机制尚不清楚。然而,同时患有肥胖症和
哮喘患者的呼吸道上皮细胞中对氧磷酶2(PON2)水平低于消瘦的哮喘患者。
此外,过氧化体增殖物激活受体γ(PPAR)对PON_2水平有调节作用。
多个组织。这项建议研究了PON_2和PPAR的变化在促进氧合作用中的作用。
肥胖和哮喘共病患者的亚硝化性应激。利用饮食诱导肥胖的小鼠模型
和臭氧暴露作为吸入性氧化应激的模型,这项提案将解决三个问题。第一,
肥胖条件下PON2的表达与氧-亚硝化应激有何关系?这
问题的答案将通过使用高脂肪、高糖饮食来诱导肥胖和急性臭氧暴露来回答,如
外源性氧化侮辱。PON2的表达,氧-亚硝化应激的标志,以及呼吸道生理学
在瘦小和肥胖的小鼠身上进行评估,以确定PON2水平与呼吸道之间是否存在关联
氧化亚硝化应激。这些发现将在相同条件下与PON2-/-小鼠进行比较,以分离出
PON的影响。为了分离肺上皮细胞在这一过程中的确切作用,培养的人呼吸道
上皮细胞将暴露在臭氧中,并评估氧-亚硝化应激。第二,PON2是如何
慢性暴露于氧化应激源后,表达变化会影响呼吸道纤维化的发展吗?
这个问题将通过喂给小鼠高脂肪、高糖或对照饮食来解决,然后长期
让他们暴露在臭氧中6周。在6周结束时,将测量呼吸道生理学和肺组织
将被评估为纤维化的发展。第三,PPAR的激活是否消除了肥胖对
PON2表达、AHR和氧-亚硝化应激标志物?这个问题将通过治疗老鼠来解决
使用PPAR激动剂吡格列酮,并重复高脂肪、高糖饮食和急性臭氧暴露
从我们第一个问题开始。然后将评估呼吸道生理学、PON_2水平和氧亚硝酸盐应激。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Experience With Trauma-Induced ARDS: A Retrospective Study of US Wartime Casualties 2003-2015.
创伤引起的 ARDS 经验:2003-2015 年美国战时伤亡情况回顾性研究。
- DOI:10.55460/mtvh-oncm
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:Nam,JasonJ;McCravy,MatthewS;Haines,KristaL;Thomas,SarahB;Aden,JamesK;Johnston,LukeR;Mason,PhillipE;Gurney,JenniferM;Sams,ValerieG
- 通讯作者:Sams,ValerieG
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Matthew McCravy其他文献
Matthew McCravy的其他文献
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{{ truncateString('Matthew McCravy', 18)}}的其他基金
The Role of PON2 in the Development of Non-Allergic Asthma in Obesity
PON2 在肥胖引起的非过敏性哮喘发展中的作用
- 批准号:
10533862 - 财政年份:2022
- 资助金额:
$ 8.53万 - 项目类别:
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