Proof of concept treatment interventions in a rodent model of the rare disease bronchiolitis obliterans
在罕见疾病闭塞性细支气管炎的啮齿动物模型中进行概念治疗干预的验证
基本信息
- 批准号:10040120
- 负责人:
- 金额:$ 24.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAirAnimal Disease ModelsAttenuatedBiologicalBiological ModelsBolus InfusionBronchiolitis ObliteransButterCellsChemicalsChronicClinicalDataDevelopmentDiacetylDiseaseDisease ProgressionDoseERBB2 geneEpidermal Growth Factor ReceptorEpithelial CellsExposure toFDA approvedFemaleFibrosisFlavoringFoodGenderGoalsHealth Care CostsHistologicHumanHuman CharacteristicsHyaluronanIndustryInflammationInhalationInterleukin-8InterventionLeadLife ExpectancyLightLinkLiquid substanceLiteratureLungMMP9 geneMetalloproteasesModelingOccupationalOccupational ExposurePhosphorylationPhysiologicalPlayPre-Clinical ModelPreventionProductionProteomicsPublishingPulmonary FibrosisQuality of lifeRare DiseasesRattusReceptor SignalingReportingRespiratory physiologyRodent ModelRoleSignal TransductionTestingTherapeutic InterventionTranslatingTranslationsTrastuzumabTreatment Efficacyairway epitheliumairway obstructionclinically relevantdrug candidateeffective therapyepithelial injuryerbB-2 Receptorerythritol anhydrideexposed human populationfirst-in-humangender differencein vitro Modelinhibitor/antagonistinsightmaleneutrophilnovelpre-clinicalpreclinical studypreventprophylacticresponsesmall molecule inhibitortherapeutic candidatetherapy developmenttreatment responsevapor
项目摘要
Bronchiolitis obliterans (BO) is a poorly understood rare disease. Inhalation of flavoring chemicals used in
the food manufacturing industry directly contributes to the development and progression of the occupational
form of BO known as ‘popcorn lung’. BO is characterized by neutrophilic inflammation, altered lung function
and persistent airway fibrosis that can lead to reduced quality of life, increased health care costs and reduced
life expectancy. Because of its rarity, there have been no effective therapies developed for any form of BO.
Critical impediments to the advancement of effective therapies for BO have been: 1) the lack of an
appropriate pre-clinical model for hypothesis driven proof of concept testing of candidate therapeutics; and, 2)
a poor understanding of basic disease mechanisms to guide hypothesis driven targeted interventions. We have
directly addressed these impediments as follows. First, we have recapitulated in rats the clinical observation
that workplace exposure to the artificial butter flavoring compound diacetyl (2-,3-butanedione; DA) causes BO
in humans1. Second, because epithelial injury is central to the development of other forms of fibrosis, we have
modeled DA vapor exposure of the human airway using primary human airway epithelial cells. Taken together
these represent the enabling advances by virtue of which this proposal was developed.
Preliminary data from our in vitro model system shows that DA exposure induces persistent selective
phosphorylation of the epidermal growth factor receptor (EGFR) and the closely related co-receptor ErbB2.
Similarly, we show that the DA exposed airway epithelium secretes significantly increased quantities of
interleukin (IL) 8, hyaluronan (HA) and matrix metalloprotease (MMP) 9 in an EGFR dependent manner. IL-8,
HA and MMP9 are all pathognomonic of BO and have been plausibly linked with the development of airway
fibrosis in other animal models of disease. Consistent with this, we show significant increases in IL-8, HA, and
MMP9 in the DA-induced rodent model as BO develops and progresses. Therefore our hypothesis is that
blocking EGFR or ErbB2 using FDA approved small molecule inhibitors will prevent disease
development and progression in our rodent model of DA-induced occupational BO. To test our
hypothesis we have developed the following Specific Aims:
Aim 1: Determine the efficacy of prophylactic inhibition of the EGFR with the FDA approved specific inhibitor
Icotinib, or ErbB2 with the FDA approved specific inhibitor Trastuzumab in attenuating the development of
neutrophilic inflammation, altered lung function and persistent airway fibrosis observed in DA-induced BO both
in male and female rats.
Aim 2: Determine the efficacy of therapeutic intervention of the EGFR with Icotinib, or ErbB2 with Trastuzumab
in preventing the progression of previously established neutrophilic inflammation, altered lung function and
persistent airway fibrosis observed in DA induced BO in both male and female rats.
闭塞性细支气管炎(BO)是一种罕见的疾病。吸入用于调味的化学物质
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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Scott M Palmer其他文献
Scott M Palmer的其他文献
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{{ truncateString('Scott M Palmer', 18)}}的其他基金
Proof of concept treatment interventions in a rodent model of the rare disease bronchiolitis obliterans
在罕见疾病闭塞性细支气管炎的啮齿动物模型中进行概念治疗干预的验证
- 批准号:
10206315 - 财政年份:2020
- 资助金额:
$ 24.15万 - 项目类别:
Improving Lung Transplant Outcomes with Coping Skills and Physical Activity
通过应对技巧和体力活动改善肺移植结果
- 批准号:
10579871 - 财政年份:2019
- 资助金额:
$ 24.15万 - 项目类别:
The Lung Transplant Clinical Trials Network (LT-CTN)
肺移植临床试验网络 (LT-CTN)
- 批准号:
8771920 - 财政年份:2014
- 资助金额:
$ 24.15万 - 项目类别:
The Lung Transplant Clinical Trials Network (LT-CTN)
肺移植临床试验网络 (LT-CTN)
- 批准号:
9100633 - 财政年份:2014
- 资助金额:
$ 24.15万 - 项目类别:
The Lung Transplant Clinical Trials Network (LT-CTN)
肺移植临床试验网络 (LT-CTN)
- 批准号:
8880119 - 财政年份:2014
- 资助金额:
$ 24.15万 - 项目类别:
Lung Repair and Regeneration Consortium Administrative Coordinating Center
肺修复与再生联盟行政协调中心
- 批准号:
8403667 - 财政年份:2012
- 资助金额:
$ 24.15万 - 项目类别:
Lung Repair and Regeneration Consortium Administrative Coordinating Center
肺修复与再生联盟行政协调中心
- 批准号:
8788546 - 财政年份:2012
- 资助金额:
$ 24.15万 - 项目类别:
Lung Repair and Regeneration Consortium Administrative Coordinating Center
肺修复与再生联盟行政协调中心
- 批准号:
8223487 - 财政年份:2012
- 资助金额:
$ 24.15万 - 项目类别:
Lung Repair and Regeneration Consortium Administrative Coordinating Center
肺修复与再生联盟行政协调中心
- 批准号:
8616781 - 财政年份:2012
- 资助金额:
$ 24.15万 - 项目类别:
Novel Cellular Immune Profiles to Predict Lung Disease Outcomes
预测肺部疾病结果的新型细胞免疫特征
- 批准号:
8073307 - 财政年份:2011
- 资助金额:
$ 24.15万 - 项目类别:
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