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)是一种了解甚少的罕见疾病。吸入调味化学品用于
食品制造业直接有助于职业的发展和进步,
一种被称为“爆米花肺”的BO。BO的特征是嗜酸性炎症,肺功能改变
和持续的气道纤维化,这可能导致生活质量下降,医疗保健费用增加,
预期寿命由于其罕见性,目前还没有针对任何形式的BO开发出有效的治疗方法。
BO有效治疗进展的关键障碍是:1)缺乏有效的治疗方法,
用于候选疗法的假设驱动的概念验证测试的适当临床前模型;以及,2)
对基本疾病机制的理解不足,无法指导假设驱动的有针对性的干预。我们有
直接解决这些障碍如下。首先,我们概括了在大鼠中的临床观察,
在工作场所接触人工黄油调味剂化合物双乙酰(2-,3-丁二酮; DA)会导致BO
在人类1.其次,由于上皮损伤是其他形式纤维化发展的核心,
使用原代人气道上皮细胞模拟人气道的DA蒸气暴露。两者合计
这些都是促成本建议的进展。
我们的体外模型系统的初步数据表明,DA暴露诱导持续的选择性,
表皮生长因子受体(EGFR)和密切相关的共受体ErbB 2的磷酸化。
同样,我们发现暴露于DA的气道上皮细胞分泌大量的
白细胞介素(IL)8、透明质酸(HA)和基质金属蛋白酶(MMP)9。IL-8,
HA和MMP 9均为BO的特异性标志物,且与气道的发生发展密切相关
其他疾病动物模型中的纤维化。与此一致,我们显示IL-8、HA和
随着BO的发展和进展,DA诱导的啮齿动物模型中的MMP 9。因此,我们的假设是,
使用FDA批准的小分子抑制剂阻断EGFR或ErbB 2将预防疾病
在我们的DA诱导的职业性BO的啮齿动物模型中的发展和进展。来测试我们
根据这一假设,我们制定了以下具体目标:
目的1:确定使用FDA批准的特异性抑制剂预防性抑制EGFR的功效
埃克替尼或ErbB 2与FDA批准的特异性抑制剂曲妥珠单抗在减弱
在DA诱导的BO中观察到嗜酸性炎症、肺功能改变和持续性气道纤维化,
在雄性和雌性大鼠中。
目的2:确定EGFR与埃克替尼或ErbB 2与曲妥珠单抗的治疗性干预的疗效
在预防先前建立的嗜肺性炎症的进展,改变肺功能,
在雄性和雌性大鼠中,在DA诱导的BO中观察到持续的气道纤维化。
项目成果
期刊论文数量(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:
8259732 - 财政年份:2011
- 资助金额:
$ 24.15万 - 项目类别:
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