Arsenic-mediated fibrosis and developmental dysregulation in the fetal lung
砷介导的胎儿肺纤维化和发育失调
基本信息
- 批准号:9453861
- 负责人:
- 金额:$ 21.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-12-15 至 2019-11-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAmericanArsenicAttenuatedCalciumCessation of lifeChestChronicChronic lung diseaseContractsCoupledDataDevelopmentDilatorDoseDyesEmbryoEnvironmentEpidermisEventExposure toFDA approvedFetal DevelopmentFetal LungFibrosisGrowthGuidelinesHealthImpairmentIsoproterenolLeadLifeLiteratureLungLung diseasesMechanicsMediatingMediator of activation proteinMicrofluidicsModelingMolecularMorbidity - disease rateMorphogenesisMusMuscleMuscle ContractionMuscle relaxation phaseMyosin Light ChainsNeonatalOrganOrgan SizePathologyPathway interactionsPeristalsisPharmacologyPhenotypePhosphorylationPhosphotransferasesPhysiologicalPlayPoliciesPopulations at RiskPredispositionPregnant WomenProphylactic treatmentPublic HealthPublishingResearchResolutionRespiratory InsufficiencyRiskRoleSignal TransductionSkinSmooth MuscleStenosisSterilitySystemTechniquesTestingTimeToxic effectTranslatingTumor Suppressor ProteinsUnited StatesUp-RegulationVascular Smooth MuscleWater SupplyWestern BlottingWorld Health Organizationairway epitheliumairway remodelingcalcium indicatorcostfetalground waterimprovedin uteroinhibitor/antagonistinnovationlung developmentlung volumemortalitynovelprenatalprenatal exposureprenatal healthpulmonary hypoplasiarespiratory smooth musclesmall molecular inhibitortherapeutic evaluationtool
项目摘要
PROJECT SUMMARY/ABSTRACT
Arsenic contamination of groundwater remains a widespread public health crisis, affecting an estimated
150 million people worldwide, including 13 million in the United States. Even at low doses, chronic arsenic
exposure leads to multiple morbidities and mortalities. A growing body of literature demonstrates the health
impacts of in utero arsenic exposure resulting in long term increases in morbidity, a prime example of which is
increased risk for chronic respiratory disease (CRD). Whereas many of the mechanisms are unclear, it is
known that in utero arsenic exposure leads to pulmonary hypoplasia, or decreased lung growth. Using a
microfluidic ex vivo culture model of the embryonic lung, we can culture lung explants in a physiologically
relevant mechanical environment and simultaneously interrogate molecular and mechanical events with high
temporal and spatial resolution. Our findings have demonstrated that branching is regulated by coordinated
airway smooth muscle (ASM) contractions and dysregulation has major functional consequences on lung
development. Additionally, we determined that arsenic alters expression of core Hippo pathway components
that are known to regulate organ size. We hypothesize that fetal arsenic exposure impairs airway
morphogenesis through two independent mechanisms: dysregulation of active smooth muscle
contractions that guide development and hyperactivation of the Hippo growth control pathway within
the airway epithelium to cause hypoplasia. We will investigate this hypothesis using our novel microfluidic
embryonic organ explant culture model in two independent aims.
In our first Aim, we test the effect of arsenic on the coordinated ASM contractions that are tightly
coupled to airway branching and lung growth. Whereas the function of ASM contractions are incompletely
understood, it is known that ASM contractions require Ca2+ signaling. Ca2+ signaling is disrupted by arsenic in
other smooth muscle tissues. Our preliminary data support dysregulated Ca2+ signaling in the ASM to cause a
hypercontracted phenotype and hypoplasia. In our second Aim, we test the importance of Hippo signaling as
a mediator of lung growth, using a combination of molecular signaling perturbation and morphometric
techniques. Hippo signaling has been implicated in controlling organ size in a variety of systems, and improper
activity can lead to dramatic hypoplasia. However, Hippo signaling has been minimally investigated in lung
development. Additionally, arsenic induced activation of Hippo has been shown in mouse epidermis. In both
Aims, we will target our hypothesized mediators of arsenic toxicity using either an FDA approved compound
(isoprotenerol) or the recently developed small-molecular inhibitor (XMU-MP-1), potentially offering a path to
prophylactic treatments for at-risk populations. In aggregate, these studies will increase understanding of the
effects of arsenic exposure on early lung development, inform new policies and EPA exposure limits for
expectant mothers, and hold promise to rapidly translate these findings to improve prenatal health.
项目摘要/摘要
地下水的砷污染仍然是一种普遍的公共卫生危机,影响到估计
全球有1.5亿人,其中包括美国的1300万人。即使在低剂量下,慢性砷
暴露会导致多种疾病和死亡。越来越多的文学作品证明了
宫内砷暴露导致发病率长期增加的影响,最好的例子是
增加患慢性呼吸道疾病(CRD)的风险。虽然许多机制尚不清楚,但它是
已知在宫内接触砷会导致肺发育不全,或肺生长减退。使用
微流控胚胎肺体外培养模型,我们可以在生理学上培养肺外植体
相关的力学环境,并同时询问分子和力学事件
时间和空间分辨率。我们的发现表明,分支是由协调的
气道平滑肌(ASM)收缩和调节失调对肺功能有重大影响
发展。此外,我们确定砷改变了河马途径核心成分的表达。
已知的调节器官大小的物质。我们假设胎儿接触砷会损害呼吸道
通过两种独立的机制实现形态发生:活性平滑肌的失调
引导河马生长控制通路发育和过度激活的收缩
引起呼吸道上皮发育不全。我们将使用我们的新型微流控芯片来研究这一假设
胚胎器官外植体培养模式的两个独立目标。
在我们的第一个目标中,我们测试砷对紧密结合的ASM协调收缩的影响
再加上呼吸道分支和肺的生长。而ASM收缩的功能不完全
了解,已知ASM收缩需要钙信号。砷对心肌细胞内钙信号传导的影响
其他平滑肌组织。我们的初步数据支持ASM中钙离子信号的失调导致
过度收缩表型和发育不全。在我们的第二个目标中,我们测试河马信号的重要性
肺生长的介体,使用分子信号扰动和形态计量学的组合
技巧。河马信号在多种系统中都与控制器官大小有关,而且不恰当。
活动会导致严重的发育不全。然而,河马信号在肺中的研究还很少。
发展。此外,在小鼠的表皮中也显示了砷诱导河马的激活。在这两个地方
AIMS,我们将使用FDA批准的化合物来针对我们假设的砷毒性介体
(异丙肾上腺素)或最近开发的小分子抑制剂(XMU-MP-1),可能提供了一条途径
对高危人群进行预防性治疗。总体而言,这些研究将增加对
砷暴露对早期肺发育的影响,告知新政策和环境保护局对
并承诺迅速将这些发现转化为改善产前健康的方法。
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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Jason Paul Gleghorn其他文献
Jason Paul Gleghorn的其他文献
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{{ truncateString('Jason Paul Gleghorn', 18)}}的其他基金
Cell-Mediated Antiretroviral Drug Transport in the Lymph Node
细胞介导的抗逆转录病毒药物在淋巴结中的转运
- 批准号:
10469495 - 财政年份:2021
- 资助金额:
$ 21.92万 - 项目类别:
Cell-Mediated Antiretroviral Drug Transport in the Lymph Node
细胞介导的抗逆转录病毒药物在淋巴结中的转运
- 批准号:
10327086 - 财政年份:2021
- 资助金额:
$ 21.92万 - 项目类别:
Pressure in lung development and congenital diaphragmatic hernia
肺部发育压力与先天性膈疝
- 批准号:
9311116 - 财政年份:2017
- 资助金额:
$ 21.92万 - 项目类别:
Pressure in lung development and congenital diaphragmatic hernia
肺部发育压力与先天性膈疝
- 批准号:
9918958 - 财政年份:2017
- 资助金额:
$ 21.92万 - 项目类别:
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