Determining the Role of Myeloid-derived HB-EGF in Pulmonary Fibrosis
确定髓源性 HB-EGF 在肺纤维化中的作用
基本信息
- 批准号:10023169
- 负责人:
- 金额:$ 3.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-01 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:AgeAgingAlveolarAnimal ModelAnimalsApoptosisAreaAttentionBiologicalBleomycinCRISPR/Cas technologyCell CommunicationCell Culture TechniquesCell MaintenanceCellsCellular StructuresCicatrixClinicalClinical DataClinical ResearchClinical TrialsCoculture TechniquesCritical ThinkingCultured CellsDTR geneDataDepositionDevelopmentDiagnosisDiseaseDisease ProgressionEnvironmentEpidermal Growth FactorEpidermal Growth Factor ReceptorEpithelialEpithelial CellsEpitheliumErbB4 geneErlotinibExtracellular Matrix ProteinsFibroblastsFibronectinsFibrosisFlow CytometryFunctional Residual CapacityFutureGefitinibGenetically Engineered MouseGrowth FactorGrowth Factor ReceptorsHeparin BindingHyperplasiaImpairmentIn VitroInduced MutationInflammationInflammatoryInjuryKidneyLigandsLinkLiverLungLung ComplianceLung InflammationLung diseasesMacrophage ActivationMeasuresMediatingMediator of activation proteinMembraneMesenchymalMethodsMitosisModelingMolecularMouse Cell LineMusMyelogenousMyeloid CellsMyofibroblastOutcomeOxygenPathogenesisPathway interactionsPatientsPermeabilityPharmaceutical PreparationsPharmacologyPhenotypePhysiologicalPhysiologyPlasmaPopulationPrevalencePreventionProductionProteinsPulmonary FibrosisReceptor InhibitionReceptor Protein-Tyrosine KinasesRegulationResearchRespiratory FailureRespiratory Signs and SymptomsRespiratory physiologyRoleScientistSignal TransductionSmall Interfering RNASmooth Muscle Actin Staining MethodSourceStomachSurfaceTestingTherapeuticTimeToxic effectTrainingTyrosine Kinase Inhibitoralveolar epitheliumangiogenesisanimal datacollagenasecytokineexperienceexperimental studyglobal healthidiopathic pulmonary fibrosisimprovedin vivoindium-bleomycininhibitor/antagonistinnovationinsightkeratinocytelung developmentlung injurymacrophagemembermigrationmonocytemortalitynovelpressurereceptorrecruitskillssuccesstargeted treatmenttherapeutic targetwound healing
项目摘要
Project Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with no known cure, with patients experiencing a
gradual loss of lung function and debilitating pulmonary symptoms that result in respiratory failure within 2-5
years after diagnosis. IPF is characterized by lung injury and inflammation, excessive deposition of extracellular
matrix proteins, fibroblast hyperplasia, and scar formation. With prevalence highly associated with age and
suboptimal treatment options, IPF is a devastating disease that is a serious global health concern in an aging
world population. Preliminary data in the Moore lab suggest that heparin-binding epidermal growth factor-like
growth factor (HB-EGF) may be critically important in the development and progression of fibrosis. HB-EGF is
an EGF receptor (EGFR) ligand that has essential roles in angiogenesis and wound healing, keratinocyte
migration and epithelial-mesenchymal transition. Recent clinical studies show that IPF patients expressing levels
of HB-EGF and its receptor above an identified threshold are more likely to experience disease progression
(HR=8.772, P=0.0053, 95% CI 1.905-40.385 and HR=2.2, P=0.0251, 95% CI 1.104-4.378 respectively).
Furthermore, the functionality of HB-EGF as a key target in prevention of fibrosis progression has been noted
via the success of receptor tyrosine kinase (RTK)-EGFR-specific antagonism in animal models. However, clinical
trials administering select RTK-EGFR inhibitors can result in toxicity and lethality in some patients, and thus
there is a need to better understand this pathway in the development of fibrosis to allow for more targeted
therapeutic options. Our lab recently conducted a preliminary study showing that mice lacking myeloid-specific
HB-EGF are protected from bleomycin-induced pulmonary fibrosis compared to wild type controls. These data
suggest that inhibition of myeloid-derived HB-EGF could serve as a viable therapeutic for IPF patients in the
future. This proposal will test the hypothesis that HB-EGF production from myeloid cells induces alveolar
epithelial cell (AEC) or fibroblast alterations that promote the development of lung fibrosis. This
hypothesis will be tested through three specific aims: (1) Demonstrate the impact of myeloid-specific HB-EGF
on parameters of pulmonary fibrosis in mice, (2) Determine if soluble or cell-associated HB-EGF is responsible
for profibrotic changes to epithelial cells or fibroblasts, and (3) Determine if HB-EGF primarily signals through
EGFR or HER4. To accomplish these specific aims, mouse cell lines and genetically engineered mouse models
will be used to perform the appropriate in vitro and in vivo experiments to study cell signaling and cell-cell
interactions with and without myeloid-derived HB-EGF. The results from these innovative studies will establish
the impacts of myeloid-HB-EGF signaling on relevant AEC and fibroblast activation outcomes with the overall
future aim of identifying myeloid-derived HB-EGF as a therapeutic target for patients. This project will also serve
as an excellent training vehicle for the applicant to gain core skills in research and critical thinking to help her
become a successful and independent scientist.
项目摘要
项目成果
期刊论文数量(0)
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