Targeting fibroblast growth factor receptors in cystic fibrosis-associated airway inflammation and mucociliary dysfunction
靶向成纤维细胞生长因子受体治疗囊性纤维化相关气道炎症和粘液纤毛功能障碍
基本信息
- 批准号:10559552
- 负责人:
- 金额:$ 45.3万
- 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:2022-02-01 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:AbateAccelerationAddressAdultAgingAirAnimal ModelAnti-Inflammatory AgentsAtherosclerosisAttenuatedBacterial InfectionsCaringCell Culture TechniquesCell physiologyChronicCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorDataDiseaseEconomic BurdenEndocrineEpithelial CellsExhibitsFGFR1 geneFibroblast Growth FactorFibroblast Growth Factor ReceptorsFunctional disorderGenesGenotypeHealthHumanImpairmentIn VitroIndividualInfectionInflammationInflammatoryInnate Immune ResponseLaboratoriesLifeLife ExpectancyLigandsLinkLiquid substanceLungLung diseasesMissionModelingMorbidity - disease rateMucociliary ClearanceMultiple Bacterial Drug ResistanceMutationNational Heart, Lung, and Blood InstituteObstructionOrganPopulationPredispositionPreventionProtein IsoformsProteinsPseudomonas aeruginosaPseudomonas aeruginosa infectionPublic HealthPublishingPulmonary Cystic FibrosisPulmonary FibrosisPulmonary InflammationQuality of lifeRattusReceptor InhibitionReceptor SignalingRecurrenceResearchRespiratory Tract InfectionsRiskRoleSepsisSerumSeveritiesSignal PathwaySignal TransductionStructureStructure of parenchyma of lungSupplementationTestingTherapeutic InterventionTransforming Growth Factor betaTransforming Growth Factorsairway inflammationairway obstructionanti agingbronchial epitheliumcomorbiditycystic fibrosis airwaycystic fibrosis patientscytokineexperiencefunctional improvementhealth economicsimprovedin vivoin vivo Modelinhibitorinterdisciplinary approachinterestliver inflammationlung injurymortalitymuco-obstructive airway diseasesmucoidmucus clearancemucus-associated lung diseasesnovelnovel therapeutic interventionoverexpressionpathogenpulmonary functionpulmonary function declinereceptorreceptor expressionrecurrent infectionsocioeconomicstherapeutic target
项目摘要
Project Summary
Cystic fibrosis (CF) is one the most common life-shortening single gene defective disorders with over 70,000
cases worldwide. Mortality of CF patients has significantly decreased over the last decades and we are facing
new treatment challenges for an aging CF population. While CF transmembrane conductance regulator (CFTR)
modulator therapy is effective for many CF manifestations, airway inflammation as a hallmark of CF lung disease
is not consistently impacted leading to impaired mucus clearance and susceptibility to chronic airway infections.
Therefore, it is of great interest to identify novel therapeutic approaches that improve CF-associated chronic
inflammation, mucociliary dysfunction and recurrent infections to be ultimately applicable for all CF patients. We
have recently published that Fibroblast Growth Factor (FGF) signaling, a well characterized pro-inflammatory
and aging signaling pathway, is activated in CF lung disease. We hypothesize that FGF receptor (FGFR)
inhibition will attenuate CF-associated inflammation and impaired mucociliary clearance. We will test our
hypothesis by employing a multidisciplinary approach combining cell culture with animal models including a
chronic airway infection model.
Aim 1 will establish the effects of FGFR inhibition in vitro on airway inflammation and mucociliary clearance in
the human CF lung using primary human bronchial epithelial cells, cultured at the air liquid interface from different
CF genotypes. The in vivo Aim 2 will recapitulate these findings in established CF rat models and assess
FGFR inhibition and its impact on CF-associated inflammation, muco-obstructive disease and lung function.
Aim 3 will further establish FGFR modulation in the chronically infected CF lung in vivo.
The overall aim of this proposal is to establish the role of FGFR modulation in CF associated lung
complications as an amenable therapeutic target to ultimately improve functional outcomes, quality of life,
and long-term survival in the growing population of aging individuals with CF.
项目摘要
囊性纤维化(CF)是一种最常见的缩短寿命的单基因缺陷性疾病,
全世界的案例。过去几十年来,CF患者的死亡率显着下降,我们面临着
老年CF人群面临新的治疗挑战。而CF跨膜传导调节因子(CFTR)
调节剂治疗对许多CF表现有效,气道炎症是CF肺病的标志
并不总是受到影响,导致粘液清除受损和对慢性气道感染的易感性。
因此,确定改善CF相关慢性炎症的新的治疗方法是非常有意义的。
炎症、粘膜纤毛功能障碍和复发性感染的治疗最终适用于所有CF患者。我们
最近发表了成纤维细胞生长因子(FGF)信号传导,一种充分表征的促炎因子,
和衰老信号通路,在CF肺病中被激活。我们假设FGF受体(FGFR)
抑制将减弱CF相关炎症和受损的粘膜纤毛清除。我们将测试我们的
通过采用多学科方法将细胞培养与动物模型相结合,
慢性气道感染模型。
目的1将在体外建立FGFR抑制对气道炎症和粘膜纤毛清除的影响,
人CF肺使用原代人支气管上皮细胞,在来自不同来源的空气-液体界面处培养,
CF基因型。体内目标2将在已建立的CF大鼠模型中概括这些发现,并评估
FGFR抑制及其对CF相关炎症、粘膜阻塞性疾病和肺功能的影响。
目的3将进一步建立体内慢性感染CF肺中的FGFR调节。
本提案的总体目标是确定FGFR调节在CF相关肺损伤中的作用。
并发症作为一个可行的治疗目标,以最终改善功能结果,生活质量,
和长期生存在不断增长的人口老龄化的个人与CF。
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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Stefanie Krick其他文献
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{{ truncateString('Stefanie Krick', 18)}}的其他基金
Targeting fibroblast growth factor receptors in cystic fibrosis-associated airway inflammation and mucociliary dysfunction
靶向成纤维细胞生长因子受体治疗囊性纤维化相关气道炎症和粘液纤毛功能障碍
- 批准号:
10339681 - 财政年份:2022
- 资助金额:
$ 45.3万 - 项目类别:
Fibroblast Growth Factor 23/Klotho Crosstalk and Airway Epithelial Senescence in COPD
成纤维细胞生长因子 23/Klotho 串扰与 COPD 中的气道上皮衰老
- 批准号:
9751171 - 财政年份:2018
- 资助金额:
$ 45.3万 - 项目类别:
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