Correcting Pathogenic TGF beta Activity in the Airway
Correcting Pathogenic TGF beta Activity in the Airway
批准号:
10347371
负责人:
Agnieszka Swiatecka-Urban
金额:
$41.18万
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
项目状态:
已结题
起止时间:
2019-02-01 至 2023-12-31
关键词:
3&apos Untranslated RegionsAffectAir PollutantsApicalBindingBinding SitesCaucasiansCause of DeathCellsChloride ChannelsChloride IonChronic Obstructive Pulmonary DiseaseCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorDataDefectDehydrationDelta F508 mutationDisabled PersonsDiseaseEpithelial CellsEpitopesFDA approvedFinancial compensationGene MutationGenesGenetic PolymorphismGenetic TranslationHealth Care CostsHomeostasisInterventionIon ChannelIon TransportLeadLearningLungLung diseasesMediatingMediator of activation proteinMessenger RNAMicroRNAsMolecularMovementMutationPathogenicityPatientsPharmaceutical PreparationsPhenotypePotassium ChannelProbabilityProteinsPulmonary Cystic FibrosisPulmonary Function Test/Forced Expiratory Volume 1RecoveryRegulationRegulator GenesRepressionResidual stateResistanceRespiratory physiologyResponse ElementsRoleSeveritiesSignal TransductionSiteSodium ChlorideStructure of parenchyma of lungTestingTherapeuticTransforming Growth Factor betaTransforming Growth FactorsTranslationsTreatment EfficacyUp-RegulationVX-770VX-809Waterairway epitheliumairway surface liquidbronchial epitheliumcigarette smokecystic fibrosis patientsdesignfunctional restorationgenetic variantimprovedimproved outcomeinhibitorinjured airwaymRNA Stabilitymutantnovelnovel strategiesnovel therapeutic interventionnovel therapeuticsnucleocytoplasmic transportpreservationpreventpulmonary functiontargeted treatment
中文摘要
摘要
英文摘要
ABSTRACT
Homeostasis of the airway surface liquid (ASL) in lung is critically dependent on chloride ion (Cl-) transport,
mediated by the apical channel, CFTR (cystic fibrosis transmembrane conductance regulator). CFTR gene
mutations associated with the most common autosomal recessive disease in Caucasians, cystic fibrosis (CF)
result in loss of CFTR function and severe impairment of the ASL volume regulation. Deletion of F508
(F508del) in the CFTR gene is present in 90% of CF patients; it blocks CFTR biosynthetic processing, reduces
CFTR Cl- channel function, and decreases CFTR mRNA stability and translation. It is estimated that the classic
severe CF phenotype develops when the CFTR channel function is less than 1% of normal and at least 10%
function is needed to alleviate the severe phenotype. Therapies targeting the basic molecular defects in CF
demonstrate potential but are insufficient for most patients. While the FDA-approved drug VX-770 potentiates
CFTR channel “open” probabilities and improves lung function for less than 10% of patients with the rare
mutation G551D, the combined use of VX-770 and a corrector VX-809 that rescues the folding and processing
defect was only marginally effective for F508del patients. CF patients with more severe lung disease were
entirely resistant to such therapy. Transforming growth factor (TGF)-β1 contributes to resistance of corrector
therapy by blocking CFTR translation and represses ancillary ion channels critical to residual ASL homeostasis
in CF, namely BK (a Ca+2-activated K+ channel) and ANO1 (a Ca+2-activated Cl- channel). High TGF-β1 levels
are seen in 40% of F508del homozygous patients due to polymorphisms in the TGF-β1 gene. Air pollutants,
including cigarette smoke also increase TGF-β1 levels. The concomitant upregulation of TGF-β1 in turn
increases the severity of CF lung disease in F508del homozygous patients and presents a major block to
therapies aimed at F508del-CFTR rescue. We propose that targeting the pathogenic TGF-β1 activity would
improve the residual ASL volume homeostasis in CF by restoring the function of BK and ANO1 channels. It
would also increase the efficacy of therapy for F508del CF patients by restoring the diminished 508del-CFTR
translation and allowing increased activity of the mutant CFTR channel function. Thus, defining TGF-β1
mediators in lung tissue presents an opportunity to design novel drugs eliminating the pathogenic TGF-β1
activity in CF patients. Our central hypothesis is that the targeted reduction of TGF-β1 activity will ameliorate
negative effects on CFTR, BK, and ANO1 channels and ASL homeostasis, and provide a novel approach to
treat F508del CF patients. Our specific aims are to test the hypothesis: (1) that Dab2 is a TGF-β1 adaptor that
inhibits the residual ASL homeostasis in CF bronchial epithelium by directing nuclear transport of Smad3 to
repress the ancillary channels, BK and ANO1; (2) that the Dab2-Smad3 interactions upregulates microRNAs
that repress the ancillary channels and block corrector-mediated rescue of F508del-CFTR; and (3) that a
Dab2-Smad3 interaction is required for the pathogenic activity of TGF-β1 in CF bronchial epithelium.
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DOI:
10.3390/biomedicines10123030
发表时间:
2022-11-24
期刊:
Biomedicines
影响因子:
4.7
作者:
[]
通讯作者:
DOI:
10.3389/fonc.2021.596861
发表时间:
2021
期刊:
Frontiers in oncology
影响因子:
4.7
作者:
[Cruz DF, Mitash N, Mu F, Farinha CM, Swiatecka-Urban A]
通讯作者:
Swiatecka-Urban A
DOI:
10.1038/s42003-023-05671-8
发表时间:
2024-01-08
期刊:
COMMUNICATIONS BIOLOGY
影响因子:
5.9
作者:
[Morotz, Gabor M., Bradbury, Neil A., Caluseriu, Oana, Hisanaga, Shin-ichi, Miller, Christopher C. J., Swiatecka-Urban, Agnieszka, Lenz, Heinz-Josef, Moss, Stephen J., Giamas, Georgios]
通讯作者:
Giamas, Georgios
The Ago2-miRNA-co-IP Assay to Study TGF- β1 Mediated Recruitment of miRNA to the RISC in CFBE Cells.
DOI:
10.3791/61571
发表时间:
2020-07-31
期刊:
Journal of visualized experiments : JoVE
影响因子:
--
作者:
[Mitash N, Donovan JE, Swiatecka-Urban A]
通讯作者:
Swiatecka-Urban A
DOI:
10.1016/j.conctc.2021.100749
发表时间:
2021-06
期刊:
Contemporary clinical trials communications
影响因子:
1.5
作者:
[Gillespie BW, Laurin LP, Zinsser D, Lafayette R, Marasa M, Wenderfer SE, Vento S, Poulton C, Barisoni L, Zee J, Helmuth M, Lugani F, Kamel M, Hill-Callahan P, Hewitt SM, Mariani LH, Smoyer WE, Greenbaum LA, Gipson DS, Robinson BM, Gharavi AG, Guay-Woodford LM, Trachtman H]
通讯作者:
Trachtman H
共 6 条
Correcting Pathogenic TGF beta Activity in the Airway
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批准号:10189898
-
项目类别:
-
资助金额:$44.66万
-
财政年份:2019
-
负责人:Agnieszka Swiatecka-Urban
-
依托单位:
Novel Pathways in TGF BETA Signaling
-
批准号:9336443
-
项目类别:
-
资助金额:$35.16万
-
财政年份:2016
-
负责人:Agnieszka Swiatecka-Urban
-
依托单位:
Regulation of the Endocytic Trafficking of CFTR
-
批准号:7842159
-
项目类别:
-
资助金额:$29.02万
-
财政年份:2009
-
负责人:Agnieszka Swiatecka-Urban
-
依托单位:
Regulation of the Endocytic Trafficking of CFTR
-
批准号:8269022
-
项目类别:
-
资助金额:$37.5万
-
财政年份:2008
-
负责人:Agnieszka Swiatecka-Urban
-
依托单位:
Regulation of the Endocytic Trafficking of CFTR
-
批准号:7840520
-
项目类别:
-
资助金额:$37.88万
-
财政年份:2008
-
负责人:Agnieszka Swiatecka-Urban
-
依托单位:
Regulation of the Endocytic Trafficking of CFTR
-
批准号:8084182
-
项目类别:
-
资助金额:$37.88万
-
财政年份:2008
-
负责人:Agnieszka Swiatecka-Urban
-
依托单位:
Regulation of the Endocytic Trafficking of CFTR
-
批准号:7652301
-
项目类别:
-
资助金额:$38.23万
-
财政年份:2008
-
负责人:Agnieszka Swiatecka-Urban
-
依托单位:
DARTMOUTH COL COBRE: P2: REGULATION OF ENDOCYTIC TRAFFICKING OF CFTR
-
批准号:7610604
-
项目类别:
-
资助金额:$11.98万
-
财政年份:2007
-
负责人:Agnieszka Swiatecka-Urban
-
依托单位:
DARTMOUTH COL COBRE: P2: REGULATION OF ENDOCYTIC TRAFFICKING OF CFTR
-
批准号:7382074
-
项目类别:
-
资助金额:$23.18万
-
财政年份:2006
-
负责人:Agnieszka Swiatecka-Urban
-
依托单位:
DARTMOUTH COL COBRE: P2: REGULATION OF ENDOCYTIC TRAFFICKING OF CFTR
-
批准号:7171305
-
项目类别:
-
资助金额:$23.09万
-
财政年份:2005
-
负责人:Agnieszka Swiatecka-Urban
-
依托单位:
LMTK2 AND TGF BETA SIGNALING IN HUMAN AIRWAY EPITHELIAL CELLS
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批准号:8875232
-
项目类别:
-
资助金额:$11.55万
-
财政年份:2005
-
负责人:Agnieszka Swiatecka-Urban
-
依托单位:
DARTMOUTH COL COBRE: P2: REGULATION OF ENDOCYTIC TRAFFICKING OF CFTR
-
批准号:6981968
-
项目类别:
-
资助金额:$21.67万
-
财政年份:2004
-
负责人:Agnieszka Swiatecka-Urban
-
依托单位:
LMTK2 AND TGF BETA SIGNALING IN HUMAN AIRWAY EPITHELIAL CELLS
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批准号:9091541
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项目类别:
-
资助金额:$11.55万
-
财政年份:--
-
负责人:Agnieszka Swiatecka-Urban
-
依托单位:
LMTK2 AND TGF BETA SIGNALING IN HUMAN AIRWAY EPITHELIAL CELLS
-
批准号:9293287
-
项目类别:
-
资助金额:$11.55万
-
财政年份:--
-
负责人:Agnieszka Swiatecka-Urban
-
依托单位:
海外基金