Role of the MUC1/HIF-1a Complex in the kidney proximal tubule during ischemia-reperfusion injury.
MUC1/HIF-1a 复合物在缺血再灌注损伤期间肾近曲小管中的作用。
基本信息
- 批准号:10541885
- 负责人:
- 金额:$ 11.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-12-15 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:2-oxoglutarate 3-dioxygenase prolineARNT proteinAcute Renal Failure with Renal Papillary NecrosisAdultAffectApicalAwardBindingBiological AssayCell LineCell NucleusCell surfaceCellsCessation of lifeChimera organismChronic Kidney FailureClinicalCo-ImmunoprecipitationsComplexDataDimerizationDistalElementsEpithelial CellsEpitheliumExcess MortalityFinancial HardshipFunctional disorderGenesGeneticGenetic TranscriptionGlucoseGoalsGrantHumanHydroxylationHypotensionHypoxiaImmunofluorescence MicroscopyIn VitroIncidenceInjuryInjury to KidneyIschemiaKidneyKnock-outKnockout MiceLimb structureLocationMediatorMembrane GlycoproteinsMercuric chlorideMetabolic dysfunctionMetabolismMorbidity - disease rateMorphologyMucin 1 proteinMusNamesNephronsNuclearOxygenPathway interactionsPatientsPhosphorylationPlayProteinsProximal Kidney TubulesPublishingPyruvate KinaseRecoveryRegulationRenal functionReperfusion InjuryReportingResearchResearch PersonnelResistanceRoleSepsisSeveritiesSignal TransductionSurfaceTestingTherapeutic InterventionThickTissuesTransactivationTranscriptional ActivationTransfectionTubular formationWorkbeta catenincareercongeniccopingexperimental studyhypoxia inducible factor 1inhibitorischemic injurykidney cellmortalitymouse modelmutantnovelnovel therapeuticspancreatic cancer cellspreventrenal damagerepairedresponsetherapy designtraffickingtranscription factorurinary
项目摘要
Project Abstract. Acute kidney injury (AKI) is a common and devastating clinical problem. Despite the morbidity,
mortality, and financial drain associated, there are no established therapies outside of dialytic treatment. Recent
work has identified adaptive responses in the tubular epithelium to cope with ischemia-reperfusion injury (IRI).
There is a critical need to identify how adaptive responses are regulated in AKI so that therapeutic interventions
to prevent and treat AKI can be developed. Hypoxia inducible factor-1 (HIF-1) is a transcription factor regarded
as the most significant mediator of cellular adaptive responses to hypoxic insult. There is emerging evidence
that the transmembrane glycoprotein mucin 1 (MUC1) expressed on the apical surface of kidney epithelia plays
a novel and important role in enhancing HIF-1 activity. We have strong preliminary data suggesting that genetic
deletion of Muc1 from mouse tubular epithelial cells exacerbates damage especially in the proximal tubule (PT)
from IRI, limits adaptive HIF-1 responses, alters tubular metabolism, and inhibits recovery. The
central hypothesis of this application is that MUC1 protects the kidney during IRI by transactivation of the HIF-1
adaptive response specifically in the recovering proximal tubule. The specific aims are:
1. To determine if MUC1 protection of the kidney during IRI requires MUC1-dependent HIF-1a nuclear
targeting and subsequently transcriptional activation of the HIF-1 pathway specifically in the recovering
PT. I will test the hypothesis that MUC1 protects the kidney during IRI by transactivation of the HIF-1 adaptive
response in the recovering PT. Experiments are proposed to stabilize HIF-1a in the proximal tubule in the Muc1
KO mice during IRI by introducing a PT KO of VHL, and treatment with vehicle or a specific MUC1 inhibitor to
block MUC1 internalization and nuclear delivery. Results of these studies will reveal if MUC1 simply stabilizes
HIF-1a levels, or if MUC1 nuclear targeting is essential for transduction of the protective HIF-1 pathway.
2. To characterize the MUC1-HIF-1a complex in cultured kidney cells. I will test the hypothesis that MUC1
stabilizes HIF-1a by direct binding. Experiments are proposed here to characterize the MUC1-HIF-1a complex
using both in vitro pull-down assays and co-IP studies in primary PT cells and human kidney cell lines with wild
type and mutant constructs, and to determine if MUC1 binding to HIF-1a results in its trafficking to the nucleus.
The goal of my research is to fully characterize the MUC1-HIF-1a interaction and determine the mechanism of
its protective role in the kidney PT during IRI. This information can be used to design therapies to induce MUC1
and limit the severity of AKI. This award will provide me with additional support to generate preliminary data
for an R01-level grant to further investigate whether increased levels of renal MUC1 provide resistance to IRI.
项目摘要。急性肾损伤(AKI)是一种常见的、毁灭性的临床问题。尽管发病率很高,
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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Mohammad Al-bataineh其他文献
Mohammad Al-bataineh的其他文献
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{{ truncateString('Mohammad Al-bataineh', 18)}}的其他基金
Role of the MUC1/HIF-1a Complex in the kidney proximal tubule during ischemia-reperfusion injury.
MUC1/HIF-1a 复合物在缺血再灌注损伤期间肾近曲小管中的作用。
- 批准号:
10349156 - 财政年份:2021
- 资助金额:
$ 11.74万 - 项目类别:
Role of Muc1 in the b-catenin Response to Acute Kidney Injury
Muc1 在 b-catenin 对急性肾损伤反应中的作用
- 批准号:
10440020 - 财政年份:2016
- 资助金额:
$ 11.74万 - 项目类别:
Role of Muc1 in the b-catenin Response to Acute Kidney Injury
Muc1 在 b-catenin 对急性肾损伤反应中的作用
- 批准号:
10323751 - 财政年份:2016
- 资助金额:
$ 11.74万 - 项目类别:
Aquaporin-2 (AQP2) Regulation by AMP-activated kinase(AMPK) in the Kidney Collec
肾集合中 AMP 激活激酶 (AMPK) 调节水通道蛋白 2 (AQP2)
- 批准号:
8457228 - 财政年份:2013
- 资助金额:
$ 11.74万 - 项目类别:
Aquaporin-2 (AQP2) Regulation by AMP-activated kinase(AMPK) in the Kidney Collec
肾集合中 AMP 激活激酶 (AMPK) 调节水通道蛋白 2 (AQP2)
- 批准号:
8630873 - 财政年份:2013
- 资助金额:
$ 11.74万 - 项目类别:
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