DNase-Targeted Mitigation of Acute Kidney Injury Due to Rhabdomyolysis
DNase 靶向缓解横纹肌溶解引起的急性肾损伤
基本信息
- 批准号:10292439
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-10-01 至 2023-09-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute Kidney FailureAcute Renal Failure with Renal Papillary NecrosisAffectAlternative SplicingApoptoticCell DeathCell NucleusChemicalsCisplatinCultured CellsDNADNA FragmentationDNA biosynthesisDataDeoxyribonuclease IDeoxyribonucleasesDevelopmentDisastersDiseaseEnzymesEpithelialEpithelial CellsEventExposure toExtravasationFluorescenceFundingFutureGlycerolGoalsGrant ReviewHealthHealthcareHeminHemodialysisHemolysisHumanIn VitroIndividualInjuryInjury to KidneyInterventionIschemiaKidneyKidney TransplantationKnockout MiceLaboratoriesLeadLifeLinkMeasurementMediatingMethodsMilitary PersonnelMitochondriaModelingMusMuscular AtrophyMutateMyoglobinNuclearOrganPathway interactionsPharmaceutical PreparationsPharmacologic SubstancePharmacologyPreventionPrevention strategyPrognosisRNARNA chemical synthesisReactive Oxygen SpeciesRegulationReperfusion TherapyReportingResearchRhabdomyolysisRibonucleasesRoleSavingsSkeletal MuscleSmall Interfering RNATestingTherapeuticTissuesToxic Environmental SubstancesToxinTraumaTubular formationUnited StatesVeteransbasecell injuryclinically relevantdisabilityendonucleaseendonuclease Gexpression vectorgene cloningimprovedin vitro Modelin vivoinhibitorkidney cellmedical countermeasuremilitary veterannovelnovel strategiesnovel therapeuticsoperationpathogenpreventtoolweapons
项目摘要
The United States Armed Forces are routinely exposed to hazardous weapons, pathogens,
environmental toxins and, later, medical countermeasures with long-term health effects. The
kidney is affected by many toxins metabolized in the body that it excretes, including products of
rhabdomyolysis (skeletal muscle degradation), hemolysis, drugs, and exogenous toxins. Many
of these compounds cause acute kidney injury (AKI) by producing reactive oxygen species
(ROS), which activate apoptotic endonucleases. The resulting acute kidney failure (AKF) is a
life-threatening condition that requires hemodialysis or kidney transplantation. This proposal is a
continuation of the previous research funded by a VA Merit Review grant. The specific aims in
the previous project have been accomplished and the new goals are logical extensions of these
aims. The results from the previous study show the importance of two DNA-degrading enzymes,
cytoplasmic deoxyribonuclease I (DNase I) and mitochondrial endonuclease G (EndoG) in
mediating myoglobinuric AKI induced by rhabdomyolysis. Our data indicate that the two
enzymes are linked in a sophisticated network. To sort out the mechanisms of endonuclease
regulation, and to develop an anti-endonuclease drugs for the future, we have identified several
non-toxic endonuclease inhibitors with promising pharmaceutical potentials. We hypothesize
that during myoglobinuric AKI, (a) endonucleases led by DNase I act as a network in which
individual enzymes can induce each other through DNA breaks; (b) EndoG can inactivate
DNase I by alternative splicing (AS) through its RNase activity; and (c) anti-endonuclease
therapy or prevention of AKI should be aimed at both individual endonucleases and the entire
network. Our specific objectives are as follows. In Aim 1, we will delineate DNase I-mediated
mechanisms of regulation of endonucleases during myoglobinuric AKI. In Aim 2, we plan to
define EndoG-mediated mechanisms of regulation of endonucleases during myoglobinuric AKI.
Aim 3 will evaluate therapeutic modulation of endonucleases for kidney tissue protection, and
assess the generality of the observed regulatory mechanisms in other AKI models.
Potential Impact on Veterans Health Care. Successful completion of these studies can
potentially lead to the development of new therapeutic tools to prevent or ameliorate
myoglobinuric AKI. Some of them will have strong translational value because they act even if
administered after kidney injury, while others can become therapeutic options of the future.
When applied to humans, the results of this study may allow saving human lives, improving the
health of veterans, and decreasing the number of disabilities in the veteran population.
美国武装部队经常暴露在危险武器、病原体、
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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Alexei G Basnakian其他文献
Cervical cancer isolate PT3, super-permissive for adeno-associated virus replication, over-expresses DNA polymerase δ, PCNA, RFC and RPA
- DOI:
10.1186/1471-2180-9-79 - 发表时间:
2009-04-23 - 期刊:
- 影响因子:4.200
- 作者:
Bum Yong Kang;Hong You;Sarmistha Bandyopadhyay;Nalini Agrawal;Russell B Melchert;Alexei G Basnakian;Yong Liu;Paul L Hermonat - 通讯作者:
Paul L Hermonat
Alexei G Basnakian的其他文献
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{{ truncateString('Alexei G Basnakian', 18)}}的其他基金
New mechanistic therapies for myoglobinuric acute kidney injury
肌红蛋白尿性急性肾损伤的新机制疗法
- 批准号:
9037502 - 财政年份:2014
- 资助金额:
-- - 项目类别:
New mechanistic therapies for myoglobinuric acute kidney injury
肌红蛋白尿性急性肾损伤的新机制疗法
- 批准号:
8821210 - 财政年份:2014
- 资助金额:
-- - 项目类别:
DNase-Targeted Mitigation of Acute Kidney Injury Due to Rhabdomyolysis
DNase 靶向缓解横纹肌溶解引起的急性肾损伤
- 批准号:
10043820 - 财政年份:2014
- 资助金额:
-- - 项目类别:
DNase-Targeted Mitigation of Acute Kidney Injury Due to Rhabdomyolysis
DNase 靶向缓解横纹肌溶解引起的急性肾损伤
- 批准号:
10516029 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Novel endonuclease-targeted approaches to nephroprotection
新型核酸内切酶靶向肾保护方法
- 批准号:
8391580 - 财政年份:2009
- 资助金额:
-- - 项目类别:
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