Inhibition of Radiation-Induced Coronary Microvascular Disease
抑制辐射引起的冠状动脉微血管疾病
基本信息
- 批准号:10329997
- 负责人:
- 金额:$ 41.25万
- 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:2021-01-15 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:AchievementAddressBirthBlood flowBypassCancer PatientCancer SurvivorCellsCessation of lifeChestClinicalCoronaryCoronary VesselsCoronary arteryDataDevelopmentDoseDrug or chemical Tissue DistributionEndothelial CellsEndotheliumEngineeringEventExtravasationFibrosisFormulationGenesGeneticGenetic TranscriptionGenetically Engineered MouseGoalsHalf-LifeHeartHeart failureHodgkin DiseaseImpairmentIncidenceInjuryInterventionIonizing radiationIonsKnowledgeLeadLip structureLiposomesLys-AspMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of thoraxMediatingMicrovascular DysfunctionModelingMolecularMolecular BiologyMusMuscle CellsMyocardialMyocardial IschemiaMyocardial dysfunctionMyocardial perfusionOperative Surgical ProceduresOrganPathologicPeptidesPermeabilityPharmacotherapyPorosityProcessPropertyProtocols documentationRadiationRadiation exposureRadiation therapyResistanceRodentRoleSerumSiteSmall Interfering RNAStentsStructureTechnologyTestingTherapeuticTight JunctionsTimeTissuesVascular Endothelial CellVascular PermeabilitiesXenograft Modelbasecancer radiation therapycardiac magnetic resonance imagingcardioprotectioncell injuryclaudin-1 proteincohortcoronary fibrosiscytotoxicdesigneffective therapyfluorescence imaginggain of functionheart functionhypoperfusionimaging approachimprovedin vivoinsightirradiationknock-downloss of functionlysylprolinemalignant breast neoplasmmolecular imagingmouse modelnanoparticlenext generationnovelnovel therapeuticsoverexpressionpreservationpreventprotective effectradiation effectreconstitutionrestorationsealsiRNA deliverysmall moleculesolutetesting uptaketherapeutic evaluationthymosin beta(4)tumoruptakewater diffusion
项目摘要
ABSTRACT
This application is designed to address the scientific goals of FOA-PA-19-112. Coronary microvascular
disease (CMD) is major sequelae of chest radiotherapy in cancer survivors. Blockade of the larger coronary
arteries can be treated by stents or surgical bypass; however, there are no effective therapies currently available
to target CMD. This project aims to investigate the novel and previously unexplored mechanisms of ionizing
radiation (IR)-induced coronary microvascular injury, and test the beneficial effects of a small molecule, N-acetyl-
ser-asp-lys-pro (Ac-SDKP), to counteract these effects. The scientific premise of this proposal is based on our
recent studies demonstrating profound endothelial cell injury with marked increase in coronary vascular
permeability, and fibrosis, after thoracic radiation exposure in rodents. We also found that radiation-induced CMD
was dose-dependently associated with the transcriptional inhibition of claudin-1 (cldn1) expression. Importantly,
administration of Ac-SDKP, a thymosin β4-derived endogenous peptide, normalized endothelial cell
permeability, reconstituted cldn1, and reduced cardiac fibrosis.
Despite its cardioprotective potential, therapeutic application of Ac-SDKP has been challenging due to
its short half-life (T1/2 of 4.5 mins) in serum. Therefore, we have developed a stable, liposomal Ac-SDKP (Lip-
Ac-SDKP) formulation, which we intend to test for sustained systemic effects. We hypothesize that Ac-SDKP
mitigates radiation-induced coronary endothelial damage, and prevents microvascular leakage by
inhibiting IR-mediated cldn1 loss. In Aim I, we will examine the uptake efficiency and bioactivity of Lip-Ac-
SDKP in the heart and in coronary microvascular endothelial cells. In Aim II, we will examine the effects of Ac-
SDKP on endothelial barrier integrity after radiation and study the role of cldn1 in this process. In Aim III, we
will determine the effects of Ac-SDKP treatment on radiation-induced coronary blood flow and regional and
global cardiac function.
We will accomplish these aims by using advanced molecular biology and imaging approaches. We have
developed a novel genetically engineered mouse model of endothelial cell-specific cldn1 gain-of-
function. We have also developed a cldn1 loss-of-function model using a next generation in vivo siRNA
delivery technology. Additionally, we will utilize tumor-bearing syngeneic and xenograft models to examine
Ac-SDKP effects after multi-dose thoracic irradiation. This project will provide mechanistic insight on the
protective effects of Ac-SDKP against radiation-induced CMD, and will have important therapeutic implications
for timely and targeted interventions in cancer patients susceptible to radiotherapy-induced CMD and cardiac
ischemia.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
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Saraswati Pokharel其他文献
Saraswati Pokharel的其他文献
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{{ truncateString('Saraswati Pokharel', 18)}}的其他基金
Inhibition of Radiation-Induced Coronary Microvascular Disease
抑制辐射引起的冠状动脉微血管疾病
- 批准号:
10544729 - 财政年份:2021
- 资助金额:
$ 41.25万 - 项目类别:
Early Detection and Immunomodulation of PD-1 Inhibitor Induced Cardiotoxicity
PD-1 抑制剂引起的心脏毒性的早期检测和免疫调节
- 批准号:
10042197 - 财政年份:2020
- 资助金额:
$ 41.25万 - 项目类别:
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