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
本申请旨在实现FOA-PA-19-112的科学目标。冠状动脉微血管
疾病(CMD)是癌症幸存者胸部放疗的主要后遗症。大冠状动脉阻塞
动脉可以通过支架或外科搭桥术治疗;然而,目前还没有有效的治疗方法
以CMD为目标该项目旨在研究新的和以前未探索的电离机制,
辐射(IR)诱导的冠状动脉微血管损伤,并测试小分子N-乙酰基-
ser-asp-lys-pro(Ac-SDKP),以抵消这些作用。这项建议的科学前提是基于我们的
最近的研究表明严重的内皮细胞损伤,
渗透性和纤维化。我们还发现辐射诱导的CMD
与claudin-1(cldn 1)表达的转录抑制呈剂量依赖性相关。重要的是,
给予Ac-SDKP,一种胸腺素β4衍生的内源性肽,正常化内皮细胞
渗透性、重建的CLDN 1和减少的心脏纤维化。
尽管具有心脏保护潜力,但Ac-SDKP的治疗应用具有挑战性,因为
其在血清中的半衰期较短(T1/2为4.5分钟)。因此,我们已经开发了一种稳定的脂质体Ac-SDKP(Lip-
Ac-SDKP)制剂,我们打算测试其持续全身作用。我们假设Ac-SDKP
减轻辐射引起的冠状动脉内皮损伤,并通过以下方式防止微血管渗漏:
抑制IR介导的cldn 1损失。在目的I中,我们将检查Lip-Ac-D-Phosphate的摄取效率和生物活性。
心脏和冠状动脉微血管内皮细胞中的SDKP。在第二章中,我们将研究AC的影响。
SDKP对辐射后内皮屏障完整性的影响,并研究cldn 1在此过程中的作用。在Aim III中,我们
将确定Ac-SDKP治疗对辐射诱导的冠状动脉血流量和局部和
整体心脏功能
我们将通过使用先进的分子生物学和成像方法来实现这些目标。我们有
开发了一种新的基因工程小鼠模型的内皮细胞特异性cldn 1增益的,
功能我们还开发了一种使用下一代体内siRNA的cldn 1功能丧失模型
交付技术。此外,我们还将利用同基因和异种移植肿瘤模型,
多剂量胸部照射后的Ac-SDKP效应。该项目将提供机械的见解,
Ac-SDKP对辐射诱导的CMD具有保护作用,并将具有重要的治疗意义
对易受放射治疗诱导的CMD和心脏病的癌症患者进行及时和有针对性的干预
缺血
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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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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