Dissecting mechanisms of anthracycline-induced cardiotoxicity
Dissecting mechanisms of anthracycline-induced cardiotoxicity
批准号:
10683784
负责人:
Rene R.S. Packard
金额:
$39.0万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-09-01 至 2024-08-31
关键词:
ANXA5 geneAddressAdolescenceAdultAffectAnthracyclineApoptosisBiochemicalBiological AssayBreast Cancer CellCASP3 geneCandidate Disease GeneCardiacCardiac MyocytesCardiomyopathiesCardiotoxicityCaspaseCell DeathCell ProliferationCessation of lifeChildChildhoodChronicClinicalCo-ImmunoprecipitationsCre-LoxPDNA DamageDatabasesDependovirusDevelopmentDiseaseDoxorubicinEFRACExcisionExhibitsExposure toFailureFamilyGenesGoalsHeartHeart InjuriesHistone H2AIn Situ Nick-End LabelingIncidenceInjuryLymphoma cellMalignant Childhood NeoplasmMalignant NeoplasmsMass Spectrum AnalysisMediatingMediator of activation proteinMolecularMolecular BiologyMusMuscle CellsNeonatalPathway interactionsPatientsPersonsPlayProcessProtein Binding DomainProteinsPublic HealthPumpRNA BindingRattusRecording of previous eventsRegimenRegulationResearchRoleSerineStressSystems BiologyTamoxifenTopoisomeraseVariantVentricularVertebral columnWhole Organismcancer cellcancer therapycardiac repaircardioprotectioncaveolin-3chemotherapychildhood cancer survivords-DNAenhanced green fluorescent proteinepidemiologic dataexperiencegene networkheart functionimaging approachimprovedin vivoinsightknock-downnotch proteinnoveloverexpressionprotective effectside effecttranscriptome sequencingtranscriptomics
中文摘要
摘要
虽然癌症在一生中影响着三分之一以上的人,但长期存活率的提高导致了
癌症治疗的心脏不良反应发生率增加。蒽环类药物
阿霉素(Dox)是各种癌症化疗的基石,然而,它们的使用因
蒽环类药物引起的心脏毒性,最常见的是心肌病。在Dox中发挥作用的机制
心脏毒性是多因素的,包括拓扑异构酶(TOP)-2β介导的最终可能导致的DNA损伤
在细胞凋亡中。为了确定疾病过程中的新因素,我们首先在
Dox心脏毒性转录研究生物医学数据库。对候选基因进行筛选
对Dox治疗的反应性,与心脏修复中牵涉的Notch和Hippo通路有关,
以及对细胞死亡的控制。这一系统的方法导致了丝氨酸结合蛋白-3(丝氨酸-3)的鉴定。
3)。W
E假设在Dox诱导的心脏毒性的背景下,Serinc3通过以下方式显示保护作用
对抗TOP-2β介导的心肌细胞凋亡--我们将从两个特定目的来探讨
。在目标1中,我们将
确定丝氨酸氨基转移酶-3在Dox损伤心肌细胞和癌细胞中的作用。我们将(I)剖析保护性
Serinc3在Dox心脏毒性中涉及的细胞凋亡途径中的作用,(Ii)确定
SERINC-3和心肌细胞中保护心脏的Notch和Hippo通路,以及(Iii)转录组
测序和量化,基因网络构建,并确定生化和功能途径
在Serinc3表达调控后的Dox处理中的富集物,(Iv)建立与
使用3xFLAG标记策略、免疫共沉淀和质谱学的血清-3,以及(V)评估
SERINC-3在乳腺癌和淋巴瘤细胞中的表达,并定量检测Dox作用后癌细胞的增殖
治疗和丝裂原-3调节。在目标2中,我们将仔细研究在体心肌细胞中血清-3的功能。
在成年小鼠DOX治疗后。我们将(I)开发他莫昔芬诱导的、心肌细胞特异性的Cre-Lox
用增强的绿色荧光蛋白成功切除SERINC-3Cre的小鼠,(Ii)定量全局(射血)
SERINC-3Cre-Lox后的心功能(分数、分数缩短)和节段性(应变、移位)
敲除或腺相关病毒-9介导的过度表达在慢性Dox损伤的背景下,(Iii)评估
丝氨酸氨基转移酶-3过表达和基因敲除对Dox诱导的细胞死亡途径的影响
Dox处理的小鼠心肌细胞通过以下转录组测序建立相关矩阵
丝氨酸蛋白-3表达的调控。拟议研究的成功实施将提供新的
对蒽环类药物引起的心脏毒性的病理生物学的机械洞察,具有翻译含义。
英文摘要
ABSTRACT
While cancer affects more than one in three people over their lifetime, improved long-term survival has led to an
increase in the incidence of adverse cardiac side-effects of cancer treatments. Anthracyclines such as
doxorubicin (Dox) are a cornerstone of chemotherapy in various cancers, however, their use is complicated by
anthracycline-induced cardiotoxicity, most commonly cardiomyopathy. The mechanisms at play in Dox
cardiotoxicity are multifactorial and include Topoisomerase (Top)-2β-mediated DNA damage that may culminate
in apoptosis. To identify novel actors in the disease process, we first conducted a comprehensive search in
biomedical databases of Dox cardiotoxicity transcriptomic studies. Candidate genes were screened for
responsiveness to Dox treatment, association with the Notch and Hippo pathways implicated in cardiac repair,
and the control of cell death. This systematic approach led to the identification of serine incorporator-3 (serinc-
3). W
e hypothesize that in the setting of Dox-induced cardiotoxicity, serinc-3 exhibits protective effects by
opposing Top-2β-mediated cardiomyocyte apoptosis that we will explore in 2 Specific Aims
. In Aim 1, we will
determine the role of serinc-3 in Dox injury in cardiomyocytes and cancer cells. We will (i) dissect the protective
role of serinc-3 on apoptosis pathways implicated in Dox cardiotoxicity, (ii) determine an association between
serinc-3 and the cardioprotective Notch and Hippo pathways in cardiomyocytes, and (iii) perform transcriptome
sequencing and quantification, gene network construction, and determine biochemical and functional pathway
enrichment in Dox treatment following serinc-3 expression modulation, (iv) establish protein interactions with
serinc-3 using a 3xFLAG tagging strategy, co-immunoprecipitation, and mass spectrometry, and (v) evaluate
serinc-3 expression in breast cancer and lymphoma cells, and quantify cancer cell proliferation following Dox
treatment and serinc-3 modulation. In Aim 2, we will scrutinize in vivo serinc-3 function in cardiomyocytes
following adult mouse Dox treatment. We will (i) develop tamoxifen-inducible, cardiomyocyte-specific Cre-Lox
mice with enhanced green fluorescent protein for successful serinc-3 Cre excision, (ii) quantify global (ejection
fraction, fractional shortening) and segmental (strain, displacement) cardiac function following serinc-3 Cre-Lox
knockdown or adeno-associated virus-9-mediated overexpression in the setting of chronic Dox injury, (iii) assess
the effect of serinc-3 overexpression and knockdown on Dox-induced cell death pathways in vivo, and (iv) isolate
cardiomyocytes from Dox treated mice to establish correlation matrices by transcriptome sequencing following
modulation of serinc-3 expression. The successful implementation of the proposed research will provide novel
mechanistic insights into the pathobiology of anthracycline-induced cardiotoxicity, with translational implications.
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Integrating 3-D Intravascular Sensors with Fractional Flow Reserve for Lipid-Rich Plaques
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批准号:10553624
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项目类别:
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资助金额:$0.0万
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财政年份:2020
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负责人:Rene R.S. Packard
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依托单位:
Integrating 3-D Intravascular Sensors with Fractional Flow Reserve for Lipid-Rich Plaques
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批准号:10436777
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项目类别:
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资助金额:$0.0万
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财政年份:2020
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负责人:Rene R.S. Packard
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依托单位:
Integrating 3-D Intravascular Sensors with Fractional Flow Reserve for Lipid-Rich Plaques
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批准号:9892828
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项目类别:
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资助金额:$0.0万
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财政年份:2020
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负责人:Rene R.S. Packard
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依托单位:
海外基金