Novel insights into intimal hyperplasia in cardiac allograft vasculopathy
对心脏同种异体移植血管病中内膜增生的新见解
基本信息
- 批准号:10090623
- 负责人:
- 金额:$ 60.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-01 至 2023-01-31
- 项目状态:已结题
- 来源:
- 关键词:ATAC-seqAddressAdverse effectsAllograftingArterial Fatty StreakAtherosclerosisBioinformaticsBiotechnologyBlood CirculationBlood VesselsBlood flowCardiovascular PathologyCellsChIP-seqChromatinChronicClonalityColorCoronary arteryDependenceDevelopmentDiffuseDonor personEnhancersEpigenetic ProcessEventFailureGene DeliveryGene ExpressionGenetic TranscriptionGoalsGrowthHeartHeart DiseasesHeart TransplantationHumanHyperplasiaImmuneInjuryInterferon Type IIInternationalInterventionKidney DiseasesKineticsLabelLesionLung diseasesMediatingMethodsMicroRNAsModelingMolecular TargetMusOperative Surgical ProceduresOrgan TransplantationOrgan failurePathogenesisPathologistPathologyPhenotypePlayProceduresProcessProliferatingPublishingRecoveryResistanceRoleScientistSirolimusSmooth MuscleSmooth Muscle MyocytesStimulusSurgeonTestingTherapeuticTransplantationVascular Diseasesblood vessel transplantationcardiovascular disorder therapycell motilitycoronary vasculaturedeep sequencingepigenomicsgenome-widehealingheart allograftimprovedinhibitor/antagonistinsightknock-downmorphogensmouse modelnovelnovel therapeutic interventionnovel therapeuticsoverexpressionpost-transplantpreventrecruitresponserestenosissingle-cell RNA sequencingtargeted treatmenttherapeutic miRNAtherapeutic targettranscriptometranscriptome sequencingtranscriptomicstransplant modelvascular smooth muscle cell proliferation
项目摘要
Novel insights into intimal hyperplasia in cardiac allograft vasculopathy
Biotechnical advances in surgical and percutaneous interventions have greatly improved cardiovascular disease
therapies. However, restenosis arising from uncontrolled vascular smooth muscle cell (SMC) proliferation and
migration leading to occlusive intimal hyperplasia, remains a major unresolved hurdle. SMC possess a unique
ability to alter their phenotype in response to environmental stimuli, which allows for vascular healing and growth.
However, this SMC plasticity also contributes to cardiovascular pathologies, including intimal hyperplasia
following revascularization procedures. A particularly resistant and deadly form of intimal hyperplasia occurs in
cardiac allograft vasculopathy (CAV) where chronic immune injury mediated by IFNγ promotes diffuse, and often
severe, SMC intimal hyperplasia throughout the vessels of the grafted organ, leading to ischemic organ failure.
A better understanding of this SMC response is urgently warranted to identify potential targets for therapy for
CAV. mTORC1 inhibitors have shown promise for CAV but are limited by adverse effects. By understanding the
molecular targets downstream of mTORC1, we may be able to recapitulate the benefits of mTORC1 inhibition
in SMC while preventing systemic complications.
The recent discovery of the clonal origin of some SMC lesions, including in atherosclerosis, has shifted
paradigms in how we view vascular disease. Indeed, such “pioneering” cells that give rise to clonal lesions may
be involved in the early pathogenesis of neointima in CAV. Moreover, epigenetics may play a major role in this
process, but we have limited understanding of how epigenetics influence CAV. We have recently identified TET2
as a master epigenetic regulator of SMC phenotype that is induced by the mTORC1 inhibitor rapamycin. TET2
is repressed in intimal hyperplasia post-injury and in atherosclerotic lesions (Circulation 2013). We now
demonstrate that TET2 is downregulated in SMC in human CAV, in mouse allograft models, and by IFNγ in
cultured SMC. In the absence of a therapeutic method to overexpress TET2 throughout the coronary vasculature,
we propose that miRNAs that repress TET2 expression, such as miR29 and others, could be targeted for CAV
therapy. To identify novel mechanisms and therapeutic targets, we have established a mouse heterotopic heart
transplant model of CAV. We hypothesize that epigenetic (chromatin and miRNAs) and transcriptional
changes alter SMC gene expression, promoting intimal hyperplasia in the coronary arteries of
transplanted hearts. Using biotechnological advances, we have developed a coordinated, complementary,
non-overlapping 3-pronged approach toward furthering our understanding of and developing new treatments for
CAV that includes: 1) clonality and initiating events, 2) epigenomics and transcriptomics, and 3) miRNA-based
therapies. We have recruited an outstanding internationally recognized team of surgeon-scientists, pathologists,
vascular biologists, epigenetics/bioinformatics and miRNA experts to address these goals.
移植心脏血管病变内膜增生的新认识
手术和经皮介入的生物技术进步极大地改善了心血管疾病
治疗然而,由不受控制的血管平滑肌细胞(SMC)增殖和血管再狭窄引起的再狭窄是一个重要因素。
导致闭塞性内膜增生的迁移仍然是一个主要的未解决的障碍。SMC拥有独特的
能够改变其表型以响应环境刺激,这允许血管愈合和生长。
然而,这种SMC可塑性也有助于心血管病理,包括内膜增生
再血管化手术后。内膜增生的一种特别顽固和致命的形式发生在
心脏移植物血管病(CAV),其中IFNγ介导的慢性免疫损伤促进弥漫性,
移植器官血管中严重的SMC内膜增生,导致缺血性器官衰竭。
迫切需要更好地了解这种SMC反应,以确定潜在的治疗靶点,
Cav. mTORC 1抑制剂已显示出对CAV的前景,但受到副作用的限制。通过了解
mTORC 1下游的分子靶点,我们可能能够概括mTORC 1抑制的益处
在SMC中,同时预防全身并发症。
最近发现的克隆起源的一些SMC病变,包括动脉粥样硬化,已经转移
我们如何看待血管疾病的范例事实上,这种引起克隆性病变的“先锋”细胞可能
参与了CAV新生内膜的早期发病过程。此外,表观遗传学可能在这方面发挥了重要作用
过程,但我们对表观遗传学如何影响CAV的了解有限。我们最近发现TET 2
作为由mTORC 1抑制剂雷帕霉素诱导的SMC表型的主要表观遗传调节剂。Tet2
在损伤后内膜增生和动脉粥样硬化病变中受到抑制(Circulation 2013)。我们现在
证明TET 2在人CAV、小鼠同种异体移植物模型中的SMC中下调,并且在人CAV和小鼠同种异体移植物模型中被IFNγ下调。
培养的SMC。在缺乏在整个冠状血管系统中过表达TET 2的治疗方法的情况下,
我们认为,抑制TET 2表达的miRNAs,如miR 29等,可以作为CAV的靶点
疗法为了确定新的机制和治疗靶点,我们建立了小鼠异位心脏
CAV移植模型。我们假设,表观遗传(染色质和miRNA)和转录
这些变化改变了SMC基因表达,促进了冠状动脉内膜增生,
移植的心脏利用生物技术的进步,我们开发了一种协调、互补、
不重叠的三管齐下的方法,以进一步了解和开发新的治疗方法,
CAV包括:1)克隆性和起始事件,2)表观基因组学和转录组学,以及3)基于miRNA的
治疗我们招募了一个国际公认的优秀团队,由外科医生、病理学家、
血管生物学家,表观遗传学/生物信息学和miRNA专家来解决这些目标。
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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Kathleen Ann Martin其他文献
Kathleen Ann Martin的其他文献
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{{ truncateString('Kathleen Ann Martin', 18)}}的其他基金
Vascular Discovery, From Genes to Medicine 2023
血管发现,从基因到医学 2023
- 批准号:
10683501 - 财政年份:2023
- 资助金额:
$ 60.39万 - 项目类别:
2022 Vascular Discovery: From Genes to Medicine
2022 年血管发现:从基因到医学
- 批准号:
10469131 - 财政年份:2022
- 资助金额:
$ 60.39万 - 项目类别:
Epigenetic control of vascular smooth muscle in cardiovascular disease
心血管疾病中血管平滑肌的表观遗传控制
- 批准号:
8761918 - 财政年份:2014
- 资助金额:
$ 60.39万 - 项目类别:
Regulation of vascular smooth muscle cell plasticity
血管平滑肌细胞可塑性的调节
- 批准号:
8998052 - 财政年份:2014
- 资助金额:
$ 60.39万 - 项目类别:
Regulation of vascular smooth muscle cell plasticity
血管平滑肌细胞可塑性的调节
- 批准号:
8630004 - 财政年份:2014
- 资助金额:
$ 60.39万 - 项目类别:
Regulation of vascular smooth muscle cell plasticity
血管平滑肌细胞可塑性的调节
- 批准号:
8798690 - 财政年份:2014
- 资助金额:
$ 60.39万 - 项目类别:
Regulation of vascular smooth muscle cell plasticity
血管平滑肌细胞可塑性的调节
- 批准号:
9211370 - 财政年份:2014
- 资助金额:
$ 60.39万 - 项目类别:
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