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：
Kathleen Ann Martin
金额：
$ 60.39万
依托单位：
YALE UNIVERSITY
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：
https://reporter.nih.gov/project-details/10090623
关键词：
ATAC-seq Address Adverse effects Allografting Arterial Fatty Streak Atherosclerosis Bioinformatics Biotechnology Blood Circulation Blood Vessels Blood flow Cardiovascular Pathology Cells ChIP-seq Chromatin Chronic Clonality Color Coronary artery Dependence Development Diffuse Donor person Enhancers Epigenetic Process Event Failure Gene Delivery Gene Expression Genetic Transcription Goals Growth Heart Heart Diseases Heart Transplantation Human Hyperplasia Immune Injury Interferon Type II International Intervention Kidney Diseases Kinetics Label Lesion Lung diseases Mediating Methods MicroRNAs Modeling Molecular Target Mus Operative Surgical Procedures Organ Transplantation Organ failure Pathogenesis Pathologist Pathology Phenotype Play Procedures Process Proliferating Publishing Recovery Resistance Role Scientist Sirolimus Smooth Muscle Smooth Muscle Myocytes Stimulus Surgeon Testing Therapeutic Transplantation Vascular Diseases blood vessel transplantation cardiovascular disorder therapy cell motility coronary vasculature deep sequencing epigenomics genome-wide healing heart allograft improved inhibitor/antagonist insight knock-down morphogens mouse model novel novel therapeutic intervention novel therapeutics overexpression post-transplant prevent recruit response restenosis single-cell RNA sequencing targeted treatment therapeutic miRNA therapeutic target transcriptome transcriptome sequencing transcriptomics transplant model vascular smooth muscle cell proliferation

ATAC-seq Address Adverse effects Allografting Arterial Fatty Streak Atherosclerosis Bioinformatics Biotechnology Blood Circulation Blood Vessels Blood flow Cardiovascular Pathology Cells ChIP-seq Chromatin Chronic Clonality Color Coronary artery Dependence Development Diffuse Donor person Enhancers Epigenetic Process Event Failure Gene Delivery Gene Expression Genetic Transcription Goals Growth Heart Heart Diseases Heart Transplantation Human Hyperplasia Immune Injury Interferon Type II International Intervention Kidney Diseases Kinetics Label Lesion Lung diseases Mediating Methods MicroRNAs Modeling Molecular Target Mus Operative Surgical Procedures Organ Transplantation Organ failure Pathogenesis Pathologist Pathology Phenotype Play Procedures Process Proliferating Publishing Recovery Resistance Role Scientist Sirolimus Smooth Muscle Smooth Muscle Myocytes Stimulus Surgeon Testing Therapeutic Transplantation Vascular Diseases blood vessel transplantation cardiovascular disorder therapy cell motility coronary vasculature deep sequencing epigenomics genome-wide healing heart allograft improved inhibitor/antagonist insight knock-down morphogens mouse model novel novel therapeutic intervention novel therapeutics overexpression post-transplant prevent recruit response restenosis single-cell RNA sequencing targeted treatment therapeutic miRNA therapeutic target transcriptome transcriptome sequencing transcriptomics transplant model vascular smooth muscle cell proliferation

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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.

对心脏同种异体移植血管病中内膜增生的新见解手术和经皮干预的生物技术进步大大改善了心血管疾病疗法。然而，不受控制的血管平滑肌细胞（SMC）增殖引起的再狭窄迁移导致闭塞性内膜增生，仍然是一个尚未解决的主要障碍。 SMC拥有独特的能够响应环境刺激而改变其表型的能力，这允许血管愈合和生长。但是，这种SMC可塑性也有助于心血管病理，包括内膜增生遵循血运重建程序。内膜增生的一种特别抗性和致命形式发生在心脏同种氏司法部（CAV），其中IFNγ介导的慢性免疫损伤会促进弥漫性，并且通常在移植器官的整个血管中严重的SMC内膜增生，导致缺血器官衰竭。迫切需要更好地了解这种SMC反应，以确定用于治疗的潜在靶标骑士。 MTORC1抑制剂已显示出对CAV的希望，但受到不利影响的限制。通过理解 MTORC1下游的分子靶标，我们可能能够概括MTORC1抑制的益处在SMC中，同时预防系统并发症。最近发现某些SMC病变的克隆起源（包括动脉粥样硬化）已发生了变化我们如何看待血管疾病的范例。确实，产生克隆病变的这种“开创性”细胞可能参与CAV中新内膜的早期发病机理。此外，表观遗传学可能在这方面发挥重要作用过程，但是我们对表观遗传学如何影响CAV的理解有限。我们最近确定了TET2 作为MTORC1抑制剂雷帕霉素诱导的SMC表型的主要表观遗传调节剂。 tet2 在伤害后和动脉粥样硬化病变中反映在内膜增生中（循环2013）。我们现在证明TET2在人类CAV，小鼠同种异体移植模型中以及IFNγ中的SMC中被下调培养的SMC。在没有治疗方法中过表达TET2的整个冠状动脉脉管系统我们建议，抑制TET2表达的miRNA，例如miR29和其他人，可以针对CAV 治疗。为了识别新型机制和治疗靶标，我们建立了小鼠异位心脏的心脏 CAV的移植模型。我们假设表观遗传学（染色质和miRNA）和转录改变改变了SMC基因表达，促进了冠状动脉的内膜增生移植的心。使用生物技术的进步，我们开发了一个协调的，完整的，不重叠的三方面方法，以进一步发展我们对 CAV包括：1）克隆性和发起事件，2）表观基因组学和转录组学，以及3）基于miRNA的疗法。我们招募了一支由外科医生，病理学家，病理学家，病理学家，病理学家，血管生物学家，表观遗传学/生物信息学和miRNA专家以解决这些目标。