Role of senescent cells in the pathogenesis of Marfan-associated cardiovascular disease

衰老细胞在马凡相关心血管疾病发病机制中的作用

基本信息

批准号：
10112292
负责人：
Jordan D Miller
金额：
$ 39.75万
依托单位：
MAYO CLINIC ROCHESTER
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：
2018-03-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10112292
关键词：
Address Affect Aging Angiotensins Animal Model Animals Aorta Aortic Aneurysm Aortic Valve Insufficiency Area Attenuated Automobile Driving Biology Cardiac Cardiovascular Diseases Cardiovascular Pathology Cardiovascular Surgical Procedures Cardiovascular system Cells Chronology Clinic Clinical Trials Dasatinib Data Dimensions Disease Disease Progression Effectiveness Evaluation Event Extracellular Matrix FBN1 Foundations Functional disorder Gene Expression Genes Genetic Genetic Models Heart Valves Innovative Therapy Intervention Investigation Life Lipodystrophy Live Birth Marfan Syndrome Matrix Metalloproteinases Measures Mitral Valve Mitral Valve Prolapse Modeling Molecular Molecular Target Mus Mutation Outcome Pathogenesis Pathologic Pathology Patients Pharmacology Phenotype Play Pre-Clinical Model Process Quercetin Reporting Research Role Series Severities Signal Transduction Stress Structure Therapeutic Therapeutic Intervention Tissue Banks Tissues Transforming Growth Factor beta aortic valve design early onset early phase clinical trial enzyme activity fisetin human disease human tissue improved in vivo innovation interstitial cell novel novel therapeutic intervention pre-clinical prospective senescence symposium therapeutic development translational study treatment strategy

项目摘要

PROJECT SUMMARY This project marks a groundbreaking first step to delineating the influence of senescent cells in the pathogenesis of cardiovascular diseases in patients with Marfan syndrome. Affecting 1 in every 5000 live births worldwide, with the multiple highly penetrant cardiac phenotypes (including mitral valve prolapse, aortic valve regurgitation, and aortic aneurysms), Marfan syndrome often leads to multiple major cardiovascular surgeries throughout a patient's life. Though it is clear that mutations in the fibrillin-1 gene and subsequent overactivation of TGFβ signaling represent a well-defined molecular origin of Marfan syndrome, development of therapeutic interventions that improve event-free and/or overall survival has been challenging at best. Convention indicates that early onset of multiple cardiovascular diseases in Marfan syndrome resembles a “progeroid-like” phenotype, and recent reports suggest that many patients develop lipodystrophy and other phenotypes associated with chronological aging. Critically, recent studies by our research group at Mayo (Miller/Kirkland) suggests that accumulation of senescent cells can drive progression of multiple diseases in pre-clinical models of chronological aging and human disease. Thus, our central hypothesis—supported by substantial preliminary data—is that accumulation of senescent cells is a major driver of increased matrix remodeling in Marfan syndrome, and represents a novel molecular mechanism contributing to initiation and progression of multiple pathological cardiovascular phenotypes. Thus, the aims of the current application are: Measure and determine the effects of genetically reducing senescent cell burden on phenotypic progression and molecular underpinnings of aortic, aortic valve, and mitral valve dysfunction in Marfanoid mice; 2) Determine whether pharmacological clearance of senescent cells can attenuate molecular drivers and slow phenotypic progression of aortic, aortic valve, and mitral valve dysfunction in Marfanoid mice, and 3) Determine the distribution and burden of senescent cells in aortic, aortic valve, and mitral valve tissues from humans with Marfan syndrome. We will use a combination of unique in vivo animal models and evaluation of normal and Marfanoid human tissue in this application to conduct key proof-of-concept studies with genetic clearance of senescent cells, translationally-relevant interventions in animals, and key confirmatory studies to bridge to human disease relevance. Collectively, we aim to demonstrate that senescent cells play a significant role in the progression of Marfan-associated cardiovascular disease, with these studies being specifically designed to lay a foundation and justification for pursuit of early clinical trials to address this critical set of diseases in patients with Marfan syndrome.

项目摘要该项目标志着描述感觉细胞在 Marfan综合征患者心血管疾病的发病机理。每5000个活着影响1个全球出生，具有多种高渗透性心脏表型（包括二尖瓣脱垂，主动脉瓣膜反流和主动脉瘤），Marfan综合征通常导致多个主要心血管整个患者一生的手术。尽管很明显，纤维蛋白-1基因中的突变及其后续 TGFβ信号传导的过度活化代表了明确的Marfan综合征的分子来源，发育在改善无事件和/或整体生存的理论干预措施中，充其量受到挑战。惯例表明，马凡综合症中多种心血管疾病的早期发作类似 “类似类似的”表型，最近的报道表明，许多患者会出现脂肪营养不良和其他与年代老化相关的表型。至关重要的是，我们的研究小组在Mayo的最新研究（Miller/Kirkland）表明，感觉细胞的积累可以驱动多种疾病的进展年代衰老和人类疾病的临床前模型。这是我们的中心假设 - 由大量的初步数据 - 感觉到感觉细胞的积累是矩阵增加的主要驱动力 Marfan综合征的重塑，代表了一种新的分子机制，有助于起始和多种病理心血管表型的进展。这是当前应用程序的目的是：测量并确定一般减少感觉细胞伯嫩对表型进程的影响 Marfanoid小鼠中主动脉瓣，主动脉瓣和二尖瓣功能障碍的分子基础； 2）确定感觉细胞的药理清除率是否可以衰减分子驱动因素并缓慢主动脉瓣，主动脉瓣和二尖瓣功能障碍的表型进展，3）从主动脉瓣，主动脉瓣和二尖瓣组织中的感觉细胞的分布和燃烧人类患有马凡综合症。我们将结合独特的体内动物模型和评估在这一应用中，正常和marfanoid人组织进行遗传学的关键概念验证研究感觉细胞的清除，动物中的转换干预措施以及关键的确认研究与人类疾病相关的桥梁。总体而言，我们旨在证明感觉细胞起着重要的作用在与Marfan相关的心血管疾病的进展中的作用，这些研究专门旨在为追求早期临床试验奠定基础和理由，以解决这一关键集 Marfan综合征患者的疾病。