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

项目摘要 该项目标志着开创性的第一步，描绘衰老细胞的影响， 马凡综合征患者心血管疾病的发病机制。影响每5000人中的1人 全球范围内的出生，具有多种高度渗透的心脏表型（包括二尖瓣脱垂，主动脉瓣脱垂， 瓣膜返流和主动脉瘤），马凡氏综合征通常导致多种主要心血管疾病， 在病人的一生中，虽然很明显，在p53 -1基因和随后的突变， TGFβ信号的过度激活代表了马凡综合征的明确分子起源， 改善无事件生存期和/或总生存期的治疗性干预措施一直是具有挑战性的。 传统认为，马凡氏综合征早期发生的多种心血管疾病类似于 “类早老样”表型，最近的报告表明，许多患者发展脂肪营养不良和其他 表型与时间老化有关。重要的是，我们在马约的研究小组最近的研究 （米勒/柯克兰）表明，衰老细胞的积累可以驱动多种疾病的进展， 年龄老化和人类疾病的临床前模型。因此，我们的中心假设-支持 大量初步数据表明，衰老细胞的积累是基质增加的主要驱动力， 马凡氏综合征的重塑，并代表了一种新的分子机制，有助于启动和 多种病理性心血管表型的进展。因此，本申请的目的是： 测量和确定遗传减少衰老细胞负荷对表型进展的影响 Marfanoid小鼠主动脉、主动脉瓣和二尖瓣功能障碍的分子基础; 2） 确定衰老细胞的药理学清除是否可以减弱分子驱动因子， Marfanoid小鼠中主动脉、主动脉瓣和二尖瓣功能障碍的表型进展，和3） 确定衰老细胞在主动脉、主动脉瓣和二尖瓣组织中的分布和负荷， 患有马凡氏综合征的人我们将使用独特的体内动物模型和评估的组合， 正常和马凡样人类组织在本申请中进行关键的概念验证研究， 衰老细胞的清除，动物中的预防性相关干预，以及关键的验证性研究， 与人类疾病相关的桥梁。总的来说，我们的目标是证明衰老细胞在衰老过程中起着重要的作用。 在马凡相关心血管疾病进展中的作用，这些研究特别 旨在为追求早期临床试验奠定基础和理由，以解决这一关键问题。 马凡氏综合征患者的疾病。

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.