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

项目总结 这一项目标志着描绘衰老细胞在体内的影响的开创性的第一步 马凡综合征患者心血管疾病的发病机制。每5000人中就有1人受到影响 全球出生，具有多种高穿透性心脏表型(包括二尖瓣脱垂、主动脉瓣脱垂 瓣膜返流和主动脉瘤)，马凡综合征通常导致多个主要心血管疾病 手术贯穿了病人的一生。尽管很明显，纤维蛋白-1基因的突变和随后的 转化生长因子β信号过度激活是马凡综合征发生、发展的一个明确的分子起源 改善无事件和/或总体存活率的治疗干预措施充其量也是具有挑战性的。 惯例表明，马凡综合征早期发作的多种心血管疾病类似于 “类孕激素”表型，最近的报告表明，许多患者发展为脂肪营养不良和其他 与时间顺序老化相关的表型。关键的是，我们梅奥研究小组最近的研究 (Miller/Kirkland)认为，衰老细胞的积累可以推动多种疾病的进展 时序衰老和人类疾病的临床前模型。因此，我们的中心假设--由 大量的初步数据-衰老细胞的积累是基质增加的主要驱动因素 马凡综合征的重塑，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研究进展。因此，当前应用程序的目标是： 测量和确定遗传降低衰老细胞负荷对表型进展的影响 和Marfan样鼠主动脉、主动脉瓣和二尖瓣功能障碍的分子基础；2) 确定衰老细胞的药物清除是否可以减弱分子驱动因素并减缓 Marfan样鼠的主动脉、主动脉瓣和二尖瓣功能障碍的表型进展，以及3) 测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 患有马凡综合症的人类。我们将结合使用独特的活体动物模型和评估 在这一应用中对正常和类马凡尼类人体组织进行关键的概念验证研究 衰老细胞的清除，动物中翻译相关的干预，以及关键的验证性研究 桥梁与人类疾病的相关性。总而言之，我们的目标是证明衰老细胞在 在马凡相关心血管疾病进展中的作用，这些研究特别是 旨在为追求早期临床试验奠定基础和理由，以解决这一关键的 马凡综合征患者的疾病。

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.