Naturally occurring canine myxomatous mitral valve disease as a large animal model for human non-syndromic mitral valve prolapse

项目总结 非综合征性二尖瓣脱垂(MVP)，一种常见的瓣膜心脏病，影响2%-3%的人类 可导致二尖瓣返流、心功能不全、充血性心力衰竭甚至猝死。 由于缺乏药物治疗来管理这种疾病，MVP目前通过手术干预进行治疗。 对医疗管理的不完全理解阻碍了有效医疗管理战略的发展 疾病病理生理学，特别是关于驱动瓣膜间质细胞(VICs)分化的因素 从成纤维细胞到肌成纤维细胞样细胞，导致粘液瘤病理。此外，转基因 无法获得真实再现人类MVP病理的动物模型，部分原因是 被发现与疾病易感性相关的遗传因素的复杂性。有趣的是，MVP(也称为 粘液瘤性二尖瓣退行性变)经常发生在狗身上，估计发病率大于 50%。之前对犬和人MVP的比较表明，它们在几个关键的组织病理学上是相同的 这些特征表明，自发性犬病可能代表了一个很好的翻译模型。使用警犬 MVP作为模板，我一直在研究细胞外小泡(EV)和miRNAs在 推动成纤维细胞向成肌细胞转换。EVS是膜结合的细胞衍生颗粒，用于细胞间 通过蛋白质和非编码(NC)RNA的转移来传递信号，它们参与了 几种疾病的传播，包括阿尔茨海默氏症和癌症。我们的初步数据显示犬类受害者 产生的无细胞miRNA和EV相关ncRNA信号与来自 正常的瓣膜。因此，这个提议背后的假设是，狗的MVP可以被用来研究 EV信号介导的推动粘液瘤瓣膜退变的因素，最终目标是 识别和验证用于早期检测和治疗干预的新靶点。要完成 为此，我将首先在组织病理学和分子水平上完成对犬MVP的描述 直接与人MVP比较，然后询问EV和ncRNA介导的信号对VIC的影响 基因表达谱和功能。这些数据将有助于更全面地了解电动汽车是如何- 介导的信号影响MVP的进化，并为纳入自发性犬创造蓝图 MVP进入翻译管道，以优化早期检测和干预的新方法。有钱人 塔夫茨大学及其合作伙伴的研究环境，包括兽医、医学院、 营养与研究生科学，塔夫茨医学中心，塔夫茨临床转化科学研究所，以及 麻省理工学院确保获得成功完成拟议工作所需的资源和专业知识。 我在工程和医学心脏病学方面的训练，以及我的指导团队Bridging的指导 人类心脏病学、比较医学、EV/ncRNA生物学和生物信息学/生物统计学方面的专业知识使 我处于有利地位，可以成功地过渡到一名独立的临床医生兼科学家。

PROJECT SUMMARY Non-syndromic mitral valve prolapse (MVP), a common valvular heart disease affecting 2-3% of the human population, can lead to mitral regurgitation, cardiac dysfunction, congestive heart failure and even sudden death. Given the lack of medical therapeutics to manage this disease, MVP is currently treated by surgical intervention. Development of effective strategies for medical management has been hindered by an incomplete understanding of disease pathophysiology, specifically regarding factors that drive differentiation of valve interstitial cells (VICs) from fibroblast- to myofibroblast-like cells, resulting in myxomatous pathology. Furthermore, genetically modified animal models that faithfully recapitulate human MVP pathology are unavailable, in part due to the relative complexity of genetic factors found to be associated with disease predisposition. Interestingly, MVP (also termed myxomatous mitral valve degeneration) occurs frequently in dogs with an estimated incidence of greater than 50%. Previous comparisons of canine and human MVP demonstrated that they share several key histopathologic features suggesting that the spontaneous dog disease may represent a good translational model. Using canine MVP as a template, I have been investigating the potential role of extracellular vesicles (EVs) and miRNAs in driving the fibroblast to myoblast switch. EVs are membrane-bound cell-derived particles used for inter-cell signaling through the transfer of proteins and noncoding (nc)RNA, and they have been implicated in the propagation of several diseases including Alzheimer's and cancer. Our preliminary data show that canine VICs from diseased valves produce different cell-free miRNA and EV-associated ncRNA signatures than cells from normal valves. As such, the hypothesis underlying this proposal is that canine MVP can be leveraged to study EV-signaling mediated factors that drive myxomatous valve degeneration, with the ultimate goal of identifying and validating novel targets for early detection and therapeutic intervention. To accomplish this, I will first complete the characterization of canine MVP at the histopathologic and molecular levels with a direct comparison to human MVP, and then interrogate the impact of EV and ncRNA mediated signaling on VIC gene expression profiles and function. These data will facilitate a more complete understanding of how EV- mediated signaling influences the evolution of MVP and create a blueprint for incorporating spontaneous canine MVP into the translational pipeline to optimize novel approaches for early detection and intervention. The rich research environment at Tufts University and its partners including schools of Veterinary Medicine, Medicine, Nutrition and Graduate Sciences, Tufts Medical Center, the Tufts Clinical Translational Sciences Institute, and MIT ensure access to the resources and expertise necessary for successful completion of the proposed work. My training in engineering and medical cardiology combined with guidance from my mentoring team bridging expertise in human cardiology, comparative medicine, EV/ncRNA biology and bioinformatics/biostatistics makes me well positioned to successfully transition to an independent clinician-scientist.