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

自然发生的犬粘液性二尖瓣疾病作为人类非综合征性二尖瓣脱垂的大型动物模型

• 批准号: 10206285
• 负责人: VICKY K. YANG
• 金额: $ 13.81万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10206285
• 关键词: Adult; Affect; Age; Alzheimer' s Disease; Animal Model; Automobile Driving; Bioinformatics; Biology; Biometry; Canis familiaris; Cardiac; Cardiology; Cell physiology; Cells; Clinical; Code; Congestive Heart Failure; Data; Degenerative Disorder; Development; Diagnosis; Disease; Disease Management; Disease model; Dog Diseases; Early Diagnosis; Early Intervention; Effectiveness; Engineering; Ensure; Environment; Evaluation; Evolution; Family; Fibroblasts; Functional disorder; Gene Expression; Genes; Genetic; Genetic Diseases; Genetic study; Genetically Modified Animals; Goals; Harvest; Heart Diseases; Heart Valve Diseases; Histologic; Histology; Human; Immunohistochemistry; In Vitro; Incidence; Individual; Institutes; Intervention; Lead; Left Ventricular Dysfunction; Malignant Neoplasms; Mediating; Medical; Medical center; Medicine; Membrane; Mentors; MicroRNAs; Missense Mutation; Mitral Valve; Mitral Valve Insufficiency; Mitral Valve Prolapse; Modeling; Molecular; Molecular Disease; Molecular Profiling; Myoblasts; Myocardial dysfunction; Myofibroblast; Normal tissue morphology; Operative Surgical Procedures; Pathogenesis; Pathology; Patients; Pattern; Phenotype; Population; Positioning Attribute; Predisposition; Prevalence; Proteins; RNA; Research; Resources; Role; Science; Scientist; Signal Transduction; Structure; Sudden Death; Therapeutic; Therapeutic Intervention; Training; Translational Research; Universities; Untranslated RNA; Variant; Veterinary Medicine; Veterinary Schools; Work; comorbidity; comparative; differential expression; disease phenotype; extracellular vesicles; genome wide association study; human disease; insight; interstitial cell; mRNA sequencing; mortality; next generation sequencing; novel; novel strategies; nutrition; particle; patient population; translational model; translational pipeline; treatment optimization

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.

项目概要 非综合征性二尖瓣脱垂 (MVP)，一种常见的瓣膜性心脏病，影响 2-3% 的人类 人群中，可导致二尖瓣关闭不全、心功能不全、充血性心力衰竭甚至猝死。 由于缺乏治疗这种疾病的医学疗法，MVP 目前通过手术干预进行治疗。 由于不完全理解，有效的医疗管理策略的制定受到阻碍 疾病病理生理学，特别是驱动瓣膜间质细胞 (VIC) 分化的因素 从成纤维细胞转变为肌成纤维细胞样细胞，导致粘液瘤病理学。此外，转基因 忠实再现人类 MVP 病理学的动物模型尚不可用，部分原因是相对 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 粘液瘤性二尖瓣变性）经常发生在狗身上，估计发生率大于 50%。之前对犬类和人类 MVP 的比较表明，它们具有几个关键的组织病理学特征 这些特征表明，自发性狗疾病可能代表了一个很好的转化模型。使用犬科动物 以MVP为模板，我一直在研究细胞外囊泡（EV）和miRNA在 驱动成纤维细胞向成肌细胞的转换。 EV 是膜结合的细胞衍生颗粒，用于细胞间相互作用 通过蛋白质和非编码 (nc)RNA 的转移传递信号，它们与 包括阿尔茨海默病和癌症在内的多种疾病的传播。我们的初步数据显示，犬类 VIC 来自患病瓣膜的细胞产生与来自患病瓣膜的细胞不同的游离 miRNA 和 EV 相关 ncRNA 特征 普通阀门。因此，该提案的假设是可以利用犬类 MVP 来研究 EV信号介导的因素驱动粘液瘤性瓣膜变性，最终目标是 识别和验证早期检测和治疗干预的新靶标。为了完成 为此，我将首先在组织病理学和分子水平上完成犬 MVP 的表征 与人类 MVP 直接比较，然后探讨 EV 和 ncRNA 介导的信号传导对 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如何 介导的信号传导影响 MVP 的进化并为纳入自发犬类创建蓝图 将 MVP 纳入转化流程，以优化早期检测和干预的新方法。有钱人 塔夫茨大学的研究环境及其合作伙伴，包括兽医学院、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培训与我的指导团队的指导相结合 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得 我完全有能力成功转型为一名独立的临床医生科学家。