Serotonergic Receptor Targeted Therapy for Degenerative Aortic Valve Disease

描述（由申请人提供）：年龄相关性心脏瓣膜病是心血管疾病的第三大原因，在老年人中尤为普遍。研究表明，退行性主动脉瓣疾病影响超过25%的65岁以上人群，在4-8年内导致钙化性主动脉瓣疾病（CAVD）。目前，晚期CAVD唯一有效的长期治疗方法是瓣膜置换术，这是一种针对老年患者的有创、高风险手术。因此，一种非侵入性的治疗方法来阻止CAVD的进展将极大地有利于那些最有可能发展为严重CAVD的人。在细胞水平上，CAVD被认为是由AV间质细胞（AVICs）激活为肌成纤维细胞表型而引发的。一旦被激活，这些细胞会增加细胞外基质沉积，尤其是I型胶原，这直接导致在CAVD中观察到的小叶顺应性降低。转化生长因子-b1 （TGF-b1）是CAVD研究最广泛的细胞因子引发物；然而，5-羟色胺（5-HT）和其他5-羟色胺能受体激动剂已被证明通过5-羟色胺能受体5-HT2B的信号传导导致TGF-b1上游的CAVD。遗传上，NOTCH1单倍不全导致人类患者的CAVD具有100%的外显率。Notch1+/-导致小鼠AV小叶中BMP2和TGF-b1的合成和/或信号传导增加，从而导致CAVD。因此，Notch1+/-小鼠为研究抗CAVD策略提供了临床相关的动物模型。在这里，我们证明了5-HT2B拮抗剂可以阻止体外TGF-b1对AVICs的表型改变。此外，我们提供的证据表明，5-HT2B拮抗剂可阻止AVICs中的非典型TGF-b1信号传导。因此，我们假设5-HT2B可以特异性拮抗AVIC肌成纤维细胞活化，并为治疗CAVD提供早期时间点分子靶点，我们将在Notch1+/-动物和分离的AVIC动物和人身上验证这一假设。我们期望这项研究计划将展示一种新的治疗CAVD的策略。此外，本研究计划将阐明潜在的分子机制，同时量化5-HT2B拮抗剂引起的生物力学变化和功能血流动力学。

DESCRIPTION (provided by applicant): Age-related heart valve disease is the 3rd leading cause of cardiovascular disease and is especially prevalent among the elderly. Studies have shown that degenerative aortic valve disease affects over 25% of people over 65 years of age, leading to calcific aortic valve disease (CAVD) in 4-8 years. Currently, the only effective long- term treatment for advanced CAVD is valve replacement surgery, an invasive, high-risk procedure for elderly patients. For this reason, a non-invasive therapeutic to stop the progression of CAVD would greatly benefit those most at risk for developing severe CAVD. At the cellular level, CAVD is believed to be initiated by activation of AV interstitial cells (AVICs)to a myofibroblast phenotype. Once activated, these cells increase extracellular matrix deposition, particularly type I collagen, which directly leads to decreased compliance of the leaflets observed in CAVD. Transforming growth factor-b1 (TGF-b1) has been the most extensively studied cytokine initiator of CAVD; however, serotonin (5-HT) and other serotonergic receptor agonists have been shown to lead to CAVD upstream of TGF-b1 through signaling at the serotonergic receptor, 5-HT2B. Genetically, NOTCH1 haploinsufficiency results in CAVD with 100% penetrance in human patients. Notch1+/- leads to increased synthesis and/or signaling of both BMP2 and TGF-b1 in the AV leaflets of mice, which results in CAVD. Therefore, Notch1+/- mice provide a clinically relevant animal model to examine strategies against CAVD. Here, we show evidence that 5-HT2B antagonism prevents phenotypic alteration of AVICs by TGF-b1 in vitro. Moreover, we present evidence that 5-HT2B antagonism prevents non-canonical TGF-b1 signaling in AVICs. We therefore hypothesize that 5-HT2B can be specifically antagonized to prevent AVIC myofibroblast activation and provide early time point molecular targets to treat CAVD and we will test this hypothesis in Notch1+/- animals and isolated AVICs both for these animals and humans. We anticipate that this research plan will demonstrate a novel treatment strategy for CAVD. Further, this research plan will elucidate the underlying molecular mechanism, while also quantifying biomechanical changes and functional hemodynamics due to 5-HT2B antagonism.