Serotonergic Receptor Targeted Therapy for Degenerative Aortic Valve Disease

描述（由申请人提供）：心血管相关心脏瓣膜疾病是心血管疾病的第三大主要原因，在老年人中尤其普遍。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，导致4-8年内发生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侵入性高风险手术。因此，阻止CAVD进展的非侵入性治疗将使那些最有可能发展为严重CAVD的人受益匪浅。在细胞水平，CAVD被认为是通过AV间质细胞（AVIC）活化为肌成纤维细胞表型而引发的。一旦激活，这些细胞增加细胞外基质沉积，特别是I型胶原，这直接导致CAVD中观察到的瓣叶顺应性降低。转化生长因子-b1（TGF-β 1）是CAVD研究最广泛的细胞因子引发剂;然而，5-羟色胺（5-HT）和其他β-羟色胺能受体激动剂已被证明通过β-羟色胺能受体5-HT 2B的信号传导导致TGF-β 1上游的CAVD。在遗传学上，NOTCH 1单倍不足导致人类患者中CAVD的100%突变率。Notch 1 +/-导致小鼠AV小叶中BMP 2和TGF-β 1的合成和/或信号传导增加，这导致CAVD。因此，Notch 1 +/-小鼠提供了一种临床相关的动物模型，以检查针对CAVD的策略。在这里，我们显示的证据表明，5-HT 2B拮抗作用防止AVIC表型改变的TGF-β 1在体外。此外，我们提出的证据表明，5-HT 2B拮抗剂防止非典型的TGF-β 1信号在AVIC。因此，我们假设5-HT 2B可以被特异性拮抗以防止AVIC肌成纤维细胞活化，并提供早期时间点分子靶点以治疗CAVD，我们将在Notch 1 +/-动物和分离的AVIC中测试这一假设，包括这些动物和人类。我们预计，这项研究计划将证明一种新的治疗CAVD的策略。此外，这项研究计划将阐明潜在的分子机制，同时还量化由于5-HT 2B拮抗作用引起的生物力学变化和功能性血液动力学。

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.