Serotonergic Receptor Targeted Therapy for Degenerative Aortic Valve Disease

退行性主动脉瓣疾病的血清素受体靶向治疗

• 批准号: 8505790
• 负责人: WILLIAM D MERRYMAN
• 金额: $ 36.59万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8505790
• 关键词: Affect; Age-Years; Agonist; Animal Model; Animals; BMP2 gene; Biomechanics; Cardiac; Cardiovascular Diseases; Cell Line; Cells; Chest; Clinical; Collagen Type I; Deposition; Early Intervention; Elderly; Epidemiologic Studies; Extracellular Matrix; Family suidae; Genetic; Goals; Heart Valve Diseases; Human; In Vitro; Intervention; Lead; MAPK14 gene; Mechanics; Mediating; Molecular; Molecular Target; Mus; Myofibroblast; NOTCH1 gene; Nodule; Operative Surgical Procedures; Patients; Penetrance; Phenotype; Physicians; Prevention; Procedures; Quality of life; Research; Risk; Serotonin; Serotonin Receptor 5-HT2B; Signal Pathway; Signal Transduction; Staging; Testing; Therapeutic; Thoracic Surgical Procedures; Time; Tissue Model; Tissues; Transforming Growth Factors; age related; aortic valve; aortic valve disorder; aortic valve replacement; calcification; clinically relevant; cytokine; drug candidate; hemodynamics; high risk; in vivo; inhibitor/antagonist; interstitial cell; novel; novel strategies; older patient; prevent; public health relevance; receptor; response; small molecule; treatment strategy; valve replacement

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.

描述(申请人提供)：与年龄相关的心脏瓣膜疾病是心血管疾病的第三大原因，尤其在老年人中流行。研究表明，在65岁以上的人群中，退行性主动脉瓣疾病的发病率超过25%，可在4-8年内导致钙化性主动脉瓣疾病(CAVD)。目前，对于晚期CAVD，唯一有效的长期治疗方法是瓣膜置换手术，这是一种对老年患者来说具有侵入性、高风险的手术。因此，一种阻止CAVD进展的非侵入性治疗将极大地惠及那些发展为严重CAVD的最高风险人群。在细胞水平上，CAVD被认为是由房室间质细胞(AVICs)激活为肌成纤维细胞表型而启动的。一旦被激活，这些细胞会增加细胞外基质的沉积，特别是I型胶原，这直接导致CAVD中观察到的小叶顺应性降低。转化生长因子-β1(TGF-β1)是研究最广泛的CAVD细胞因子启动剂；然而，5-羟色胺(5-HT)和其他5-羟色胺能受体激动剂通过5-羟色胺受体(5-HT2B)信号通路导致CAVD。从遗传学上讲，NOTCH1单倍体缺陷导致人类患者出现100%外显率的CAVD。NOTCH1+/-导致BMP2和转化生长因子-β1在小鼠房室叶中的合成和/或信号增加，从而导致CAVD。因此，Notch1+/-小鼠为研究防治CAVD的策略提供了一个具有临床意义的动物模型。在此，我们证明了5-HT2B拮抗剂可以在体外阻止转化生长因子-β1对血管内皮细胞表型的改变。此外，我们提出的证据表明，5-HT2B拮抗可以阻止AVICs中非典型的转化生长因子-β1信号转导。因此，我们假设5-HT2B可以被特异性地拮抗以阻止AVIC肌成纤维细胞的激活，并提供早期的时间点分子靶点来治疗CAVD，我们将在Notch1+/-动物和这些动物和人类的分离的AVICs中验证这一假设。我们期待这项研究计划将展示一种新的治疗CAVD的策略。此外，这项研究计划将阐明潜在的分子机制，同时量化由于5-HT2B拮抗而引起的生物力学和功能血流动力学的变化。