Investigating the role of CaV1.2 in aortic valve stenosis

研究 CaV1.2 在主动脉瓣狭窄中的作用

• 批准号: 10421276
• 负责人: Geoffrey S Pitt
• 金额: $ 79.49万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10421276
• 关键词: Alternative Therapies; Aortic Valve Stenosis; Bioinformatics; Calcium Channel Blockers; Cells; Clinical; Clinical Data; Complementary DNA; Coronary Arteriosclerosis; Data; Development; Disease; Disease Progression; Early treatment; Etiology; Family suidae; Gene Expression Profile; Gene set enrichment analysis; High Fat Diet; Human; Hyperlipidemia; Inflammatory Response; L-Type Calcium Channels; Lesion; Life; Medical; Meta-Analysis; Motivation; Mus; Myofibroblast; Nodule; Pathology; Pathway Analysis; Pathway interactions; Patients; Process; Quantitative Trait Loci; Reporting; Risk Factors; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Susceptibility Gene; System; Testing; Tissues; Transfection; Validation; advanced disease; antagonist; aortic valve; aortic valve disorder; calcification; candidate identification; effective therapy; efficacy testing; genetic association; genome wide association study; in vivo; innovation; interstitial cell; macrophage; mouse model; normotensive; novel; novel therapeutics; osteogenic; overexpression; pre-clinical; prevent; success; targeted treatment; therapeutic target; voltage

Calcific aortic valve disease (CAVD) is a progressive life-threatening disorder characterized by dystrophic and/or osteogenic transformation of valve cells (VICs), both leading to calcification. There are no medical therapies to prevent or delay CAVD. Building on a recent meta-analysis of genome-wide association studies that unexpectedly identified CACNA1C, encoding the pore-forming α subunit of the voltage gated L-type calcium channel CaV1.2, as a candidate CAVD susceptibility gene, we present preliminary data suggesting that Ca2+ influx through CaV1.2 in VICs is causal for CAVD. This raises the tantalizing possibility that clinically used Ca2+ channel antagonists (CCBs) may be an effective therapy. Although CCBs are generally contraindicated in patients with severe CAVD, they would be reasonable therapies earlier in the disease process. We propose to test the overall hypotheses that: 1) increased Ca2+ influx through CaV1.2 in VICs leads to dystrophic and/or osteogenic transformation; and 2) reduction of Ca2+ influx through CaV1.2 with CCBs and/or by targeting Ca2+- dependent signaling molecules downstream of CaV1.2 in VICs delays CAVD progression. We developed novel mouse models and innovative VIC cultures to test those overall hypotheses with the following Aims: Aim 1: Can elevated Ca2+ influx through CaV1.2 activate VICs and/or increase expression of signaling pathway genes leading to dystrophic or osteogenic calcification in the AoV? Using porcine and murine VICs enhanced by transfection of informative cDNAs, we have developed means to dissect the Ca2+-dependent signaling pathways downstream of CaV1.2 that contribute to CAVD, and thereby to discover new potential therapeutic targets. We propose a multi-pronged approach to identify the critical downstream Ca2+-dependent signaling molecules and pathways leading to activation of dystrophic VICs and/or osteogenic transformation of VICs; Aim 2: Can inhibition of CaV1.2 signaling pathways in the aortic valve decrease the valve pathology? With novel mouse models that mimic the increased CaV1.2 expression and signaling in human CAVD, we propose to test if CCBs ameliorate valve lesions and reverse the disease process once calcification is initiated. We further propose to build upon our identification of novel candidate targets from Aim 1 to test if manipulating these targets similarly reduces or slows CAVD progression. Aim 3: Does excess Ca2+ influx through CaV1.2 contribute to CAVD in the context of hyperlipidemia? Hyperlipidemia is a prominent CAVD risk factor. In coronary artery disease, a related disorder, long ignored data point to a synergistic interaction between CaV1.2 and hyperlipidemia. We propose: to test with novel mouse models whether Ca2+ influx through CaV1.2 in VICs or macrophages accelerates AoV lesions in the context of hyperlipidemia and, as a corollary, whether CCBs are effective when the disease process is driven by hyperlipidemia, thereby determining whether targeting the CaV1.2 pathway is broadly applicable in patients.

钙化主动脉瓣疾病（CAVD）是一种逐渐威胁生命的疾病，其特征是营养不良和/或 瓣膜细胞（VIC）的成骨转化都导致钙化。没有医疗疗法 预防或延迟CAVD。基于最近对全基因组关联研究的荟萃分析 出乎意料地识别出Cacna1c，编码电压门控L型钙的孔形成α亚基 通道Cav1.2，作为候选CAVD敏感性基因，我们提供了初步数据，表明CA2+ VIC中通过CAV1.2的影响是Cavd的因果。这增加了临床使用Ca2+的诱人可能性 通道拮抗剂（CCB）可能是一种有效的疗法。尽管CCB通常是禁忌的 患有严重CAVD的患者，在疾病过程中，他们将是合理的疗法。我们建议 测试以下总体假设：1）VIC中通过CAV1.2增加Ca2+影响会导致营养不良和/或 成骨转化； 2）通过CCB和/或通过靶向Ca2+ - 通过CAV1.2减少Ca2+影响。 VIC中Cav1.2下游的依赖信号传导分子延迟Cavd进程。我们开发了小说 鼠标模型和创新的VIC文化以以下目的测试这些总体假设：AIM 1：CAN 通过CAV1.2激活VIC和/或增加信号通路基因表达的升高Ca2+影响。 在AOV中进行营养不良或成骨计算？通过转染增强的猪和鼠vics 在内容丰富的cDNA中，我们开发了剖析CA2+依赖性信号通路的手段 cav1.2有助于CAVD，从而发现新的潜在治疗靶标。我们提出了一个 多管齐下的方法来识别临界下游Ca2+依赖性信号分子和途径 导致营养不良的VIC和/或VIC的成骨转化；目标2：可以抑制CAV1.2 主动脉瓣中的信号通路会降低瓣膜病理？用新颖的鼠标模型模仿 CAV1.2的表达和人体CAVD的信号传导增加，我们建议测试CCBS是否改善瓣膜病变 一旦启动计算，就会扭转疾病过程。我们进一步建议以我们的身份建立 AIM 1的新型候选目标的测试是否同样减少或减慢CAVD 进展。目标3：在高脂血症的背景下，通过CAV1.2超过Ca2+影响会导致CAVD吗？ 高脂血症是一个突出的CAVD危险因素。在冠状动脉疾病中，一种相关疾病，长期以来忽略了数据 指向CAV1.2和高脂血症之间的协同相互作用。我们建议：用新颖的鼠标测试 模型Ca2+通过VIC中的Cav1.2影响或巨噬细胞在 高脂血症，作为推论，CCB是否在疾病过程被驱动时是否有效 高脂血症，从而确定针对CAV1.2途径是否广泛适用于患者。