Role of RAGE in Bicuspid Aortic Valve Syndrome

RAGE 在二叶式主动脉瓣综合征中的作用

• 批准号: 9175654
• 负责人: Giovanni Ferrari
• 金额: $ 42.34万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-08 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9175654
• 关键词: Address; Advanced Glycosylation End Products; Affect; Algorithms; Aneurysm; Angiotensin II; Aorta; Aortic Aneurysm; Aortic Valve Stenosis; Apoptosis; Architecture; Area; Assimilations; Basic Science; Biomechanics; Blood Vessels; Body Weight; Caliber; Cardiac; Caring; Cells; Chronic; Clinical; Clinical Management; Congenital Heart Defects; Coupled; Cytoskeleton; Data; Diagnostic; Dilatation - action; Dissection; Down-Regulation; Enrollment; Event; Excision; Fibronectins; Functional disorder; Genes; Genetic; Goals; Guidelines; HMGB1 gene; Heart Diseases; Histologic; Homeostasis; Human; Image Analysis; Imaging Techniques; In Vitro; Individual; Infusion procedures; Injection of therapeutic agent; Lead; Letters; Life; Literature; Manuscripts; Measurement; Medial; Mediating; Mediator of activation protein; Methodology; Modeling; Molecular; Mus; Operative Surgical Procedures; Outcome; Oxidative Stress; Pathology; Patient risk; Patients; Phenotype; Physicians; Population; Porphyrins; Predisposition; Preventive treatment; Process; Production; Public Health; Reactive Oxygen Species; Regulation; Regulatory Pathway; Reporting; Resected; Risk; Role; Rupture; Scientist; Signal Transduction; Small Interfering RNA; Smooth Muscle Myocytes; Specimen; Stratification; Support Groups; Surface; Surgeon; Syndrome; Testing; Therapeutic; Thoracic Aortic Aneurysm; Tissues; United States National Institutes of Health; Vascular Diseases; Vascular Smooth Muscle; ascending aorta; base; bicuspid aortic valve; circulating biomarkers; connective tissue growth factor; high risk; human tissue; in vivo; mimetics; model design; mouse model; myocardin; novel; novel strategies; patient population; personalized medicine; premature; receptor; reconstruction; tool; transcriptome sequencing

SUMMARY. Bicuspid Aortic Valve (BAV) is the most common congenital heart defect in the US and is associated with frequent and premature occurrence of aortic stenosis (AS) and ascending thoracic aortic aneurysm (TAA). It has been estimated that 30-50% of BAV patients will require surgical intervention in their life for valvulopathy, aortopathy or both. While AS is a degenerative process that span over a decade, a dissection or rupture of the aorta has devastating consequences. One of today’s major clinical controversies among cardiologists and cardiac surgeons is the management of BAV patients for the risk of adverse aortic events. According to the the current guidelines, BAV patients are risk-stratified using metric measurements obtained by imaging techniques. Although aortic diameter, expansion rate, and ratio of aortic area/diameter to body weight/surface are the current indications for elective surgical intervention, they are imperfect predictors of aortic dissection and rupture. The lack of correlation between diameter and histologic abnormality in the setting of BAV highlights the inadequacy of diameter alone as a reason for aortic resection. New approaches to study aortic wall homeostasis are clearly needed, and new methodologies to implement imaging techniques based on aortic wall microstructure should be prioritized. In doing so, this application addresses areas that the NIH has identified as important, understudied topics, including the characterization of pre-onset identification and preventive treatment of vascular diseases. Failing to do so, will lead to the continued use of inadequate clinical managements of BAV patients with suboptimal care. This application fills this gap. Our goal is to investigate BAV predisposition to adverse aortic events and to unveil the diagnostic and therapeutic potentials of the AGE/ROS/myocardin axis. Aim 1 will determine BAV predisposition to proximal aortopathies and is association to altered AGE/ROS/myocardin signaling in human VSMCs and aortic wall tissues. BAV patients will be enrolled and risk-stratified according to sRAGE level and analyzed ex vivo for dysfunction of the aortic wall by biomechanical testing. BAV-derived VSMC plasticity will be determined in vitro by dissecting RAGE/ROS/myocardin signaling using novel SOD mimetics (MnTE-2-PyP5+ and MnTnBuOE-2-PyP5+), anti- and pre-miR143, and myocardin siRNA. Endpoints and readouts will include ECM remodeling, VSMC phenotype, proliferation, and apoptosis. Cell- and tissue-derived data will be coupled with circulating markers and imaging analysis for the risk stratification of BAV patients including different BAV anatomical configuration. Notably, we have the ability to test over a thousand non surgical patients. Thus, our data move beyond purely basic science questions and begin to address questions about clinical management based on new risk- stratification tools. Aim 2 will modulate AGE/ROS/myocardin signaling in vivo and determine its impact on aortic wall remodeling in BAV and TAV murine models. AGE/ROS/myocardin axis will be dissected at multiple level in vivo by implementing pharmacological approaches and selected genetic backgrounds. Capitalizing on Myocd conditional (SM-MyHC-CreERT/MyocdF/F), RAGE-/-, and eNOS-/- (selected for BAV presence by echo), we will test the role of Ang II chronic infusion on AV and ascending aortic remodeling modulating miR143 (Pre-miR143 and LNAmiR143) or oxidative stress (Mn-porphyrins). AV function and aortic dilation will be tested echocardiographically; aortic remodeling will be determined by VSMC phenotype and ECM remodeling. Thus, this application has two important outcomes for public health: in the short term, it will provide physicians and scientists a tool (in addition to the current imaging techniques), to identify a patient population at high risk of valve and vascular pathologies. In the long term, it will provide mechanistic information on the cellular and molecular events leading to ascending aortopathies, which will be integral to personalized therapies for high-risk individuals.

概括。 二叶式主动脉瓣 (BAV) 是美国最常见的先天性心脏病，与 主动脉瓣狭窄（AS）和升主动脉瘤（TAA）频繁且过早发生。它有 据估计，30-50% 的 BAV 患者一生中需要因瓣膜病进行手术干预， 主动脉病或两者兼而有之。虽然 AS 是一个持续十多年的退行性过程，但 AS 的解剖或破裂 主动脉具有毁灭性的后果。当今心脏病专家和心脏病专家之间的主要临床争议之一 心脏外科医生负责管理 BAV 患者的主动脉不良事件风险。根据 根据当前指南，使用成像技术获得的度量测量对 BAV 患者进行风险分层。 尽管主动脉直径、扩张率以及主动脉面积/直径与体重/表面积的比率是当前的 择期手术干预的适应症，但它们并不是主动脉夹层和破裂的完美预测因子。 BAV 情况下直径与组织学异常之间缺乏相关性凸显了 仅直径不足作为主动脉切除术的原因。研究主动脉壁稳态的新方法 显然需要新的方法来实施基于主动脉壁微结构的成像技术 应优先考虑。在此过程中，该应用程序解决了 NIH 确定的重要领域， 未充分研究的主题，包括发病前识别的特征和预防性治疗 血管疾病。如果不这样做，将导致继续使用不充分的 BAV 临床管理 护理欠佳的患者。该应用程序填补了这一空白。 我们的目标是调查 BAV 对主动脉不良事件的易感性，并揭示诊断和治疗方法 AGE/ROS/心肌素轴的电位。目标 1 将确定 BAV 对近端主动脉病的易感性 并且与人类 VSMC 和主动脉壁组织中 AGE/ROS/心肌素信号传导的改变有关。 BAV 将根据 sRAGE 水平对患者进行登记和风险分层，并进行离体功能障碍分析 通过生物力学测试主动脉壁。 BAV 衍生的 VSMC 可塑性将通过解剖在体外测定 使用新型 SOD 模拟物（MnTE-2-PyP5+ 和 MnTnBuOE-2-PyP5+）的 RAGE/ROS/心肌素信号转导，抗 和 pre-miR143 和心肌素 siRNA。端点和读数将包括 ECM 重塑、VSMC 表型、增殖和凋亡。细胞和组织来源的数据将与循环标记相结合 对包括不同 BAV 解剖结构的 BAV 患者进行风险分层的影像学分析。 值得注意的是，我们有能力对一千多名非手术患者进行测试。因此，我们的数据超越了纯粹的 基础科学问题，并开始解决基于新风险的临床管理问题 分层工具。目标 2 将调节体内 AGE/ROS/心肌素信号传导并确定其对主动脉的影响 BAV 和 TAV 小鼠模型中的壁重塑。 AGE/ROS/心肌素轴将在多个层面进行解剖 通过实施药理学方法和选定的遗传背景来体内治疗。利用 Myocd 有条件 (SM-MyHC-CreERT/MyocdF/F)、RAGE-/- 和 eNOS-/-（通过回声选择 BAV 存在），我们将 测试 Ang II 慢性输注对 AV 和升主动脉重塑调节 miR143（Pre-miR143 和 LNmiR143）或氧化应激（锰卟啉）。将测试 AV 功能和主动脉扩张 超声心动图；主动脉重塑将由 VSMC 表型和 ECM 重塑决定。 因此，该应用程序对公共卫生有两个重要成果：在短期内，它将为医生提供 科学家们可以使用一种工具（除了当前的成像技术之外）来识别高危患者群体 瓣膜和血管病变。从长远来看，它将提供有关细胞和 导致升主动脉病的分子事件，这将是高危个体化治疗不可或缺的一部分 个人。