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: 9313307
• 负责人: Giovanni Ferrari
• 金额: $ 11.38万
• 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 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9313307
• 关键词: Address; Advanced Glycosylation End Products; Affect; Age; Algorithms; Anatomy; 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; Letters; Life; Literature; Manuscripts; Measurement; Medial; Mediating; Mediator of activation protein; Methodology; Modeling; Molecular; Mus; Muscle Cells; Operative Surgical Procedures; Outcome; Oxidative Stress; Pathology; Patient risk; Patients; Pharmacology; Phenotype; Physicians; Population; Porphyrins; Predisposition; Preventive treatment; Process; Production; Public Health; Reactive Oxygen Species; Regulation; Regulatory Pathway; Reporting; Resected; Risk; Risk stratification; Role; Rupture; Scientist; Signal Transduction; Small Interfering RNA; Specimen; 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.

总结。 二尖瓣主动脉瓣是美国最常见的先天性心脏病，与 主动脉狭窄(AS)和升主动脉瘤(TAA)的频繁和过早发生。它有 据估计，30%-50%的BAV患者因瓣膜病需要在一生中进行手术治疗， 大动脉病变或两者兼而有之。虽然AS是一个跨越十年的退行性过程，但解剖或断裂 大动脉会带来毁灭性的后果。当今心脏病专家之间的主要临床争议之一是 心脏外科医生管理的是BAV患者发生不良主动脉事件的风险。据The the the 根据目前的指南，使用成像技术获得的度量测量对BAV患者进行风险分层。 虽然主动脉直径、扩张率和主动脉面积/直径与体重/表面积的比率是目前的趋势 选择性手术干预的适应症，它们不是主动脉夹层和破裂的完美预测指标。 在BAV的环境中，直径和组织学异常之间缺乏相关性，突出了 仅以直径不足作为行主动脉切除的原因。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 应该优先考虑。在这样做的过程中，这项申请涉及美国国家卫生研究院确定为重要的领域， 未充分研究的专题，包括发病前识别和预防性治疗的特征 血管疾病。如果做不到这一点，将导致继续使用不适当的BAV临床管理 治疗效果不佳的病人。这个应用程序填补了这一空白。 我们的目标是调查BAV对不良主动脉事件的易感性，并揭示其诊断和治疗 AGE/ROS/Myocardin轴的电位。AIM 1将确定BAV对近端主动脉病变的易感性 并与人VSMCs和主动脉壁组织中AGE/ROS/myocardin信号的改变有关。BAV 将根据SRAGE水平对患者进行入选和风险分层，并在体外分析患者的功能障碍 主动脉壁生物力学测试。BAV来源的VSMC的可塑性将通过解剖在体外确定 使用新的SOD模拟物(MnTE-2-PyP5+和MnTnBuOE-2-PyP5+)的RAGE/ROS/myocardin信号转导，抗- 和前miR143，以及Myocardin siRNA。终端和读数将包括ECM重塑、VSMC 表型、增殖和凋亡。细胞和组织衍生的数据将与循环标记物相结合 对不同BAV解剖形态的BAV患者进行危险分层的影像分析。 值得注意的是，我们有能力对1000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。AIM 2将在体内调节AGE/ROS/Myocardin信号并确定其对主动脉的影响 BAV和TAV小鼠模型的室壁重塑。AGE/ROS/Myocardin轴将在 通过实施药理学方法和选定的遗传背景，进行活体实验。利用MYOCD 有条件的(SM-MyHC-CreERT/MyocdF/F)、RAGE-/-和eNOS-/-(通过ECHO选择用于BAV存在)，我们将 血管紧张素转换酶II慢性输注对房室和升主动脉重构调节miR143(Pre-miR143)的作用 和LNAmiR143)或氧化应激(锰卟啉)。将对房室功能和主动脉扩张进行测试 超声心动图显示，VSMC表型和ECM重塑将决定主动脉重塑。 因此，这项应用对公共卫生有两个重要的结果：在短期内，它将为医生提供 科学家提供了一种工具(除了目前的成像技术之外)，来识别高危患者群体。 瓣膜和血管病理。从长远来看，它将提供关于细胞和 导致升主动脉病变的分子事件，这将是高危患者个性化治疗的组成部分 个人。