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.

概括。 双质主动脉瓣（BAV）是美国最常见的先天性心脏缺陷，与 它经常出现主动脉瓣狭窄（AS）和上升胸动脉瘤（TAA）。 据估计，有30％至50％的BAV患者将需要手术干预瓣膜病的生活， 主动脉疾病或两者兼而有之。而跨越十年的退化过程也是如此的解剖或破裂 主动脉有毁灭性的后果。心脏病专家和 心脏外科医生是BAV患者患有主动脉事件的风险的管理。根据 当前的准则，使用成像技术获得的度量测量值将BAV患者进行风险分解。 尽管主动脉直径，膨胀率和主动脉面积/直径与体重/表面的比率是电流 选修手术干预的适应症，它们是主动脉夹层和破裂的不完美预测指标。 在BAV的情况下，直径与组织学异常之间缺乏相关性突出了 直径不足是主动脉切除的原因。研究主动脉壁体内平衡的新方法 显然需要，以及基于主动脉墙微观结构实现成像技术的新方法 应优先考虑。这样，此应用程序解决了NIH已确定为重要的领域， 研究的主题，包括表征前发作的识别和预防性处理 血管疾病。如果不这样做，将导致继续使用BAV的临床管理不足 次优护理的患者。此应用程序填补了此空白。 我们的目标是研究BAV易感性事件的易感性，并揭示诊断和治疗 年龄/ROS/心肌蛋白轴的电势。 AIM 1将确定BAV倾向的近端主动脉疾病 并且与人VSMC和主动脉壁组织中的年龄/ROS/肌动蛋白信号变化有关。 bav 患者将根据SRAGE水平进行招募和风险分层 通过生物力学测试的主动脉壁。通过解剖，将在体外确定BAV衍生的VSMC可塑性 使用新型SOD Mimetics（MNTE-2-PYP5+和MNTNBUOE-2-PYP5+）的愤怒/ROS/心肌蛋白信号传导，抗 - 和mir143和心肌蛋白siRNA。终点和读数将包括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耦合 以及对BAV患者的风险分层的成像分析，包括不同的BAV解剖构型。 值得注意的是，我们有能力测试一千多名非手术患者。那，我们的数据纯粹是纯粹的 基础科学问题，并开始根据新的风险解决有关临床管理的问题 - 分层工具。 AIM 2将在体内调节年龄/ROS/心肌信号传导，并确定其对主动脉的影响 BAV和TAV鼠模型中的墙改造。年龄/ROS/心肌蛋白轴将在多个级别上解剖 通过实施药物方法和选定的遗传背景来体内。利用MyOCD 有条件的（sm-myhc-creert/myocdf/f），rage - / - 和eNos - / - （通过Echo选择BAV），我们将 测试ANG II慢性输注在AV和升主主动脉重塑调节miR143上的作用（PER-MIR143 和lnamir143）或氧化应激（Mn-porphyrins）。 AV功能和主动脉词字典将进行测试 超声心动图；主动脉重塑将由VSMC表型和ECM重塑确定。 这是该应用程序对公共卫生有两个重要的结果：在短期内，它将提供医生 和科学家使用工具（除了当前的成像技术之外），以确定具有高风险的患者 瓣膜和血管病理。从长远来看，它将提供有关细胞和细胞的机械信息 分子事件导致升高性主动脉疾病，这将是高风险个性化疗法不可或缺的 个人。