CaMKII regulates key mechanisms of vascular response to injury in vivo

CaMKII 调节体内血管损伤反应的关键机制

• 批准号: 8459392
• 负责人: Isabella Maria Grumbach
• 金额: $ 35.94万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-16 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8459392
• 关键词: Atherosclerosis; Balloon Angioplasty; Binding; Blood Vessels; Calmodulin; Cardiovascular system; Cause of Death; Coronary Artery Bypass; Data; Dependence; Development; Disease; Disease Resistance; Endarterectomy; Endothelium; Enzymes; Equilibrium; Event; Fostering; Goals; Growth Factor; Health; Health Care Costs; Hyperplasia; In Vitro; Injury; Knowledge; Lead; Ligation; Mediating; Medicine; Mission; Morbidity - disease rate; Muscle Contraction; Myocardial Infarction; Operative Surgical Procedures; Outcome; Pathway interactions; Phosphotransferases; Prevention strategy; Protein-Serine-Threonine Kinases; Public Health; Publishing; Regulation; Research; Role; Signal Transduction; Site; Stents; Stroke; Testing; Therapeutic; Translating; Validation; Vascular Smooth Muscle; Veins; Work; base; calmodulin-dependent protein kinase II; cytokine; design; graft failure; improved; in vivo; in vivo Model; inhibitor/antagonist; innovation; meetings; methionine sulfoxide reductase; migration; neointima formation; novel; novel strategies; oxidation; prevent; programs; response; response to injury; restenosis; tool

DESCRIPTION (provided by applicant): The function of the multifunctional Ca2+/calmodulin-dependent kinase II (CaMKII) remains poorly understood in the vasculature. Our data suggest that CaMKII is instrumental in mediating neointima formation and remodeling after vascular injury. Neointima formation and remodeling occur in vein graft failure after coronary artery bypass surgery, after balloon angioplasty and surgical endarterectomy and have a significant impact in terms of morbidity and health care cost. Our long-term goal is to study the function of CaMKII in the vasculature, specifically CaMKII modulation as new approach to treat vascular injury. The objective of this application is to determine how CaMKII is activated in injury, directy test whether CaMKII inhibition will confer disease resistance in vascular injury and delineate the dependance of VSMC migration and proliferation upon the oxidative activation of CaMKII. The central hypothesis of this application is that CaMKII is activated by oxidation of Met281/282 in vascular injury and that oxidative activation of CaMKII is necessary for neointimal hyperplasia, VSMC proliferation and migration. This hypothesis is based on our preliminary data that CaMKII is essential in neointima formation and remodeling after injury. Oxidized CaMKII (ox-CaMKII) is readily detected in the neointima after vascular injury. In addition, we have compelling evidence that key activators in the response to injury induce ox-CaMKII in vitro. The rationale of the proposed research is that understanding how CaMKII is activated after vascular injury, has the potential to translate into better strategies to prevent the deleterious effects after vascular injry. Guided by strong preliminary data, the central hypothesis will be tested in three specific aims: 1) Dissect the mechanisms of CaMKII activation in vascular injury in vivo; 2) Determine the role of methionine sulfoxide reductase A (MsrA), the enzyme that controls the balance between active ox-CaMKII and reduced inactive CaMKII, in the response to injury; 3) Dissect the mechanisms of CaMKII activation in VSMC migration, proliferation in vitro. In the first aim, a novel in vivo model will be used to test if the blockade of oxidative CaMKII activation is sufficient to abrogate the response to injury. Under aim 2, we will define whether MsrA can modulate neointimal hyperplasia through ox-CaMKII. In aim 3, we will delineate how CaMKII is activated by key cytokines and growth factors relevant for vascular injury in vitro and how the activation pathways correlate with VSMC migration and proliferation. The approach is innovative because of its use of novel in vivo models and specific tools to dissect CaMKII signaling. The proposed research is significant because it is expected to advance the field by identifying CaMKII activating events in vivo. Ultimately, such knowledge may allow for the development of new preventive strategies for vascular injury.

描述（由申请人提供）：多功能Ca2+/钙调蛋白依赖性激酶II（CAMKII）的功能在脉管系统中仍然鲜为人知。我们的数据表明，CAMKII在介导新内膜形成和血管损伤后进行了重塑作用。冠状动脉血管成形术和手术性内膜切除术后冠状动脉搭桥手术后的静脉移植手术后，新内膜形成和重塑发生在静脉移植手术后，并且在发病率和医疗保健成本方面产生了重大影响。我们的长期目标是研究CAMKII在脉管系统中的功能，特别是CAMKII调节作为治疗血管损伤的新方法。该应用的目的是确定CAMKII如何在受伤中激活，直接测试CAMKII抑制是否会赋予血管损伤中的抗病性，并描述VSMC迁移的依赖性以及对CAMKII氧化激活的增殖。该应用的中心假设是CAMKII通过在血管损伤中的MET281/282氧化而激活CAMKII，CAMKII的氧化激活对于新的增生，VSMC增殖和迁移是必需的。该假设是基于我们的初步数据，即CAMKII在损伤后的新内膜形成和重塑中至关重要。血管损伤后，在新内膜中很容易检测到氧化的CAMKII（OX-CAMKII）。此外，我们还有令人信服的证据表明，对损伤的反应中的关键激活因素在体外诱导了牛camkii。拟议的研究的基本原理是，了解血管损伤后如何激活CaMKII，有可能转化为更好的策略，以防止血管生成后的有害作用。在强大的初步数据的指导下，中央假设将以三个特定目的进行检验：1） 解剖体内血管损伤中CaMKII激活的机制； 2）确定蛋氨酸还原酶A（MSRA）的作用，该酶控制着活性的OX-CAMKII和降低的无效CAMKII之间的平衡，对损伤的反应； 3）在VSMC迁移，体外增殖中剖析CAMKII激活的机制。在第一个目标中，新型体内模型将用于测试氧化camkii激活的阻塞是否足以消除 对伤害的反应。在AIM 2下，我们将定义MSRA是否可以通过Ox-Camkii调节新的增生。在AIM 3中，我们将描述CAMKII如何通过与血管损伤相关的关键细胞因子和体外的生长因子激活，以及激活途径与VSMC迁移和增殖的相关性如何。这种方法具有创新性，因为它使用了新型体内模型和特定工具来剖析CAMKII信号传导。拟议的研究非常重要，因为预计通过识别CAMKII激活体内事件将推进该领域。最终，这种知识可以允许制定新的预防性血管损伤策略。