AntimiR-199a for cardiac ischemia and failure

AntimiR-199a 用于治疗心脏缺血和衰竭

• 批准号: 7909709
• 负责人: Patricio Abarzua
• 金额: $ 13.22万
• 依托单位: VASADE BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-16 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7909709
• 关键词: Attention; Cardiac; Cells; Coronary artery; Dose; Down-Regulation; Economic Inflation; Effectiveness; Embolism; Failure; Healthcare; Heart; Hypoxia; Injury; Ischemia; Knowledge; Life; Longevity; Measures; Methods; MicroRNAs; Modification; Mus; Muscle Cells; Myocardial Ischemia; Myocardium; Oligonucleotides; Organ; Organogenesis; Pathogenesis; Phase; Play; Preventive; Process; Reperfusion Injury; Risk; Role; Specificity; Techniques; Testing; Therapeutic; Time; Transgenic Mice; Up-Regulation; clinical application; hypoxia inducible factor 1; in vivo; knock-down; mouse model; phase 1 study; preconditioning; public health relevance; research and development; research study

DESCRIPTION (provided by applicant): Protecting the heart against ischemia or ischemia/reperfusion injury is one of the top health care objectives. Currently, one of the most effective mechanisms is ischemia preconditioning, which is achieved by intermittent occlusion of the coronary artery via balloon inflation. Unfortunately, though, its clinical applicability is hampered by the fact that its effectiveness is short-lived and, thus, requires prior knowledge of the time of an ischemic episode. Moreover, it is an invasive technique that carries the risk of atherosclerotic emboli. Thus, identification of factors that can mimic this process would be a great benefit to ischemic heart disease. MicroRNAs (miRNA) are posttranscriptional regulators that play a fundamental role in a cell's fate. While most of the studies in the field have focused on miRNA that are involved in cardiac organogenesis and pathogenesis, we have turned our attention to miRNA that are involved in protection against ischemic injury. We have recently identified miR-199a as an obligatory direct regulator of hypoxia-inducible factor 1 alpha (Hif- 1a) and Sirt1, two key molecules that are required for preconditioning of cells against hypoxia, and longevity, respectively. Hypoxia induces downregulation of miR-199a, which is required for upregulation of Hif-1a and Sirt1. By knocking down miR-199a in cultured myocytes or in a transgenic mouse model we were able to recapitulate the effects of hypoxia preconditioning and protect the cells against hypoxic damage. Modulating the expression of miRNA in vivo for therapeutic advantages remains a challenge. In phase I of this study we will experiment with different forms, doses, duration, and methods of delivery, of antimiR-199a in mice to establish its efficacy and specificity in reducing the levels of endogenous miRNA-199a and upregulation of its targets. These experiments are a prelude to phase II that will involve testing its effectiveness in protection of the heart against ischemic damage. The overall objective is to evaluate the potential of antimiR-199a delivery to the heart as a, preventive, preconditioning measure for the ischemic heart and, thus, establish the scientific merit and feasibility of the proposed R&D. Our hypotheses are, 1) systemic delivery of antimiR-199a to the heart will induce downregulation of endogenous miR-199a that will result in upregulation of Hif-1a and Sirt1 in all organs involved, including the heart, 2) the different modifications of the injected antimiR-199a oligo will impact its effectiveness, dose, and duration required for knockdown of endogenous miR-199a in the heart, and 3) locally delivered antimiR-199a will effectively knockdown miR-199a and induce upregulation of its targets in the injected myocardium and beyond, but not in any other organs. Our aim is to test different forms, doses, duration, and methods of delivery, of antimiR-199a in mice to establish its efficacy and specificity in reducing the levels of endogenous miRNA-199a and upregulation of its targets. PUBLIC HEALTH RELEVANCE: Protecting the heart against ischemia or ischemia/reperfusion injury is one of the top health care objectives. Currently, one of the most effective mechanisms is ischemia preconditioning, which is achieved by intermittent occlusion of the coronary artery via balloon inflation. Unfortunately, though, its clinical applicability is hampered by the fact that its effectiveness is short-lived and, thus, requires prior knowledge of the time of an ischemic episode. Moreover, it is an invasive technique that carries the risk of atherosclerotic emboli. Thus, identification of factors that can mimic this process would be a great benefit to ischemic heart disease. We have recently identified miR-199a that has the potential to fulfill that purpose, which will be investigated in this proposal.

描述（由申请人提供）：保护心脏免受缺血或缺血/再灌注损伤是最重要的医疗保健目标之一。目前，最有效的机制之一是缺血预处理，其通过经由球囊膨胀间歇性闭塞冠状动脉来实现。然而，不幸的是，它的临床应用受到其有效性是短暂的事实的阻碍，因此，需要缺血发作时间的先验知识。此外，它是一种有创技术，具有动脉粥样硬化栓塞的风险。因此，识别能够模拟这一过程的因素将对缺血性心脏病有很大的益处。 microRNA（miRNA）是转录后调节因子，在细胞命运中起着重要作用。虽然该领域的大多数研究都集中在参与心脏器官发生和发病机制的miRNA上，但我们已经将注意力转向参与保护缺血性损伤的miRNA。我们最近发现miR-199 a是低氧诱导因子1 α（Hif- 1a）和Sirt 1的强制性直接调节因子，这两个关键分子分别是细胞缺氧预处理和长寿所需的。缺氧诱导miR-199 a下调，这是上调Hif-1a和Sirt 1所必需的。通过在培养的心肌细胞或转基因小鼠模型中敲低miR-199 a，我们能够概括缺氧预处理的作用并保护细胞免受缺氧损伤。 调节体内miRNA的表达以获得治疗优势仍然是一个挑战。在本研究的第一阶段，我们将在小鼠中试验不同形式、剂量、持续时间和递送方法的antimiR-199 a，以确定其在降低内源性miRNA-199 a水平和上调其靶标方面的功效和特异性。这些实验是第二阶段的前奏，第二阶段将涉及测试其保护心脏免受缺血性损伤的有效性。总体目标是评估将antimiR-199 a递送至心脏作为缺血性心脏的预防性预处理措施的潜力，从而确立所提出的研发的科学价值和可行性。 我们的假设是，1）将antimiR-199 a全身递送至心脏将诱导内源性miR-199 a的下调，这将导致包括心脏在内的所有相关器官中的Hif-1a和Sirt 1的上调，2）注射的antimiR-199 a寡核苷酸的不同修饰将影响其在心脏中敲低内源性miR-199 a所需的有效性、剂量和持续时间，和3）局部递送的antimiR-199 a将有效地敲低miR-199 a，并诱导其靶在注射的心肌和更远处，但不在任何其它器官中的上调。我们的目标是在小鼠中测试antimiR-199 a的不同形式、剂量、持续时间和递送方法，以确定其在降低内源性miRNA-199 a水平和上调其靶点方面的功效和特异性。 公共卫生关系： 保护心脏免受缺血或缺血/再灌注损伤是最重要的医疗保健目标之一。目前，最有效的机制之一是缺血预处理，其通过经由球囊膨胀间歇性闭塞冠状动脉来实现。然而，不幸的是，它的临床应用受到其有效性是短暂的事实的阻碍，因此，需要缺血发作时间的先验知识。此外，它是一种有创技术，具有动脉粥样硬化栓塞的风险。因此，识别能够模拟这一过程的因素将对缺血性心脏病有很大的益处。我们最近发现了有潜力实现这一目的的miR-199 a，这将在本提案中进行研究。