DYRK1a as a therapeutic target to treat myocardial infarction

DYRK1a作为治疗心肌梗死的治疗靶点

基本信息

批准号：
10274952
负责人：
Matthew J Wolf
金额：
$ 40.38万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10274952
关键词：
Ablation Address Adult Apoptosis Arrhythmia Blood capillaries Cardiac Myocytes Cardiovascular Diseases Cell Cycle Cells Cessation of life Clinical Complement Data Development Diphtheria Toxin Future Genetic Goals Harmine Heart Heart failure Hyperplasia Infarction Injury Investigation Ischemia Knock-out Knockout Mice Left Ventricular Function Left Ventricular Remodeling Morbidity - disease rate Mosaicism Mus Muscular Atrophy Myocardial Myocardial Infarction Myocardial Ischemia Myocardial Reperfusion Myocardium Neonatal Outcome Pathway interactions Pharmaceutical Preparations Pharmacology Phosphotransferases Regenerative capacity Reperfusion Therapy Reporter RiboTag Ribosomal Proteins Signal Pathway Signal Transduction Societies Specificity Technology Testing Transcript Transgenic Mice Tyrosine Phosphorylation Ventricular Function Work base candidate identification density design druggable target event cycle functional improvement heart function improved improved outcome inhibitor/antagonist ischemic cardiomyopathy kinase inhibitor mortality novel paracrine secretory protein therapeutic target

项目摘要

ABSTRACT Although outcomes after myocardial infarctions (MIs) have improved, cardiomyocytes (CMs) are lost even with successful reperfusion. This loss contributes to adverse remodeling, ischemic cardiomyopathy, heart failure, arrhythmia, and death. Current therapies can only slow or reverse isolated aspects of ischemic heart disease, and there are no reliable therapies available to replace the cardiac muscle loss to MI. Identifying therapeutic targets and drugs to protect the myocardium after injury will be groundbreaking, address unmet clinical needs, and represent new strategies to treat cardiovascular diseases. Our goals are to identify and validate druggable targets that induce controlled CM cycling and improve heart function after injury. However, two challenges exist: (1) the identification of candidate pathways to stimulate CM cycling with the intent to improve cardiac function after injury, and (2) the accurate quantification of CM cycling events in adult myocardium. Therefore, we conducted investigations to address the two challenges. First, we identified an inhibitor of dual-specificity tyrosine phosphorylation-regulated kinase 1a (DYRK1a), Harmine, increased CM cycling, and improved ventricular function after MI. Next, we generated CM-specific DYRK1a knockout mice and observed CM hyperplasia at baseline and improved LV function after MI, suggesting DYRK1a contributes to CM function. Second, we designed and validated a unique transgenic mouse (denoted αDKRC) that drives Cre in adult cycling CMs. αDKRC complements existing technologies such as Mosaic Analysis with Double Markers (MADM); however, the ability to restrict Cre expression to adult cycling CMs is an advance in the field. We used αDKRC::DTA mice to express Diphtheria toxin in adult cycling CMs and observed that the loss of endogenously cycling CMs worsened myocardial function after MI. Since cycling CMs are scarce, the findings suggest that cycling CMs may contribute to myocardial function beyond the concept of a CM as only a contractile cell, perhaps by expressing paracrine factors. This potential mechanism suggests that modest increases in cycling CMs may have a more significant impact on cardiac function after MI because cycling CMs serve functions beyond the concept of contractility. Based on preliminary data, we hypothesize that the inhibition of DYRK1a improves myocardial function after MI, in part, through enhanced CM cycling and the cycling CMs exert their effects via paracrine factors. We will test our hypothesis in the following Aims: (1) The CM-specific ablation of DYRK1a during development protects LV function after MI through enhanced cell cycling, (2) The post- developmental ablation of DYRK1a in adult CMs will improve LV function after MI, and (3) Cycling CMs contribute to LV function after MI by expressing paracrine factors. The proposed investigations will define the potential of DYRK1a inhibition as a treatment of MI, identify the mechanisms through which DYRK1a exerts its effects in CMs, and characterize novel paracrine factors expressed by cycling CMs that potentially serve as new future therapeutic targets.

抽象的尽管心肌梗死（MIS）后的结果有所改善，但心肌细胞（CMS）即使丢失了成功再灌注。这种损失导致不良重塑，缺血性心肌病，心力衰竭，心律不齐和死亡。当前的疗法只能缓慢或反向缺血性心脏病的孤立方面，而且没有可靠的疗法可将心肌损失替换为MI。识别疗法受伤后保护心肌的靶标和药物将是开创性的，满足未满足的临床需求，并代表治疗心血管疾病的新策略。我们的目标是识别和验证可吸毒的影响控制CM循环并改善受伤后心脏功能的目标。但是，存在两个挑战：（1）鉴定候选途径以刺激CM循环的意图，以改善心脏功能受伤后，以及（2）成人心肌中CM循环事件的准确定量。因此，我们进行了调查以应对这两个挑战。首先，我们确定了双特异性酪氨酸的抑制剂磷酸化调节的激酶1A（DYRK1A），Harmine，CM循环增加并改善心室 Mi后的功能。接下来，我们生成了CM特异性的DyRK1A敲除小鼠，并观察到CM增生 MI后基线和提高的LV功能，表明DYRK1A有助于CM功能。第二，我们设计并验证了独特的转基因小鼠（表示为αDKRC），该小鼠在成人循环中驱动CRE CMS。 αDKRC完成现有技术，例如带有双重标记的马赛克分析（MADM）；但是，将CRE表达限制为成人循环CM的能力是该领域的进步。我们使用αDKRC:: DTA小鼠在成人循环CMS中表达白喉毒素，并观察到丢失内源性循环CM在MI后加剧了心肌功能。由于骑自行车的CMS很少，因此发现建议骑自行车的CMS可能会导致心肌功能，而不是CM的概念细胞，也许是通过表达旁分泌因子。这种潜在的机制表明，适度的增加循环CMS可能会对MI后心脏功能产生更大的影响，因为骑自行车CMS服务功能超出了收缩概念。根据初步数据，我们假设抑制 DYRK1A通过增强的CM循环和循环CMS执行MI后改善心肌功能它们通过旁分泌因素的影响。我们将在以下目的中检验我们的假设：（1）CM特异性消融发育过程中的dyRK1a通过增强的细胞循环保护MI后的LV功能，（2）成人CMS中DYRK1A的发育消融将改善MI后LV功能，（3）循环CMS贡献通过表达旁分泌因子在MI后至LV功能。拟议的调查将确定 dyRK1a抑制作用作为MI的治疗，确定DYRK1A在 CMS，以及通过循环CM表达的新型旁分泌因子的特征，这些因子有可能充当新的未来治疗靶标。