Microsensors to Study Electrical and Mechanical Coupling of Injured Myocardium

描述（由申请方提供）：尽管有目前的治疗方案，但心力衰竭仍然是美国和发达国家发病率和死亡率的主要原因，原因是未能充分替代缺血诱导的梗死所致的心室心肌丢失。成年哺乳动物心室心肌细胞具有有限的分裂能力，并且这种增殖不足以克服心室损伤引起的心肌显著损失。然而，斑马鱼（Danio rerio）具有在受损心脏中再生大量心肌的显著能力，因此，代表了再生医学和心血管研究的新兴脊椎动物模型。虽然斑马鱼系统的小尺寸允许高通量研究，但小的心脏尺寸（长度为1-2 mm）使得进行功能生理分析具有挑战性。为此，我们的合作努力使微心电图（ECG）和高频超声换能器（>45 MHz）的应用，以进一步研究损伤的斑马鱼心脏再生心肌的电气和机械属性。我们已经观察到，心室复极（ST间期和T波）未能正常化，尽管完全再生心肌在心室截肢后60天，这表明进一步的心脏重塑可能需要完全整合再生心肌与宿主心肌。我们假设早期再生的心肌细胞可能缺乏电和机械心脏表型，因此可能需要额外的心脏细胞重塑，以充分的电和机械整合到受伤的心脏。为了评估心脏再生过程中心脏功能的恢复，我们提出将可植入柔性微电极阵列与高频超声换能器和光学电压标测连接以测试传导和机械表型，然后通过条件性阻断或激活Wnt/2-连环蛋白和FGF信号传导途径进行机制评估。植入式柔性微电极阵列、高频超声换能器的开发和应用在干细胞和再生医学领域具有广阔的应用前景。总之，我们的共同努力将可能提供新的技术和新的机制的见解心脏传导和机械表型响应遗传，表观遗传和药物干扰与再生医学。 公共卫生相关性：在干细胞和再生医学的时代，有相当大的兴趣来评估受损和早期再生心肌细胞的表型。微机电系统（MEMS）传感器的出现使我们能够在小动物系统中以高空间和时间分辨率测量损伤和再生心脏的传导和机械表型。因此，我们的目标是测试这一假设，再生心肌可能需要额外的心脏细胞重塑，以充分的电气和机械整合到受伤的心脏。

DESCRIPTION (provided by applicant): Despite current treatment regimens, heart failure remains the leading cause of morbidity and mortality in the US and developed world due to failure to adequately replace lost ventricular myocardium from ischemia- induced infarct. Adult mammalian ventricular cardiomyocytes have a limited capacity to divide, and this proliferation is insufficient to overcome the significant loss of myocardium from ventricular injury. However, zebrafish (Danio rerio) possess the remarkable capacity to regenerate a significant amount of myocardium in injured hearts, and thus, represent an emerging vertebrate model for regenerative medicine and cardiovascular research. While the small size of zebrafish system allows for high-throughput research, the small heart size (1-2 mm in length) renders it challenging to perform functional physiological analyses. Toward this end, our collaborated efforts have enabled the applications of the micro-electrical cardiogram (ECG) and high-frequency ultrasonic transducers (>45 MHz) to further investigate the electrical and mechanical attributes of regenerating myocardium in injured zebrafish hearts. We have observed that ventricular repolarization (ST intervals and T waves) failed to normalize despite fully regenerated myocardium at 60 days post ventricular amputation, suggesting further cardiac remodeling may be required to fully integrate regenerating myocardium with host myocardium. We hypothesize that early regenerating cardiomyocytes may lack the electrical and mechanical cardiac phenotypes, and thus may require additional cardiac cellular remodeling for full electrical and mechanical integration into injured hearts. To assess the restoration of cardiac function during cardiac regeneration, we propose to interface implantable flexible micro-electrode arrays with high- frequency ultrasonic transducers and optical voltage mapping to test the conduction and mechanical phenotypes, followed by mechanistic assessment by conditionally blocking or activating Wnt/2-catenin and FGF signaling pathways. The development and application of implantable and flexible micro-electrode arrays, high frequency ultrasonic transducers hold a great promise in the era of stem cell and regenerative medicine. In sum, our concerted efforts will likely provide both novel technology and new mechanistic insights into cardiac conduction and mechanical phenotypes in response to genetic, epigenetic, and pharmaceutical perturbations with relevance to regenerative medicine. PUBLIC HEALTH RELEVANCE: In the era of stem cell and regenerative medicine, there is a considerable interest to assess the phenotypes of injured and early regenerated cardiomyocytes. The advent of Micro-electro-mechanical systems (MEMS) sensors has enabled us to measure conduction and mechanical phenotypes of injured and regenerating hearts with both high spatial and temporal resolution in the small animal system. Thus, our goal is to test the hypothesis that regenerating myocardium may require additional cardiac cellular remodeling for full electrical and mechanical integration into injured hearts.