Physiologically relevant cardiac tissue culture model for drug testing and disease modeling

培养中的人体组织建模是药物发现和筛选以及疾病建模的主要挑战。 理想的心脏组织培养模型（CTCM）应该准确地重建关键器官水平的结构， 功能CTCM的成功取决于模仿人体生理和生理过程中发生的事情的能力。 病理生理条件。心脏是一个独特的器官，它受到连续循环的交替 由于血流动力学加载和卸载引起的压力和拉伸。这些血流动力学应激源是至关重要的 对心脏功能和代谢在健康和疾病中的重要性。生理范围内的应力变化 导致生理重塑，而显著变化（例如，高血压、局部缺血、瓣膜疾病） 导致不利的病理性重构，导致心血管功能障碍。我们最近开发了一个系统 培养300µM厚的人类心脏切片，通过提供 精确的心动周期血流动力学压力、应力和电刺激。该技术提供 获得与人类心脏组织高度相似的完整3D多细胞系统， 生理或病理条件，功能上和结构上。在我们的CTCM中，我们可以控制 电刺激（电流幅度和频率）以及关键机械参数，包括 前负荷、后负荷、压力、压力变化率和心率（HR），以准确模拟正常和 病理性疾病 我们假设建立生理相关的人心脏组织培养模型需要 对经历所有体内样结构复制的人心脏组织的连续功能监测 以及健康和疾病期间的功能适应。通过持续监测心脏的任何变化， 功能，该系统将能够准确地评估药物的毒性和疗效，在健康和患病的心脏 组织.为了验证这一假设，我们提出了以下目标： 具体目标1：（a）纳入对收缩力、应变和 （B）在培养物中培养12天以验证CTCM的电生理特性，以及 监测以准确预测药物心脏毒性（12种心脏毒素。具体目标2：心脏建模 使用CTCM进行病理学检查和测试以测试药物功效。 该项目的成功完成将验证我们的CTCM系统，并满足 制药工业和监管机构的中等通量，组织培养技术，忠实地 复制人类细胞和病理生理学，对药物的心脏毒性反应高度敏感 用于药物发现和筛选。这样一个系统将能够更好地理解心力衰竭的机制 治疗，最大限度地减少患者中药物相关的不良反应，并使更快，更具成本效益的药物 开发和筛选，并增强监管机构对候选药物的信心（例如，FDA）。

Human tissue modelling in culture is a major challenge for drug discovery and screening, and disease modeling. The ideal cardiac tissue culture model (CTCM) should accurately recreate the critical organ-level structure and function. The success of CTCM depends on ability to mimic what occurs in the human body in physiological and pathophysiological conditions. The heart is a unique organ that is subject to continuous cycles of alternating pressure and stretch due to hemodynamic loading and unloading. These hemodynamic stressors are of critical importance to cardiac function and metabolism in health and disease. Changes in stress within physiologic range result in physiological remodeling, whereas significant changes (e.g., hypertension, ischemia, valve disease) result in adverse pathological remodeling leading to cardiovascular dysfunction. We recently developed a system to culture 300µM thick human heart slices that fully maintains their functionality for over 12 days through providing the precise-cardiac-cycle hemodynamic pressures, stresses and electrical stimulation. This technology provides access to complete 3D multicellular system that is highly similar to human heart tissue and emulates physiological or pathological conditions, both functionally and structurally. Within our CTCM, we can control electrical stimulation (current amplitude and frequency) as well as the critical mechanical parameters including preload, afterload, pressures, rate of pressure change, and heart rate (HR) to accurately model normal and pathological diseased conditions. We hypothesize that establishment of physiologically relevant Human cardiac Tissue Culture Model needs continuous functional monitoring of the human heart tissue that undergo a replication of all in vivo–like structural and functional adaptation during health and disease. Through continuous monitoring of any changes on cardiac function, this system will be able to accurately assess drug toxicity and efficacy in healthy and diseased cardiac tissue. We will validate To test this hypothesis, we propose the following aims: Specific Aim 1: (a) Incorporation of real-time monitoring of contractile force, strain, and electrophysiological properties in culture for 12 days, and (b) validate the CTCM with real-time monitoring to accurately predict drug cardiotoxicity (12 cardiotoxins. Specific Aim 2: Modeling cardiac pathology using CTCM and testing for testing drug efficacy. Successful completion of this project will validate our CTCM system and fulfill a significant need by the pharmaceutical industry and regulatory bodies for a medium throughput, tissue culture technology that faithfully replicates the human cellular and pathophysiology and is highly sensitive for cardiotoxicity responses to drugs for drug discovery and screening. Such a system will enable better mechanistic understanding of heart failure therapies, minimize drug related adverse effects in patients and enable faster, and more cost-effective drug development and screening and enhance the confidence in a candidate drug by regulatory bodies (eg. FDA).