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

用于药物测试和疾病建模的生理相关心脏组织培养模型

• 批准号: 10654152
• 负责人: Guruprasad A Giridharan
• 金额: $ 46.42万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-03 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654152
• 关键词: 3-Dimensional; Address; Adult; Adverse drug effect; Biological Models; Cardiac; Cardiac Myocytes; Cardiotoxicity; Cardiovascular Diseases; Cardiovascular system; Categories; Cells; Characteristics; Clinical; Consumption; Culture Media; Data; Direct Lytic Factors; Disease; Disease model; Drug Industry; Drug Modelings; Drug Screening; Drug toxicity; Effectiveness; Electric Stimulation; Electrocardiogram; Electrophysiology (science); FDA approved; Frequencies; Functional disorder; Health; Heart; Heart Diseases; Heart Rate; Heart failure; Hip region structure; Human; Human body; Hypertension; Hypertrophy; Ischemia; Measures; Mechanics; Metabolism; Modeling; Monitor; Myocardium; Nutrient; Organ; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Property; Research; Safety; Slice; Stimulus; Stress; Stretching; Structure; System; Technology; Testing; Therapeutic; Thick; Time; Tissue Model; Tissues; Toxic effect; Treatment Efficacy; Treatment Failure; aorta constriction; cell type; cost; cost effective; drug candidate; drug development; drug discovery; drug efficacy; drug testing; efficacy testing; fetal; first-in-human; functional adaptation; heart function; heart metabolism; hemodynamics; human tissue; imaging system; improved; in vivo; pre-clinical; pressure; real time monitoring; response; sensor; stressor; success; therapeutic evaluation; tissue culture; voltage

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).

培养中的人体组织建模是药物发现和筛查以及疾病建模的主要挑战。 理想的心脏组织培养模型（CTCM）应准确地重新创建关键器官级结构和 功能。 CTCM的成功取决于模仿人体在生理和 病理生理状况。心脏是一个独特的器官，受到改变的连续周期 压力和由于血流动力学负荷和卸载而引起的。这些血液动力学压力源至关重要 对健康和疾病中心脏功能和代谢的重要性。生理范围内压力的变化 导致物理重塑，而重大变化（例如，高血压，缺血，瓣膜疾病） 导致病理重塑导致心血管功能障碍。我们最近开发了一个系统 培养300µm厚的人心切片，通过提供12天以上的功能，可以完全维持其功能 精确的心脏周期血流动力学压力，应力和电刺激。该技术提供 访问与人类心脏组织高度相似并模拟的完整3D多细胞系统 物理或病理状况，无论是在功能和结构上。在我们的CTCM中，我们可以控制 电刺激（电流放大器和频率）以及关键的机械参数 预加载，后负载，压力，压力变化速率和心率（HR）准确对正常建模，并且 病理疾病。 我们假设建立与物理相关的人类心脏组织培养模型需求 对所有体内结构的复制的人类心脏组织的连续功能监测 和健康和疾病期间的功能适应。通过连续监测心脏的任何变化 功能，该系统将能够准确评估健康和患病的药物的毒性和易害性 组织。我们将验证检验这一假设，我们提出以下目的： 特定目的1：（a）收缩力，应变和 培养中的电生理特性12天，（b）实时验证CTCM 监测以准确预测药物心脏毒性（12个心脏毒性。特定目标2：对心脏建模 使用CTCM和测试药物效率的病理。 该项目的成功完成将验证我们的CTCM系统，并满足 中等吞吐物组织培养技术的制药行业和监管机构 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 用于药物发现和筛查。这样的系统将使心力衰竭更好地理解 疗法，最小化患者药物相关的不良反应，并更快地启用药物，更具成本效益的药物 通过监管机构（例如FDA）开发和筛查并增强对候选药物的信心。