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

基本信息

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
项目类别：
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

项目摘要

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）应准确地重建关键的器官水平结构并 CTCM 的成功取决于模仿人体生理和功能的能力。心脏是一个独特的器官，会经历连续的交替循环。由于血流动力学加载和卸载而产生的压力和拉伸这些血流动力学应激源至关重要。生理范围内的压力变化对心脏功能和代谢的重要性。导致生理重塑，而显着变化（例如高血压、缺血、瓣膜疾病）导致不良病理重塑，导致心血管功能障碍。培养 300μM 厚的人类心脏切片，通过提供充分保持其功能超过 12 天的时间该技术提供精确的心脏周期血流动力学压力、压力和电刺激。访问与人类心脏组织高度相似并模拟的完整 3D 多细胞系统在我们的 CTCM 中，我们可以在功能和结构上控制生理或病理条件。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疾病状况。我们利用建立生理相关的人类心脏组织培养模型的需要对人类心脏组织进行连续功能监测，该组织经历了所有体内类似结构的复制以及健康和疾病期间的功能适应。功能，该系统将能够准确评估药物对健康和患病心脏的毒性和疗效我们将验证为了检验这一假设，我们提出以下目标：具体目标 1：(a) 纳入收缩力、应变和收缩力的实时监测培养 12 天的电生理特性，以及 (b) 实时验证 CTCM 监测以准确预测药物心脏毒性（12 种心脏毒素）。具体目标 2：建立心脏模型使用 CTCM 进行病理学检查并进行药物疗效测试。该项目的成功完成将验证我们的 CTCM 系统并满足制药行业和监管机构提供中等通量的组织培养技术，忠实地复制人体细胞和病理生理学，对药物的心脏毒性反应高度敏感这样的系统将有助于更好地了解心力衰竭的机制。疗法，最大限度地减少患者与药物相关的不良反应，并实现更快、更具成本效益的药物开发和筛选并增强监管机构（例如 FDA）对候选药物的信心。