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。