An Aging Heart Model for Drug Discovery

用于药物发现的衰老心脏模型

• 批准号: 9331414
• 负责人: Tetsuro Wakatsuki
• 金额: $ 17.64万
• 依托单位: INVIVOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9331414
• 关键词: Academia; Action Potentials; Address; Adverse event; Age; Age-Years; Aging; American; Angiotensins; Animal Model; Biological; Biological Models; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular Agents; Cardiovascular Diseases; Censuses; Centers for Disease Control and Prevention (U.S.); Computer Simulation; Congestive Heart Failure; Contracts; Coupled; Coupling; Data; Developed Countries; Developing Countries; Development; Disease; Drug Industry; Drug Modelings; Drug Prescriptions; Drug user; EFRAC; Elderly; Electrophysiology (science); Engineering; Epidemic; Fibroblasts; Foundations; Gap Junctions; Heart; Heart failure; Human; Human Engineering; Hypertrophy; Incidence; Industry; Ion Channel; Lead; Longevity; Malignant Neoplasms; Measures; Modeling; Modification; Morphology; Muscle Cells; Myocardial; Myocardium; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phenotype; Physiological; Physiology; Population; Prevalence; Property; Reaction; Reproducibility; Research; Research Contracts; Research Personnel; Research Project Grants; Resistance; Risk; Safety; Scientist; Services; Stress; Tissues; Toxic effect; Toxicology; Tweens; United States; age related; aged; aging population; commercialization; density; design; drug candidate; drug discovery; drug testing; effective therapy; experience; high risk; improved; induced pluripotent stem cell; kohl; nervous system disorder; novel therapeutics; research and development; response; screening; tool

Project Summary/Abstract Cardiovascular drugs are primarily prescribed to older people (>65 years of age) since the prevalence of chronic heart failure and fibrillation increases with age. The incidence of other diseases, including cancer and neurological disorders, increases with age, too. Any medications hold potential risks to cause adverse events. Therefore, the risks of medications in older people also increase with age. While cardiac safety of drugs is one of the primary concerns among drug developers and regulatory agencies, potential new drugs are tested using animal models of normal age. Limited progress has been made in developing a tool to predict potential cardiac safety issues in aging heart, representing a significant unmet need in drug discovery industry. The United States will have 73 million aging population, (>65 years of age) in 2030. The development of a computational model that can predict potential cardiac safety reactions is a plausible step towards preparing the drug discovery industry for a rapidly approaching era of longevity. This Phase I proposal will validate and improve a computational model that incorporate potential age-related changes in regulators of excitation contraction coupling (ECC) of cardiomyocytes (CMs) and contribution of fibroblasts (FBs) that are known to increase their population in aging hearts. The specific Aims are 1) to develop and refine a computational model representing coupled FBs and CMs to simulate electrophysiology and calcium handling of aging human heart tissue, 2) to establish human engineered heart tissues by incorporating aging cardiac FBs and applying environmental stress that known to induce cardiac aging. These Aims are proposed to optimize a computational model, Wisdom Heart (WH) that mimics age-associated changes in cardiac ECC of myocardium with increasing number of FBs. The quality of WH model will be evaluated and improved against experimental data obtained from myocardium models. The established model will be shared with the consortium organized by HESI (hesiglobal.org) with FDA, industry, and academia that is trying to improve cardiac safety issues. The model will be incorporated to our services for conducting contract research projects of cardiac safety assessments and drug discovery for heart failure. We have active contracts with FDA research scientists at the National Center for Toxicological Research.

项目概要/摘要 心血管药物主要是为老年人（> 65 岁）开出的处方。 慢性心力衰竭和颤动的患病率随着年龄的增长而增加。其他发生率 疾病，包括癌症和神经系统疾病，也会随着年龄的增长而增加。任何药物 持有引起不良事件的潜在风险。因此，老年人用药的风险 也随着年龄的增长而增加。虽然药物的心脏安全性是人们最关心的问题之一 药物开发商和监管机构，使用动物模型测试潜在的新药 正常年龄。在开发预测潜在心脏病的工具方面取得了有限的进展 衰老心脏的安全问题代表了药物发现行业中未满足的重大需求。 到 2030 年，美国将有 7300 万老年人口（>65 岁）。 开发可以预测潜在心脏安全反应的计算模型是一个 为药物发现行业为快速到来的时代做好准备迈出的合理一步 长寿。该第一阶段提案将验证和改进计算模型 将与年龄相关的潜在变化纳入激发收缩耦合 (ECC) 调节器中 心肌细胞（CM）和成纤维细胞（FB）的贡献已知可增加其 人口老龄化。具体目标是 1) 开发和完善计算 代表耦合 FB 和 CM 的模型，用于模拟电生理学和钙处理 老化的人类心脏组织，2）通过整合建立人类工程心脏组织 老化的心脏 FB 和施加已知会诱发心脏老化的环境压力。 这些目标旨在优化模拟的计算模型 Wisdom Heart (WH) 随着 FB 数量的增加，心肌的心脏 ECC 发生与年龄相关的变化。这 WH模型的质量将根据获得的实验数据进行评估和改进 心肌模型。所建立的模型将与以下组织的联盟共享 HESI (hesiglobal.org) 与 FDA、工业界和学术界合作，致力于提高心脏安全 问题。该模型将纳入我们开展合同研究项目的服务中 心脏安全评估和心力衰竭药物发现。我们有有效的合同 与国家毒理学研究中心的 FDA 研究科学家合作。