An Aging Heart Model for Drug Discovery

项目概要/摘要 心血管药物主要用于老年人（>65岁）， 慢性心力衰竭和纤维性颤动的患病率随着年龄的增长而增加。其他的发生率 包括癌症和神经系统疾病在内的疾病也随着年龄的增长而增加。任何药物 存在导致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其中一个主要问题， 药物开发商和监管机构，潜在的新药使用动物模型进行测试 正常年龄。在开发一种预测潜在心脏病的工具方面取得了有限的进展， 老化心脏的安全性问题，代表药物发现行业中显著未满足的需求。 到2030年，美国将有7300万老龄人口（>65岁）。的 开发一个可以预测潜在心脏安全反应的计算模型是一个 这是一个看似合理的步骤，为药物发现行业迅速接近的时代做好准备。 中心blog第一阶段的提案将验证和改进一个计算模型， 在兴奋收缩偶联（ECC）调节器中纳入潜在的年龄相关变化 心肌细胞（CM）和成纤维细胞（FB）的贡献，已知这些细胞可以增加其 人口老龄化的心脏。具体目标是：1）开发和完善一个计算 代表耦合FB和CM的模型，用于模拟电生理学和钙处理 2）通过掺入抗衰老的人心脏组织， 老化心脏FB和施加已知诱导心脏老化的环境应力。 这些目标被提出来优化一个计算模型，智慧心（WH）， 随着FB数量的增加，心肌ECC的年龄相关变化。的 WH模型的质量将根据实验数据进行评估和改进， 心肌模型所建立的模型将与 HESI（hesiglobal.org）与FDA、行业和学术界合作，试图提高心脏安全性 问题.我们会把这个模式纳入我们的服务中，以进行合约研究计划 心脏安全性评估和心力衰竭药物研发的重要性。我们有有效的合同 与美国国家毒理学研究中心的FDA研究科学家合作。

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.