An Aging Heart Model for Drug Discovery

Project Summary Abstract Cardiovascular drugs are primarily prescribed to older peoplertyears of agesince the prevalence of chronic heart failure and fibrillation increases with ageThe incidence of other diseasesincluding cancer and neurological disordersincreases with agetooAny medications hold potential risks to cause adverse eventsThereforethe risks of medications in older people also increase with ageWhile cardiac safety of drugs is one of the primary concerns among drug developers and regulatory agenciespotential new drugs are tested using animal models of normal ageLimited progress has been made in developing a tool to predict potential cardiac safety issues in aging heartrepresenting a significant unmet need in drug discovery industryThe United States will havemillion aging populationrtyears of ageinThe 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 longevityThis Phase I proposal will validate and improve a computational model that incorporate potential age related changes in regulators of excitation contraction couplingECCof cardiomyocytesCMsand contribution of fibroblastsFBsthat are known to increase their population in aging heartsThe specific Aims areto develop and refine a computational model representing coupled FBs and CMs to simulate electrophysiology and calcium handling of aging human heart tissueto establish human engineered heart tissues by incorporating aging cardiac FBs and applying environmental stress that known to induce cardiac agingThese Aims are proposed to optimize a computational modelWisdom HeartWHthat mimics age associated changes in cardiac ECC of myocardium with increasing number of FBsThe quality of WH model will be evaluated and improved against experimental data obtained from myocardium modelsThe established model will be shared with the consortium organized by HESIhesiglobal orgwith FDAindustryand academia that is trying to improve cardiac safety issuesThe model will be incorporated to our services for conducting contract research projects of cardiac safety assessments and drug discovery for heart failureWe have active contracts with FDA research scientists at the National Center for Toxicological Research