Aging Heart Modeling with Progeria iPSCs

Project Summary Abstract The United States has the largestmillion inaging populationandgtyears of ageamong developed countries and will reachmillion byHeart failureHFis becoming an epidemic among increasing population of aging AmericansMedical costs of HF are projected to be $billionHF patients are classified by its ejection fractionEFreducedpreservedintermediateWhile various treatment options including devices are available for HF with reduced EFHFrEFno efficacious therapies have been identified for HF with preserved EFHFpEFLack of good models including animal model to understand the mechanism have been impairing the discovery of effective treatmentsHutchinson Gilford progeria syndromeHGPSprogeriais an ultra rear disease that prematurely exhibits multiple features of agingA single base substitutionGG GGC andgtGGTin LMNA was discovered to produce an abnormal lamin A proteinprogerinand cause HGPSThe most recent study ofHGPS patientsyearsshowed their development of asymptomatic left ventricular diastolic dysfunctionthe precursor to HFpEFThereforewe hypothesize that the HGPS model develops HFpEF phenotype in vitro quicker than controlwhich provides an unprecedented opportunity to understand the mechanisms of HFpEF pathogenesis and a tool to discover new treatmentsWe will developD micro heartscalledNuHeartgrowing inandwell plates using gene edited iPSCs of HGPS based on healthy donor iPSCsfree from any known HF mutationsThe proposed analyses will evaluate the modelandapos s applicability in mimicking naturally aging heart developing HFpEF and their use for drug discovery Aging Americans are expected to reachmillion inand heart failure is one of the leading cause of their deathWe will develop a model to study mechanism of heart failure and screen drug candidates using human adult stem cell isolated from inherited premature syndrome patients develop symptoms of heart failureBecause there is no effective approved therapy available for this type of heart failurea successful developing of the model will expedite the developing of therapies for rapidly aging American suffering from heart failure