Treatments for cardiovascular diseases are significant unmet needs in the global medical community. We propose to develop in vitro models of diseased cardiac tissues by using precisely controlled artificial matrix preparations. The principal objective of this project is to establish an in vitro model of human cardiac tissue based on the reconstitution of synthetic models of the human ventricular myocardium with populations of patient specific human induced pluripotent stem (hiPS) cell-derived cardiomyocytes (hiPS-CMs). For this application we have chosen to focus on a single "patient-specific" disease, long QT syndrome (LQTS), as a basis for proof-of-principle of our methodology and workflow. Prolongation of the QT interval, the electrical manifestation of cardiac ventricular repolarization, is a major cause of cardiac arrhythmias and sudden death. Thus a LQTS "patient-specific" physiologically functioning 3D model of heart tissue would be a significant advancement for understanding, studying, and developing new strategies for treating cardiac arrhythmias and other cardiovascular diseases. We propose the following specifics aims to generate a human cardiac 3D tissue model.
Aim 1. To optimize a directed differentiation method to obtain a consistent high yield (>75%) population of human CMs derived from either healthy hiPS or hiPS cells harboring gene mutations of LQTS, a potentially lethal mutation.
Aim 2. To fabricate precisely defined 3D filamentous matrices that organize the structure of healthy hiPS-CMs into a 3D in vitro model of the human cardiac tissue. To assess the functional behavior of the model by examining its electrical and mechanical activity.
Aim 3. To organize the structure of LQTS-hiPS-CMs into a 3D in vitro model of the human myocardium. To assess the functional behavior of the "diseased tissue" model by examining its electrical and mechanical activity, and response to pharmacological agents.
This application will focus on developing a patient-specific physiologically functioning three-dimensional model of cardiac tissue. This tissue model represents a significant advancement for understanding, studying, and developing new strategies for treating cardiovascular disease. This project will focus on induced pluripotent stem (iPS) cells, also known as stem cells from skin cells, to form the cardiac tissues that can be widely used by the research community.
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