EAGER: Tissue Organization Contribution to Cardiac Force Output

University Of California-Irvine, Irvine CA

Investigators

Abstract

PI: Grosberg Proposal ID: 1338609 Overview: The heart's proper function depends on muscle fibers organized on multiple length scales. There is a lack of understanding of all the mechanisms by which fiber organization remodeling leads to changes in cardiac function. This adversely impacts our ability to create predictive in vitro tools to measure cardiac function. One of the latest platforms for measuring tissue stress in vitro, "heart on a chip", has been used to characterize contractility and structure of isotropic and anisotropic cardiac tissues. We found that the current models are not able to explain the drastic loss of functionality with the loss of cellular organization. However, the "heart on a chip" technology provides the platform for experiments to explore the relationship between tissue function and structure. This project seeks to create a computational tool that will quantify the direct contribution of muscle tissue organization to the maximal developed force. The tool will be based on a more accurate model that accounts for the dipole nature of the sarcomeres, which are the force producing units in the cardiac muscle (Aim 1). The "heart on a chip" platform will be used to characterize tissues that will be designed to have a local anisotropic organization and a global isotropic organization (Aim 2). These newly engineered tissues will allow us to experimentally decouple the direct and indirect contributions of organization to changes in force output. Combining the modeling and experimental components, a comprehensive tool will be developed for quantifying the direct contribution of organization to force development in cardiac tissues (Aim 3). Beyond the scope of this grant, this tool will be used to quantify the differences between stem-cell derived and primary cardiac tissue's force production capabilities. It will also be the basic platform for expending our model into three-dimensions to compare clinical data with inherently two-dimensional in vitro experiments. BME Theme: Cellular biomechanics Intellectual Merit: Intellectually, the results of this project will provide an insight into the relationship between structure and function of muscle tissues. The quantitative tool proposed here will be useful in the future for quantitatively characterizing the down-stream effects of different gene-expression profiles on contractility. For example, stem-cell derived and native cardiac tissues that have different structures will be compared. The novel engineered tissues developed in this grant will also be useful in the future in studying global vs. local organization effects on cardiac tissue function, which can provide insight into clinical heart failure. Broader Impacts: This project will impact both the pharmaceutical industry and medicine by providing a tool to understand the effect of myofibril organization on cardiac function. To ensure broad scientific impact, it is planned to publish the findings in scientific journals and to provide public access to the computational tool developed through this work. The findings from this project will be incorporated into a graduate elective course (taught by the PI), and a team of undergraduate (2-3 students/year) will be involved in the research. The PI has also designed an outreach module for students from high-schools with under-represented populations. In summary this project has educational and outreach components and the potential to impact society as a whole by contributing to the understanding of heart function and disease.