EAGER: Tissue Organization Contribution to Cardiac Force Output

概述：心脏的正常功能取决于以多种长度尺度组织的肌肉纤维。对纤维组织重塑导致心功能改变的所有机制缺乏了解。这对我们创造预测体外工具来测量心功能的能力产生了不利影响。“芯片上的心脏”是测量体外组织应力的最新平台之一，已被用于表征各向同性和各向异性心脏组织的收缩性和结构。我们发现，目前的模型无法解释细胞组织的丧失导致的功能的急剧丧失。然而，“芯片上的心脏”技术为探索组织功能与结构之间的关系提供了实验平台。该项目旨在创建一个计算工具，以量化肌肉组织组织对最大发展力的直接贡献。该工具将基于一个更精确的模型，该模型解释了肌节的偶极子性质，肌节是心肌中的力产生单位（目的1）。“芯片上的心脏”平台将用于表征将被设计为具有局部各向异性组织和全局各向同性组织的组织（目标2）。这些新设计的组织将使我们能够通过实验将组织对力输出变化的直接和间接贡献解耦。结合建模和实验组件，将开发一个全面的工具，用于量化组织对心脏组织力量发展的直接贡献（目标3）。在此资助范围之外，该工具将用于量化干细胞衍生和原代心脏组织的力量生产能力之间的差异。它也将成为将我们的模型扩展到三维的基础平台，以便将临床数据与固有的二维体外实验进行比较。智力优势：智力上，这个项目的结果将提供一个洞察肌肉组织的结构和功能之间的关系。这里提出的定量工具将在未来用于定量表征不同基因表达谱对收缩性的下游影响。例如，将比较具有不同结构的干细胞衍生和天然心脏组织。在这项资助中开发的新型工程组织也将在未来研究全局与局部组织对心脏组织功能的影响方面发挥作用，这可以为临床心力衰竭提供见解。更广泛的影响：该项目将通过提供一种工具来了解肌原纤维组织对心功能的影响，从而影响制药业和医学。为了确保广泛的科学影响，计划在科学期刊上发表这些发现，并向公众提供通过这项工作开发的计算工具。该项目的研究结果将被纳入研究生选修课程（由PI教授），一个本科生团队（2-3名学生/年）将参与研究。PI还为来自代表性不足的高中的学生设计了一个外联模块。总而言之，该项目具有教育和推广成分，并有可能通过促进对心脏功能和疾病的了解来影响整个社会。

PI: GrosbergProposal ID: 1338609Overview: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 biomechanicsIntellectual 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.