Collaborative Research: Multiscale Cardiomyocyte Mechano-Adaptation

在每一次心跳期间，细胞随着心脏的收缩和充盈而伸展和移动。在疾病中或手术后，心脏变形的方式可能会改变，这会导致细胞适应。理想情况下，这种适应将导致更有效的心脏功能，但在某些情况下，适应会加剧功能障碍，导致心力衰竭。这个项目的中心目标是从数学上刻画心肌细胞(心脏中的主要功能细胞)如何适应机械环境的变化。这项研究将在实验上测量短期和长期拉伸下的心肌细胞的细胞结构和收缩功能。这将使用健康的心脏和因疾病或手术而变形的心脏的条件来完成。同时，我们将开发计算模型，以深入了解扰动变形如何影响心肌细胞内的关键收缩蛋白。最后，实验和计算结果将被结合起来，以创建可用于预测由于变形的任何变化而导致的细胞适应的模型。这些研究代表着朝着计算方法迈出的第一步，这种方法可以用于指导手术或设计干预措施，以优化心脏病患者的心脏适应。在这些研究的同时，加州大学欧文分校开发的心脏启动推广计划将扩展到明尼苏达大学双子城附近的高中生。此外，该课程还将扩展模块，向学生介绍心脏机械适应。对心脏细胞如何对复杂的机械负荷作出反应缺乏基本的了解。阐明心脏组织的功能适应反应将为指导外科手术、3D组织工程心脏或补片以及构建用于干预测试的体外心脏病模型提供机会。目前，大多数方法都是基于定性设计的方法。对于更定量的方法，有必要建立对心肌细胞机械适应性反应的基本理解，这些理解可以包装在一个模型中，用于预测性设计-建立适用于各种挑战的框架。因此，我们的目标是：1)阐明心肌细胞在复杂负荷下的急性机械适应性反应。我们假设，由复杂负荷引起的细胞变形改变了肌节中肌动蛋白-肌球蛋白马达的动力学，从而导致收缩效率的变化。2)阐明心肌细胞在复合负荷下的长期机械适应性反应。我们假设，收缩效率的丧失会导致心肌细胞重塑，从而使系统的自由能最小化。通过实验测量和多尺度模型的结合，该项目将阐明心肌细胞对复杂负荷的急性功能和长期重塑反应。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

During every heartbeat, the cells stretch and move as the heart contracts and fills. In disease or following surgery, the way the heart deforms can change, which causes the cells to adapt. Ideally, this adaptation will lead to more efficient heart function, but in some cases, adaptation exacerbates dysfunction, leading to heart failure. The central goal of this project is to mathematically characterize how cardiomyocytes (the primary functional cells in the heart) adapt to changes in their mechanical environment. This research will experimentally measure the cell structure and contractile function of cardiomyocytes exposed to short- and long-term stretching. This will be done using the conditions of both a healthy heart and one whose deformation is perturbed by disease or surgery. Concurrently, we will develop computational models that will provide insight into how perturbed deformations affect the key contractile proteins within the cardiomyocyte. Finally, the experimental and computational results will be combined to create models that can be used to predict cellular adaptation due to any change in deformation. These studies represent a first step toward a computational approach that could be used to guide surgeries or design interventions that optimize cardiac adaptation in heart disease patients. In parallel with these studies, the CardioStart outreach program developed at the University of California-Irvine, will be extended to reach high school students in the vicinity of the University of Minnesota-Twin Cities. Additionally, the program will be expanded with modules that introduce students to cardiac mechano-adaptation.There is a lack of fundamental understanding of how cardiac cells respond to complex mechanical loads. Elucidating the functional adaptation response of cardiac tissues would provide an opportunity to guide surgeries, 3D tissue engineered hearts or patches, and construction of in vitro heart disease models for testing of interventions. Currently, most of the methods are based on qualitative design approaches. For a more quantitative approach, it is necessary to build the fundamental understanding of the mechano-adaptive response of cardiomyocytes, which could be packaged in a model for a predictive design-build framework applicable to a wide variety of challenges. Therefore, our goals are to: 1) Elucidate the acute mechano-adaptive response of cardiomyocytes exposed to complex loads. We hypothesize that the deformation of the cells, caused by the complex loads, changes the dynamics of the actin-myosin motors in the sarcomere leading to changes in efficiency of contraction. 2) Elucidate the long-term mechano-adaptive response of cardiomyocytes exposed to complex loads. We hypothesize that the loss of efficiency in contraction leads to remodeling of the cardiomyocytes to minimize the free energy of the system. Through the combination of experimental measurements and multi-scale models, this project will elucidate both the acute functional and long-term remodeling response of the cardiomyocytes to complex loads.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.