Myocardial Remodeling: Role of Microstructural Cell-ECM Mechanical Interaction

高血压导致心力衰竭的主要原因之一是心脏组织的结构随着时间的推移而改变，从而改变其机械能力。心脏组织主要由两种“材料”组成：细胞（称为肌细胞）和纤维（特别是胶原纤维）。当心脏跳动时，细胞和纤维相互“推拉”：这被称为机械耦合。因为高血压改变了组织的组成--细胞变大，纤维数量增加--直觉上认为它也会影响细胞和纤维的相互作用。该项目的目标是使用先进的建模和计算以及仔细的实验来了解高血压如何影响机械耦合以及这种耦合的变化如何导致心功能障碍。这项研究将在再生医学和组织工程领域产生影响，特别是在新出现的心力衰竭治疗方面。最后，该项目还将作为一个平台，推出一个创新的外展计划（“我心生物力学”），教育和提高公众对生物力学研究的认识。 本课题假设细胞与胶原纤维网络之间的机械耦合不仅在高血压大鼠心脏病理性重构过程中发生变化，而且是驱动重构的重要力量之一。该项目的首要目标是阐明细胞和细胞外基质之间的机械耦合如何（1）驱动健康和患病心脏的微观结构变化，（2）影响左心室在重塑的各个阶段的机械特性，以及（3）有助于心脏组织的病理变化。该方法包括新的本构方程，有限元建模，并在完整的组织，以及在主动和被动条件下与孤立的组件组织的实验。在此过程中，还将开发一种方法来量化和纳入一个新的微观结构模型的心室mechanics.This奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

One of the main reasons for heart failure due to hypertension is that the structure of the heart tissue changes with time, altering its mechanical capabilities. The heart tissue is mainly made of two "materials": cells (called myocytes) and fibers (specifically, collagen fibers). Cells and fibers "push and pull" on one another while the heart beats: this is called mechanical coupling. Because hypertension alters the composition of the tissue -- cells become bigger and fibers grow in number -- it is intuitive to think that it will also have an impact on how cells and fibers interact. The goal of this project is to use advanced modeling and computations and careful experiments to understand how hypertension affects the mechanical coupling and how this change in coupling contributes to cardiac dysfunction. This study will have impact in the fields of regenerative medicine and tissue engineering, specifically in the case of new emerging heart failure treatments. Finally, this project will also serve as a platform to launch an innovative outreach program ("I heart Biomechanics") to educate and enhance public awareness of biomechanics research. In this project, it is hypothesized that the mechanical coupling between cells and collagen fiber network not only changes during pathological remodeling in the heart of hypertensive rats, but also is one of the significant forces driving remodeling. The overarching goal of this project is to elucidate how mechanical coupling between cells and extracellular matrix (1) drives microstructural changes in healthy and diseased hearts, (2) affects mechanical properties of the left ventricle at various stages of the remodeling, and (3) contributes to the pathological changes of the heart tissue. The approach consists of new constitutive formulations, finite element modeling, and experiments on intact tissues as well as tissues with isolated components under both active and passive conditions. In the process, a methodology will also be developed to quantify and incorporate the collagen-cells mechanical coupling into a new microstructural model for ventricular mechanics.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.