CAREER: A Systems Approach to Discovering Mechanical Sensors in Heart Muscle Cells

就像身体中的每一个组织一样，心肌适应机械负荷。一个例子是耐力跑的影响，这往往会扩大心脏的主要泵血室的体积。举重运动员的心壁增厚，而不是体积增加。关于心脏细胞如何将不同类型的运动或机械负荷转化为自我重塑的模式，人们知之甚少。为了理解为什么不同的运动会导致不同的心肌变化，将创建心脏组织的计算机模型。虚拟组织将以不同的方式拉伸，以产生数十种细胞反应预测，这些预测将与相同的实验结果进行比较。通过将模型预测与实验数据进行比较，可以解释肌肉细胞如何检测不同类型的机械负荷。这个教师早期职业发展（CAREER）计划研究项目有两个教育目标，一个侧重于研究生学员，另一个面向本科生。 该项目的本科生研究职位将被创建，PI将继续通过耶鲁大学的项目对20名本科生进行持续的指导。心脏细胞可以区分不同类型的机械负荷，在运动员中观察到的不同类型的心脏重塑就证明了这一点。当这种机械感觉过程被破坏时，就会导致疾病。虽然到目前为止已经在心肌细胞中鉴定出许多机械感觉成分，但建立对该系统、其传感器及其效应器的综合理解仍然具有挑战性。该提案的目的是绘制心脏细胞中许多候选机械敏感蛋白与它们影响的细胞过程之间的关系。这首先涉及创建一个新的理论框架，能够使用宏观组织变形来预测特定细胞蛋白质的微观变形。一旦完成，该模型将用于为工程心脏组织规划多种宏观加载方案，这些方案将以不同的方式扭曲亚细胞结构。然后将设计的负载施用到真实的工程化组织，并测量它们对细胞生长反应的影响。一种被称为“线索-信号-反应分析”的系统生物学方法将被用来将生长反应与模型预测的亚细胞蛋白质扭曲模式相关联。在这样做的过程中，新的机械传感器及其特定功能将被曝光。

Like every tissue in the body, heart muscle adapts to mechanical loading. One example is the effect of endurance running, which tends to enlarge the volume of the heart's main pumping chamber. Weight lifters experience a thickening of the heart walls instead of increased volume. Little is known about how heart cells translate different types of exercise or mechanical loads into patterns of self-remodeling. In order to understand why different exercises cause different heart muscle changes, a computer model of heart tissue will be created. The virtual tissue will be stretched in different ways to produce dozens of cell response predictions that will be compared to identical experimental results. By comparing the model predictions to experimental data an explanation of how the muscle cells detect different types of mechanical load will emerge. This Faculty Early Career Development (CAREER) Program research project has two educational objectives, one focused on post-graduate trainees and the other towards undergraduate students. Undergraduate research positions on the project will be created and the PI will continue ongoing mentoring of 20 undergraduate students through programs based at Yale University.Cardiac cells can distinguish between different types of mechanical loads, as evidenced by diverse types of cardiac remodeling observed in athletes. When this mechanosensory process is disrupted, it results in disease. While many mechanosensory components have been identified in cardiomyocytes so far, building an integrated understanding this system, its sensors, and their effectors, remains challenging. The purpose of this proposal is to map the relationships between many candidate mechanosensitive proteins in cardiac cells and the cellular processes they affect. This involves first creating a new theoretical framework capable of using macroscopic tissue deformation to predict the microscopic distortion of specific cellular proteins. Once complete, the model will be used to plan multiple macroscopic loading schemes for engineered heart tissue that will distort subcellular structures in diverse ways. The designed loads will then be administered to real engineered tissues, and their effect on cellular growth responses will be measured. A systems biology approach known as 'cue-signal-response analysis' will be used to correlate growth responses with patterns of subcellular protein distortion predicted by the model. In so doing, new mechanosensors and their specific functions will be exposed.