Elucidating the myocardial energy demand-supply-production feedback system

心脏的功能是由机械和电子工作所需的能量与新陈代谢所提供的能量之间的密切相互作用决定的。心脏的新陈代谢需要嵌入心脏组织的血管中的氧气运输。由于心脏几乎消耗了其血液供应中的所有氧气，它向血管发出信号，以扩张和增加血流量和氧气输送。虽然这些过程的基础是已知的，但保持系统在最佳水平上工作所需的关键反馈回路尚未解决。该项目将使用先进的工程学、建模和实验技术来了解心脏如何在生理条件下和在生理受损条件下的应激期间调节其功能并保持充足的血液流动。这个项目将通过让高中生、本科生和研究生接触工程、计算和心血管原理来影响社会；导致开发一门连接工程学和生理学的新课程；并从代表性不足的人群中招募人才，以改善公平。最终，这个项目将有助于激励新一代STEM学生为社会做出更好的贡献。核心是一个设计良好的系统，能够将能源需求与能源生产和能源供应相匹配。具体地说，心泵功能内在地依赖于线粒体产生的能量(以三磷酸腺苷的形式)，而线粒体又依赖于嵌入并包裹心脏组织的冠状血管中氧气的运输。然而，除了心脏-冠脉信号机制外，冠状动脉血管系统的灌流还受到心脏机械收缩的影响。因此，心脏是一个闭合的反馈循环系统。这一系统的每个组成部分都具有独特的、在某些情况下以协调方式运行的一般反馈机制。虽然我们花了很大的精力单独研究这些系统组件中的每一个，但我们缺乏必要的洞察力来拼凑每个组件在集成到一起时是如何连接以及相互作用的。作为回应，该项目将结合先进的计算建模和实验验证研究，以阐明控制心脏在生理和病理条件下调节其功能的反馈机制。该项目将首先使用多尺度计算模型阐明与心脏力学、新陈代谢和血流调节相关的主要耦合因素。下一步，微血管功能和线粒体能量学之间的关系将得到解决。最后，将使用从健康和患病动物模型获得的数据，使用各种血流动力学扰动来验证该模型。总体而言，该项目将有助于促进我们对健康和患病心脏中运行的反馈机制的集体理解。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。

The heart’s function is determined by the close interaction between the energy demanded by mechanical and electrical work with the energy supplied by metabolism. Metabolism in the heart requires the transport of oxygen in blood vessels embedded in the heart tissue. Since the heart consumes nearly all the oxygen in its blood supply, it signals to the blood vessels to dilate and increase blood flow and oxygen delivery. While the basics of these processes are known, the critical feedback loops required to keep the system working at an optimal level are unresolved. This project will use advanced engineering, modeling and experimental techniques to understand how the heart regulates its function and maintains adequate blood flow during physiology conditions and during stress in physiologically impaired conditions. This project will impact society by exposing high school, undergraduate, and graduate students to engineering, computational, cardiovascular principles; lead to the development of a new course that bridges engineering and physiology; and recruit from underrepresented populations to improve equity. In the end, this project will help motivate a new generation of STEM students for the betterment of society.The heart is a well-designed system capable of matching energy demand with energy production and energy supply. Specifically, cardiac pump function inherently depends on energy (in the form of adenosine triphosphate, ATP) produced by the mitochondria, which in turn depends on the transport of oxygen in the coronary vasculature that is embedded and envelopes the cardiac tissue. Perfusion in the coronary vasculature, however, is affected by mechanical contraction of the heart in addition to cardiac-coronary signaling mechanisms. As such, the heart is a closed-feedback loop system. The components of this system each possess unique, and in some cases, general feedback mechanisms that operate in a coordinated fashion. While great effort has gone into studying each of these system components in isolation, we lack the necessary insight to piece together how each component is wired and interacts with each other when integrated together. In response, this project will combine advanced computational modeling and experimental validation studies to elucidate the feedback mechanisms governing the heart’s ability to regulate its function under physiological and pathological conditions. The project will first elucidate the primary coupling factors associated with cardiac mechanics, metabolism, and blood flow regulation using a multiscale computational model. Next, the relationship between microvascular function and mitochondrial energetics will be resolved. Finally, the model will be validated using a variety of hemodynamic perturbations using data acquired from healthy and diseased animal models. Overall, this project will help further our collective understanding on the feedback mechanisms operating in the healthy and diseased heart.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.