Elucidating the myocardial energy demand-supply-production feedback system

阐明心肌能量需求-供应-生产反馈系统

• 批准号: 2222066
• 负责人: Lik Chuan Lee
• 金额: $ 41.7万
• 依托单位: Michigan State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2222066&HistoricalAwards=false
• 关键词: Elucidating; myocardial; energy; demand; supply

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.

心脏的功能是由机械和电气工作所需的能量与新陈代谢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在嵌入心脏组织的血管中运输氧气。由于心脏消耗了血液供应中几乎所有的氧气，它向血管发出信号，要求血管扩张，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循环尚未解决。该项目将使用先进的工程、建模和实验技术来了解心脏如何在生理条件下和生理受损条件下调节其功能并保持足够的血流量。该项目将通过让高中生、本科生和研究生接触工程、计算、心血管原理来影响社会；引导工程学与生理学相结合的新课程的发展；并从代表性不足的人群中招聘，以提高公平。最后，这个项目将有助于激励新一代的STEM学生，以改善社会。心脏是一个精心设计的系统，能够将能量需求与能量生产和供应相匹配。具体来说，心脏泵的功能本质上依赖于线粒体产生的能量（以三磷酸腺苷（ATP）的形式），而线粒体产生的能量又依赖于包裹心脏组织的冠状动脉血管中的氧气运输。然而，冠状动脉血管的灌注除了受到心脏-冠状动脉信号机制的影响外，还受到心脏机械收缩的影响。因此，心脏是一个闭环反馈系统。该系统的每个组件都具有独特的，在某些情况下，以协调的方式运作的一般反馈机制。虽然我们已经花费了大量的精力来单独研究这些系统组件，但我们缺乏必要的洞察力来拼凑每个组件是如何连接的，以及当集成在一起时如何相互交互。为此，本项目将结合先进的计算建模和实验验证研究来阐明在生理和病理条件下调节心脏功能的反馈机制。该项目将首先利用多尺度计算模型阐明与心脏力学、代谢和血流调节相关的主要耦合因素。接下来，微血管功能和线粒体能量学之间的关系将得到解决。最后，该模型将使用从健康和患病动物模型中获得的数据进行各种血液动力学扰动验证。总的来说，这个项目将有助于我们进一步了解在健康和患病心脏中运作的反馈机制。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。