Blood Flow Regulation in Normal and Diseased Tissues: Signal Transduction and Integration in Physiological Systems

1133260Carlson描述：在正常和疾病状态下，如何调节血流以匹配组织代谢需求，如高血压，在生理学领域仍然是一个开放的问题。已知的是，微循环中的血流是通过血管的扩张和收缩来调节的，血管的收缩和收缩影响着围绕着调节微血管的血管平滑肌细胞的收缩和松弛。已知的几种局部血管和组织水平的刺激可以控制血管平滑肌细胞的收缩状态，如管腔内压力、施加在血管壁上的剪应力和周围组织的代谢状态。这项拟议的研究旨在通过理论和实验分析相结合的方法，了解这些机械、化学和电刺激是如何结合在一起来调节正常和高血压微血管血流的。这种方法的理论部分将使用包含分子、细胞、单血管和组织尺度的细节的模型，这些模型将使用从文献和当前的实验合作中获得的细胞(离子通道和细胞电生理学、血管平滑肌细胞内钙离子等)、单血管(孤立的血管对机械和化学刺激的反应)和组织(组织血流观察)水平的实验数据进行参数化和验证。将细胞和单血管理论模型集成到组织水平的微血管网络模型中，将有助于预测正常调节网络和高血压改变的调节网络之间的功能差异。在目标1中，将开发单血管监管模型并将其参数化。这些理论模型将为目标2中的微血管网络的组织水平调控模型提供基础，目标3中的组织水平调控模型将被用作描述高血压存在的血管调节功能障碍的预测工具。拟议研究的智力优点：拟议的研究基本上旨在揭示机械、化学和电刺激在微血管系统中促进血流调节的量化整合。到目前为止，还没有开发出一种旨在描述在细胞、血管和组织水平上汇编的大量实验数据的完全综合的方法。在了解血流调节反应的组织水平表型的过程中，研究人员将能够从功能上检验关于细胞水平机械刺激的转导、血管平滑肌和血管壁内皮细胞之间的化学和电子通讯以及各种刺激在血管和组织水平的整合的假设。研究人员在开发和测试这些模型时使用的方法是基于使用多个理论假说来表示实验数据，这些假说可以通过对模拟和实验结果的分析来确认或消除，从而允许开发进一步的假说和进行实验研究，通过这种系统的方法，将发展对如何通过从分子到组织尺度的操作过程的协同操作来控制血液流动的机械理解。拟议研究的更广泛影响：该项目涉及NSF任务中概述的两个重要考虑因素，即促进科学进步和促进我们国家健康繁荣。该项目旨在通过以血流调节系统为例，在更广泛的意义上促进科学进步，说明如何整合由各种局部刺激提供的信息，这些信息在最小的系统规模上被感知，以管理整个系统的全球反应。该系统与机械转导和细胞通讯机制一起，可以很容易地应用于其他生物系统。此外，通过跨越数学、计算和生物学科，该项目为培训下一代跨学科研究人员提供了机会。在该项目下开发的模型和分析将用于生理学研究生的课程作业，这是一门迫切需要接受计算建模方法培训的年轻研究人员的学科。此外，本科生将有机会参加威斯康星医学院独立资助的暑期研究项目。这项拟议的研究将通过使用这些模型作为预测工具来开发与高血压血管功能障碍有关的新的和可检验的假说，从而促进国家健康繁荣。高血压是一种影响超过25%美国人口的疾病。拟议中的研究结果的其他应用将与伴随其他疾病(如肾脏和心血管疾病)的微血管功能障碍相关。

1133260CarlsonDescription: How blood flow is regulated to match tissue metabolic demand in normal and disease states such as hypertension is still an open-ended question in the field of physiology. What is known is that blood flow is modulated in the microcirculation by vascular dilation and constriction affected by contraction and relaxation of the vascular smooth muscle cells that encircle regulatory microvessels. Several local vessel and tissue level stimuli are known to control the contractile state of vascular smooth muscle cells such as intraluminal pressure, shear stress imparted on the vessel walls and metabolic state of the surrounding tissue. This proposed study aims to understand how these mechanical, chemical and electrical stimuli are integrated together to modulate normal and hypertensive microvascular blood flow by using a combination of theoretical and experimental analyses. The theoretical portion of this approach will use models containing detail at molecular, cellular, single vessel and tissue scales and these models will be parameterized and validated using experimental data obtained at the cellular (ion channel and cellular electrophysiology, vascular smooth muscle cytosolic Ca2+, etc.), single vessel (isolated vessel response to mechanical and chemical stimuli) and tissue (tissue blood flow observations) levels both from literature and current experimental collaborations. Integration of the cellular and single vessel theoretical models into a tissue level microvascular network model will facilitate the prediction of functional differences between normal regulatory networks and those altered by hypertension. In Objective 1 single vessel regulatory models will be developed and parameterized. These theoretical models will provide the foundation for tissue level regulatory models of microvascular networks in Objective 2, which will be in turn used as a predictive tool to describe the vascular regulatory dysfunction present in hypertension in Objective 3.Intellectual Merits of the Proposed Research: The proposed research is fundamentally aimed at uncovering the quantitative integration of mechanical, chemical and electrical stimuli in the microvasculature facilitating the regulation of blood flow. A fully integrative approach aimed at describing the large body of experimental data compiled at the cellular, vessel and tissue levels has not been developed to date. In the process of understanding the tissue level phenotype of blood flow regulatory response the investigators will be able to functionally test hypotheses concerning transduction of mechanical stimuli at the cellular level, chemical and electrical communication between vascular smooth muscle and endothelial cells in the vessel wall and integration of a variety of stimuli at the vessel and tissue level. The method the investigators will use in developing and testing these models is based on representation of experimental data using multiple theoretical hypotheses which in turn can be either confirmed or eliminated through analysis of simulation and experimental results allowing further hypotheses to be developed and experimental investigations to be performed, Via this systematic approach a mechanistic understanding of how blood flow is controlled through the synergistic operation of processes operating from the molecular to tissue scales will be developed. Broader Impact of the Proposed Research: This project addresses two important considerations outlined in the NSF Mission, namely to promote the progress of science and to advance our national health prosperity. This project aims to promote the progress of science in a broader sense by using the blood flow regulatory system as an example of how information provided by various local stimuli, sensed at the smallest system scale, are integrated to govern global response of the entire system. This system along with mechanisms of mechanotransduction and cellular communication can be readily applied to other biological systems. Furthermore, by spanning mathematical, computational and biological disciplines this project provides the opportunity for training the next generation of interdisciplinary researchers. Models and analysis developed under this project will be used in coursework for graduate students in physiology, a discipline in desperate need of young investigators trained in computational modeling methods. In addition undergraduate students will have the opportunity to participate through independently funded summer research programs at the Medical College of Wisconsin. The proposed research will advance the national health prosperity by using these models as predictive tools to develop novel and testable hypotheses relating to vascular dysfunction in hypertension, a disease affecting over 25% of the U.S. population. Additional applications of the findings from the proposed study will be relevant to microvascular dysfunction that accompanies other diseases such as renal and cardiovascular disease.