Integrative modeling to link vascular phenotype to gene expression

描述：涉及血管阻力、血流和压力调节的复杂信号机制还不是很清楚。这是一个重要的问题，因为这些机制与各种病理情况密切相关，如高血压和心力衰竭。实验已经开始解开这些错综复杂的调控机制，并不断提供新的见解。然而，只有有限的理论发展来帮助阐明日益复杂的系统。在这一建议中，数学模型被开发出来，能够将宏观现象，如血管反应性，与潜在的生化机制联系起来。总体目标是提供一个理论框架，将有助于血管病理生理学的研究。目标是 在这一特殊应用中是为了研究高血压血管调节失调的机制。这一建议的中心假设是，参与血管细胞电生理学和钙动力学的基因表达改变，导致疾病状态下血管的异常反应性。提出这项研究的理由是，可以将微血管表型与潜在的生化途径联系起来的模型可以为健康和疾病中的血管自我调节提供新的见解。一旦能够更好地了解调节外周血管阻力的机制，这将在垂直方向上促进我们对心血管疾病病理的了解。依赖于数学模型的重大先期发展，这项提议的总体目标将通过追求两个具体目标来实现：在目标1中，我们将开发多尺度模型，将血管直径的宏观尺度响应与潜在的细胞信号和离子通道活动联系起来。我们将把具有生物力学描述的血管内皮细胞和平滑肌细胞的详细电生理学和钙动力学模型集成到正常血压和高血压血管的多细胞模型中。在目标2中，将评估高血压微循环中的基因表达和血管反应性。我们将检验这一假设，即血管反应性的疾病相关性差异与关键细胞成分的基因表达失调有关。候选基因将被确定，它们对高血压表型的贡献将通过目标1中的模型进行评估。该提案概述了一种新的方法，通过一个集成的理论框架来检查血管功能，使我们能够将来自基因和细胞水平的数据与血管水平的宏观观察相关联。这项拟议的研究将提供对血流和血压调节机制的更好理解，同时为病理生理学研究开发一个通用的理论框架。

DESCRIPTION: The complex signaling mechanisms involved in the regulation of vascular resistance, blood flow and pressure are not well understood. This represents an important problem as these mechanisms are closely associated with a variety of pathological conditions such as hypertension and heart failure. Experimentation has begun to untangle these regulatory mechanisms and continuously provides new insights. There is, however, only limited theoretical development to assist in the elucidation of systems of increased complexity. In this proposal, mathematical models are developed capable of relating macroscopic phenomena such as vessel reactivity, to the underlying biochemical mechanisms. The overall goal is to provide a theoretical framework that will assist in investigations of vascular pathophysiology. The objective in this particular application is to investigate mechanisms contributing to vascular dysregulation in hypertension. The central hypothesis of this proposal is that altered expression of genes involved in vascular cell electrophysiology and Ca2+ dynamics, leads to abnormal vessel reactivity in disease states. The rationale for the proposed research is that models that can link microvascular phenotype to the underlying biochemical pathways can provide new insights into vascular autoregulation in health and in disease. Once a better understanding of mechanisms that regulate peripheral vascular resistance can be accomplished this will vertically advance our knowledge on the pathology of cardiovascular diseases. Relying on significant prior development of mathematical models, the overall objective of this proposal will be accomplished by pursuing two specific aims: In Aim 1, we will develop multiscale models that will relate macroscale responses in vessel diameter, to the underlying cellular signaling and ion channel activity. We will integrate detailed electrophysiology and Calcium dynamics models for vascular endothelial and smooth muscle cells with biomechanical descriptions into multicellular models of normotensive and hypertensive vessels. In Aim 2, gene expression and vasoreactivity will be evaluated in the hypertensive microcirculation. We will test the hypothesis that disease dependent differences in vessel reactivity correlate to gene expression dysregulation of key cellular components. Candidate genes will be identified and their contribution to hypertensive phenotype will be evaluated by the model in Aim 1. The proposal outlines a new approach to examine vascular function through an integrated theoretical framework that enables us to correlate data from the gene and the cellular level to mascroscopic observations at the vessel level. The proposed research will provide a better understanding of the mechanisms that regulate blood flow and pressure while developing a versatile theoretical framework for pathophysiological investigations.