A mathematical model of microvascular remodeling: Endothelial dysfunction in obes

描述(申请人提供)：肥胖、糖尿病和高血压影响数百万人，并与心血管疾病和死亡率有关。虽然血管重塑发生在健康条件下，并受到细胞对血液动力学和生化刺激的反应的调节，但这种对刺激的反应在许多疾病中都会降低。事实上，小血管的病理性结构重构已经成为这些疾病影响的关键因素，包括导致高血压、器官损害和组织缺血。特别是，在疾病状态下观察到的血管异常重塑可能是由内皮细胞失去正常功能所驱动的，内皮细胞负责感知血流动力学和代谢变化。在过去的十年中，Pries、Secomb和他的同事开发了一个微血管重构的动态模型，该模型在概念上很简单，但基于生物观察到的刺激，如壁剪切应力、周向应力和代谢需求。这一优雅的模型捕捉了健康血管重建的关键方面，并提供了对某些以前较少认识的影响重建的因素的作用的生物学见解。我们将以Pries-Secomb模型为基础，对肥胖、糖尿病和高血压患者内皮功能障碍对微血管重构的影响进行数学建模。为了做到这一点，我们将使用细胞水平的生物学理解肥胖、糖尿病和高血压的内皮功能障碍，以指导发展内皮功能变化的数学描述。这些将被合并到Pries-Secomb模型的现有框架中，以对照实验结果进行验证。在这项工作中，我们将考虑单血管模型，它允许对平衡解和重塑动力学进行彻底的数学分析，以及对小型或大型网络的数值模拟，它可能捕捉到更多生理上相关的现象。多种方法将有助于最大限度地理解数学建模结果，以及它们如何捕捉微血管重构的实验观察。这项工作的总体目标是在数学建模和实验工作之间建立更深层次的联系，以便深入了解各种疾病状态的潜在生物学，以便采取更有效的干预措施来治疗疾病。 公共卫生相关性：肥胖、糖尿病和高血压等常见疾病中血管重塑的变化被认为是导致这些疾病相关的一些发病率的原因，包括器官损伤和组织缺血。这项拟议的工作旨在使用实验驱动的血管重塑的数学模型来了解这一过程，而这一过程很难通过实验获得。增加我们对重塑过程的了解最终将导致更有效的临床干预。

DESCRIPTION (provided by applicant): Obesity, diabetes, and hypertension affect millions of people and are associated with cardiovascular mor- bidity and mortality. While blood vessel remodeling occurs under healthy conditions, and is modulated by cellular responses to hemodynamic and biochemical stimuli, this responsiveness to stimuli is reduced in many diseases. In fact, pathological structural remodeling of small blood vessels has emerged as a key contributor to the effect of these diseases, including driving high blood pressure, organ damage, and tis- sue ischemia. In particular, the abberrant remodeling of blood vessels observed in disease states is likely driven by the loss of normal function in endothelial cells, which are responsible for sensing hemodynamic and metabolic changes. Over the last decade, Pries, Secomb, and colleagues have developed a dynamic model of microvascular remodeling that is conceptually simple, yet based on biologically observed stimuli such as wall shear stress, circumferential stress, and metabolic demand. This elegant model captures key aspects of vascular remodeling by healthy vessels and has provided biological insight about the role of certain previously less appreciated factors influencing remodeling. We will mathematically model the effect of endothelial dysfunction on microvascular remodeling in obesity, diabetes, and hypertension, using the Pries-Secomb model as a basis. To do this, we will use a cellular-level biological understanding of endothelial dysfunc- tion in obesity, diabetes, and hypertension to guide development of mathematical descriptions of changes in endothelial function. These will be incorporated into the existing framework of the Pries-Secomb model for validation against experimental results. In this work, we will move between consideration of single vessel models, which allow thorough mathematical analysis of equilibrium solutions and remodeling dy- namics, and numerical simulation of small or large networks, which may capture more physiologically relevant phenomena. Multiple approaches will help to maximize our understanding of mathematical modeling results and how they capture experimental observations of microvascular remodeling. The overall goal of this work is to create a deeper link between mathematical modeling and experimental work in order to gain insight into the underlying biology of various disease states in order to work to- wards more effective interventions to treat diseases. PUBLIC HEALTH RELEVANCE: Changes in blood vessel remodeling that occur in prevalent diseases such as obesity, diabetes, and hy- pertension are thought to cause some of the morbidity associated with these diseases including organ damage and tissue ischemia. The proposed work aims to use experimentally-motivated, mathematical models of vessel remodeling to gain understanding of this process that would be difficult to obtain exper- imentally. Increasing our knowledge about the remodeling process will ultimately lead to more effective clinical interventions.