Multiscale Network Modeling of Hemodynamically-Driven Vascular Adaptation

描述（由申请人提供）：心脏病、中风和肢体丧失继续导致死亡率和发病率。尽管外科手术和血管内治疗取得了进展，但这些干预措施的长期成功仍然有限。研究人员已经应用了多种方法来改变新生内膜增生和血管重塑，以改善结果；然而，由于对干预后血流动力学因素、生化介质和细胞效应器导致血管闭塞表型的具体因果关系的理解不完全，这些尝试在很大程度上是无效的。先前的研究几乎完全集中在静态分离的物理或生物成分上。例如，我们证实壁面剪切应力是血管结构的关键调节因子。与此同时，我们确定了暂时性不同的血管壁炎症事件（由血液单核细胞介导）预测长期形态。然而，完全缺乏对物理力量和细胞炎症因子之间的动态相互作用的理解，这些因素调节了局部壁重塑的变化，以及最终干预的成功或失败。将临床相关的静脉旁路移植术作为模型系统，该建议将促进血管生物学家、工程师和数学家的协同作用，他们将采用系统生物学方法研究血管适应的复杂机制。这个已建立的团队将构建和优化开创性的多尺度模型，以了解微尺度物理和生物力在静脉移植物壁行为中的相互作用。提出的假设驱动模型将血管适应过程概念化为两个平行但相互关联的过程。全球重塑反应是通过基因调控网络的变化来介导的（Specific Aim 1），而病变发展的焦点是通过单核细胞归巢到血流改变区域的动态来调节的（Specific Aim 2）。本建议的一般方法是使用稳健但经过验证的计算算法来开发每个模块。每个模块与大量的体内实验数据相结合，为整个模型提供了一个新的结构集成水平。编译完成后，最终模型将利用迭代循环，采用有限元计算技术（血流动力学模块）驱动贝叶斯网络（基因调控模块）和一系列偏微分方程（单核细胞动力学模块），通过细胞自动机接口输出结果，预测组织结构的变化，这些变化反馈到血流动力学模块以启动一个新的循环。结构保持空间完整性，预测模型的潜在力量是在复杂的三维几何结构中检查疾病进展的区域差异。这项工作不仅为改善旁路移植术耐久性提供了直接的临床翻译，而且最重要的是，它代表了严格的系统生物学方法的强大当代应用，以理解和治疗复杂的医学疾病。

DESCRIPTION (provided by applicant): Heart disease, strokes, and limb loss continue to lead mortality and morbidity. Despite advances in surgical and endovascular treatments, long-term success of these interventions remains limited. Researchers have applied a variety of approaches to modify neointimal hyperplasia and vascular remodeling in an effort to improve the outcomes; however, attempts have been largely ineffective due to incomplete understanding of the specific cause/effect links through which hemodynamic factors, biochemical mediators, and cellular effectors lead to an occlusive vascular phenotype after intervention. Prior research has focused almost exclusively on either the static isolated physical or biologic components. For instance, we confirmed that wall shear stress stands as a key regulator of vascular architecture. In parallel, we established that temporally distinct vessel wall inflammatory events (mediated by blood monocytes) predict long-term morphology. However, completely lacking is an understanding of the dynamic interplay between physical forces and cellular inflammatory elements that modulate local variations in wall remodeling, and ultimately success or failure of the intervention. Focusing on clinically relevant vein bypass grafting as a model system, this proposal will fuel the synergy of vascular biologists, engineers, and mathematicians who will employ systems biology approaches to the complex mechanisms of vascular adaptation. This established team will construct and optimize pioneering multi-scale models to understand the interplay of micro-scale physical and biologic forces in vein graft wall behavior. The proposed hypothesis driven model conceptualizes the process of vascular adaptation as two parallel, but interconnected processes. The global remodeling response is mediated through variations in the gene regulatory network (Specific Aim 1), while the focality of lesion development is modulated through the dynamics of monocyte homing to regions of altered flow (Specific Aim 2). The general approach of this proposal is the use of robust but validated computational algorithms for the development of each module. Interfaced with extensive in vivo experimental data, each module contributes a new structural integration level to the overall model. Upon compilation, the final model will utilize an iterative loop, employing a finite element computational technique (hemodynamic module) that drives a Bayesian network (gene regulatory module) and series of partial differential equations (monocyte kinetic module), with resulting outputs interfaced through a cellular automata to predict changes in tissue architecture, which feeds back into the hemodynamic module to initiate a new cycle. Structured to maintain spatial integrity, the underlying power of the predictive model is to examine the regional difference in disease progression in a complex three- dimensional geometry. This work not only provides direct clinical translation toward improved bypass graft durability, but most importantly it stands as a powerful contemporary application of rigorous systems biology approaches to understand and treat complex medical diseases. PUBLIC HEALTH RELEVANCE: Heart attack and stroke continue to be the leading cause of mortality and morbidity in the United States. Available treatments, such as vein bypass surgery or angioplasty, currently provide only short-term improvements, and are prone to failure due to aggressive scar formation. The current proposal uses systems biology approaches to study the complex mechanisms of the vascular response to injury, providing a predictive model with application both as a research tool and in the care of patients.