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。为了改善预后，研究人员应用了多种方法来改变新生内膜增生和血管重塑；然而，由于对血流动力学因素、生化介质和细胞效应物导致干预后闭塞血管表型的具体因果联系了解不完全，这些尝试在很大程度上是无效的。以往的研究几乎完全集中在静态、隔离的物理或生物成分上。例如，我们证实了壁切应力是血管结构的关键调节因素。同时，我们建立了时间上不同的血管壁炎症事件(由单核细胞介导)预测长期形态的结论。然而，完全缺乏对物理力量和细胞炎症因素之间的动态相互作用的了解，这些因素调节了室壁重塑中的局部差异，并最终决定了介入治疗的成败。以临床相关的静脉旁路移植作为模型系统，这一提议将促进血管生物学家、工程师和数学家的协同作用，他们将使用系统生物学方法来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量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。整体重塑反应是通过基因调控网络的变化来调节的(特定目标1)，而病变发展的焦点是通过单核细胞归巢到改变的血流区域的动态(特定目标2)来调节的。这一提议的一般方法是使用健壮但经过验证的计算算法来开发每个模块。结合大量的活体实验数据，每个模块为整体模型贡献了一个新的结构集成水平。在编译后，最终的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(基因调节模块)和一系列偏微分方程式(单核细胞运动模块)，所产生的输出通过细胞自动机连接以预测组织结构的变化，该变化反馈到血流动力学模块以启动新的周期。为了保持空间的完整性，预测模型的潜在功能是在复杂的三维几何图形中检查疾病进展的区域差异。这项工作不仅为提高搭桥术的耐用性提供了直接的临床转化，而且最重要的是，它是严格的系统生物学方法在理解和治疗复杂医学疾病方面的强大当代应用。 公共卫生相关性：心脏病发作和中风仍然是美国死亡和发病的主要原因。现有的治疗方法，如静脉搭桥手术或血管成形术，目前只能提供短期改善，而且容易因侵袭性瘢痕形成而失败。目前的建议使用系统生物学的方法来研究血管对损伤反应的复杂机制，提供了一个预测模型，作为研究工具和患者护理的应用。

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.