Translational and Computational Analysis of Dialysis Fistula Maturation Failure-2

摘要 许多关于病理性与适应性动脉重塑的见解是通过详细的 了解内皮/平滑肌细胞生物学与局部血流动力学之间的联系 调节它们的反应模式。在正常的动脉循环中， 流动模式占主导地位，干预后的反应模式已得到很好的描述， 成功疗法的基石相反，复杂的，高能量的，混沌的流动环境， 表征AVF，打破这些已建立的血液动力学-生物学关系。目标1将探讨 机械传感机制，有助于解释这些力量，并检查他们的 下游效应使平滑肌细胞（SMC）转变为促增殖的合成表型。中 更全面地了解AVF流动环境中的独特响应模式， 有助于推动该领域的发展，并提供必要的见解，以设计下一代的 改善AVF结局的生物疗法。目标2和目标3将对关键问题进行系统分析， 决定AVF重塑成功与失败的基因组变化，并利用多尺度模型来识别 网络中的那些关键元素应该向前推进，以进行进一步的翻译研究。 在我们的初步数据的支持下，我们提出内膜和中膜有独特的反应模式 创建AVF后。利用激光捕获显微切割、高通量基因组学和先进的网络 分析，目前的项目将产生一个多尺度，计算模型链接基因表达的变化 网络的SMC和基质生物学的改变，并最终改变重塑反应的 AVF架构。使用该模型，对基因组扰动的生物反应的系统分析可以 进行探索，有效地进行计算机模拟实验，以确定这些关键机会， 在扩张性重塑和调节性增生之间需要平衡的基因组反应 增长可以实现。在这方面，提出了以下目标： 特定目的1：探索AVF创建和SMC表型之间的生物力学联系，并评估 这些变化对AVF适应和成功（或失败）生理成熟的影响。 具体目标2：描述与AVF形成相关的全基因组表达模式的变化， 鉴定与成功AVF重塑相关的独特基因组特征。 具体目标3：创建和探索一个动态的基因调控网络，结合多尺度 血管适应的计算模型，确定具有最显著的基因的子集， 对AVF置入后增强外向重塑和减少内膜增生的影响。

ABSTRACT Many of the insights into pathologic versus adaptive arterial remodeling have been achieved through a detailed understanding of the linkage between endothelial/smooth muscle cell biology and the local hemodynamic forces that modulate their response pattern. In the normal arterial circulation, where moderate shear stress, laminar flow patterns predominate, the response patterns following intervention have been well delineated and are the cornerstone for successful therapies. In contrast, the complex, high-energy, chaotic flow environment, which characterizes the AVF, breaks these established hemodynamic-biologic relationships. Aim 1 will explore the mechanosensing mechanisms that are instrumental in the interpretation of these forces and examine their downstream effect on shifting the smooth muscle cell (SMC) to a pro-proliferative, synthetic phenotype. In a more global sense, understanding the unique response patterns within the AVF flow environment are instrumental to moving the field forward and providing the needed insights to design the next generation of biologic therapies to improve AVF outcomes. Aims 2 and 3 will perform a systems-based analysis of the critical genomic changes that dictate successful versus failed AVF remodeling and utilize a multi-scale model to identify those key elements within the network that should move forward for further translational investigation. Supported by our preliminary data, we propose that the intima and media have unique response patterns following AVF creation. Using laser capture microdissection, high-throughput genomics and advanced network analysis, the current project will produce a multi-scale, computational model links changes in gene expression network to alterations in SMC and matrix biology and ultimately alterations in the remodeling response of the AVF architecture. Using this model, a systematic analysis of the biologic response to genomic perturbations can be explored, effectively performing a progression of in silico experiments to identify those key opportunities in the genomic response where the needed balance between expansive remodeling and modulated hyperplastic growth can be achieved. Within this context, the following Aims are proposed: SPECIFIC AIM 1: Explore the biomechanical linkage between AVF creation and SMC phenotype and evaluate the impact of these changes on AVF adaptation and successful (or failed) physiological maturation. SPECIFIC AIM 2: Delineate the changes in genome-wide expression patterns associated with AVF creation and identify unique genomic signatures that are associated with successful AVF remodeling. SPECIFIC AIM 3: Create and explore a dynamic gene regulatory network, which in combination with a multiscale computational model of vascular adaptation, identifies the subset of genes that have the most significant influence on augmenting outward remodeling and reducing intimal hyperplasia following AVF placement.