Translational and Computational Analysis of Dialysis Fistula Maturation Failure-2

摘要 许多对病理性动脉重塑与适应性动脉重塑的见解都是通过详细的 了解血管内皮细胞/平滑肌细胞生物学与局部血流动力的关系 来调节它们的反应模式。在正常的动脉循环中，适中的切应力，层流 流动模式占主导地位，干预后的反应模式已经被很好地描绘出来，是 是治疗成功的基石。相比之下，复杂、高能、混沌的流动环境， 动静脉动静脉瘘的特征，打破了这些既定的血流动力学-生物关系。目标1将探索 机械传感机制有助于解释这些力，并检查它们的 下游效应使平滑肌细胞(SMC)转变为促增殖的合成表型。在一个 更具全球意义，了解AVF流动环境中的独特响应模式是 有助于推动该领域向前发展，并提供设计下一代 改善动静脉瘘预后的生物疗法。AIMS 2和3将执行基于系统的关键 决定AVF重塑成功与否的基因组变化，并利用多尺度模型来识别 网络中应继续进行进一步翻译调查的关键要素。 在我们的初步数据的支持下，我们认为内膜和中膜具有独特的反应模式 在创建AVF之后。利用激光捕获显微切割、高通量基因组学和先进网络 分析，目前的项目将产生一个多尺度、计算模型环节的基因表达变化 网络对SMC和基质生物学的改变以及最终重塑反应的改变 AVF架构。使用这个模型，对基因组扰动的生物反应的系统分析可以 被探索，有效地执行硅胶实验的进展，以确定这些关键的机会 扩张性重塑和调节性增生之间所需平衡的基因组反应 增长是可以实现的。在这方面，提出了以下目标： 具体目标1：探索动静脉动静脉瘘的产生与SMC表型之间的生物力学联系，并评估 这些变化对AVF适应和生理成熟成功(或失败)的影响。 特定目的2：描述与AVF产生和相关的全基因组表达模式的变化 确定与成功的房室瘘重塑相关的独特的基因组特征。 具体目标3：创建和探索一个动态的基因调控网络，与多尺度相结合 血管适应的计算模型，确定具有最显著意义的基因子集 AVF置入对增强血管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.