Translational and Computational Analysis of Dialysis Fistula Maturation Failure-2

透析瘘成熟失败的转化和计算分析-2

• 批准号: 10256010
• 负责人: Scott A Berceli
• 金额: $ 57.53万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-18 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10256010
• 关键词: Anastomosis - action; Anatomy; Angioplasty; Animal Model; Architecture; Arteriovenous fistula; Biological; Biological Response Modifier Therapy; Biology; Biomechanics; Blood Circulation; Blood Vessels; Bypass; Cardiovascular system; Cell Cycle Kinetics; Cell Proliferation; Cellular biology; Central Vein; Clinical; Complex; Computer Analysis; Computer Models; Coronary; Coupled; Data; Deposition; Dialysis procedure; Elements; Endothelium; Environment; Equilibrium; Failure; Fistula; Gene Expression; General Population; Genes; Genomics; Goals; Growth; Hemodialysis; Human; Hyperplasia; Inflammatory; Intervention; Investigation; Link; Maintenance; Mediator of activation protein; Modeling; Natural experiment; Outcome; Pathologic; Pathology; Pathway Analysis; Pathway interactions; Pattern; Pharmacology; Phase; Phenotype; Physiological; Physiology; Regulator Genes; Research; Sampling; Smooth Muscle Myocytes; Stents; System; Therapeutic; Thinness; Veins; arterial remodeling; base; design; experimental study; genome-wide; genomic signature; hemodynamics; improved; in silico; insight; intima media; laser capture microdissection; mechanotransduction; metabolomics; migration; mortality; multi-scale modeling; next generation; response; response to injury; restraint; shear stress; trend

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.

抽象的 关于病理性动脉重塑与适应性动脉重塑的许多见解都是通过详细的研究获得的。 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 调节他们的反应模式。在正常的动脉循环中，中等剪切应力、层流 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，并且是 成功治疗的基石。相比之下，复杂、高能、混沌的流动环境， AVF 的特征，打破了这些已建立的血流动力学-生物学关系。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 将平滑肌细胞 (SMC) 转变为促增殖合成表型的下游效应。在一个 更具全球意识，了解 AVF 流环境中的独特响应模式 有助于推动该领域的发展并提供设计下一代所需的见解 生物疗法可改善 AVF 结局。目标 2 和 3 将对关键问题进行基于系统的分析 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 网络中应推进进一步转化调查的关键要素。 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 创建 AVF 后。使用激光捕获显微切割、高通量基因组学和先进网络 分析表明，当前项目将产生一个多尺度的计算模型，将基因表达的变化联系起来 SMC 和基质生物学的改变以及最终重塑反应的改变 AVF 架构。使用该模型，可以对基因组扰动的生物反应进行系统分析 进行探索，有效地进行一系列计算机实验，以确定这些关键机会 基因组反应，其中扩张重塑和调节增生之间需要平衡 可以实现增长。在此背景下，提出以下目标： 具体目标 1：探索 AVF 形成和 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）的生理成熟的影响。 具体目标 2：描述与 AVF 产生和相关的全基因组表达模式的变化 识别与成功 AVF 重塑相关的独特基因组特征。 具体目标 3：创建和探索动态基因调控网络，结合多尺度 血管适应的计算模型，识别具有最显着性的基因子集 对 AVF 放置后增强向外重塑和减少内膜增生的影响。