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 通过详细的了解，对病理和自适应动脉重塑的许多见解已实现 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 这调节了他们的响应模式。在正常的动脉循环中，中等剪切应力，层层 流动模式占主导地位，干预后的响应模式已被很好地描述，并且是 成功疗法的基石。相反，复杂的，高能的混乱流动环境，该环境 表征AVF，打破了这些已建立的血液动力学生物学关系。 AIM 1将探索 在解释这些力并检查它们的机械传感机制 下游对将平滑肌细胞（SMC）转移到促增强的合成表型的效果。在 更全球的意义，了解AVF流动环境中独特的响应模式是 有助于向前推进领域并提供所需的见解，以设计下一代 生物疗法改善AVF结果。目标2和3将对关键的基于系统的分析 基因组变化决定了成功与失败的AVF重塑，并利用多尺度模型来识别 网络中的那些关键要素应该向前迈进，以进行进一步的翻译调查。 在我们的初步数据的支持下，我们建议内部媒体和媒体具有独特的响应模式 遵循AVF创建。使用激光捕获显微解剖，高通量基因组学和高级网络 分析，当前的项目将产生多尺度的计算模型链接基因表达的变化 网络与SMC和基质生物学的改变，并最终改变了重塑响应的变化 AVF架构。使用此模型，对基因组扰动的生物反应的系统分析可以 探索，有效地执行硅实验中的进展，以确定这些关键机会 基因组反应，其中所需的膨胀重塑与调制增生之间的平衡 可以实现增长。在这种情况下，提出了以下目标： 特定目标1：探索AVF创建与SMC表型之间的生物力学联系并评估 这些变化对AVF适应和成功（或失败）生理成熟的影响。 特定目标2：描述与AVF创建相关的全基因组表达模式的变化 确定与成功的AVF重塑相关的独特基因组特征。 特定目标3：创建和探索动态基因调节网络，该网络与多尺度结合 血管适应的计算模型，识别具有最重要的基因的子集 AVF放置后，对增强向外重塑并减少内膜增生的影响。