权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Hemodynamics, Uremia & Vascular Biology: Interactive Pathways for AVF Maturation

血流动力学、尿毒症

基本信息

批准号：
9223568
负责人：
PRABIR ROY-CHAUDHURY
金额：
--
依托单位：
SOUTHERN ARIZONA VA HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-10-01 至 2020-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9223568
关键词：
Address Angioplasty Animal Model Animals Arteriovenous fistula Atherosclerosis Balloon Dilatation Bioinformatics Biological Biology Blood Vessels Blood flow Caliber Chronic Kidney Failure Clinical Comorbidity Complex Control Animal Control Groups Development Dialysis procedure Dilatation - action End stage renal failure Epidemic Event Exposure to Failure Family suidae Functional disorder Future Gene Expression Genes Genomics Grant Head Hemodialysis Histologic Histology Hyperplasia Inflammation Inflammatory Injury Intervention Kidney Failure Knowledge Light Link Magnetic Resonance Imaging Measures Modeling Outcome Oxidative Stress Pathway interactions Patients Phenotype RNA Sequences Radiology Specialty Reverse Transcriptase Polymerase Chain Reaction Risk Factors Sampling Stenosis Stress System Technology Thick Time Tissue Sample United States Uremia Vascular Diseases Vascular System Venous Veterans Work clinically relevant cost effective therapy endothelial dysfunction hemodynamics innovation knowledge base next generation sequencing novel novel therapeutics predictive marker prevent public health relevance response response to injury shear stress success transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Although arteriovenous fistulae (AVFs) are widely considered to be the best form of dialysis vascular access they currently have very significant problems with maturation failure, which is an inability to achieve adequate venous dilatation and flow to support dialysis. At a radiological level AVF maturation failure is characterized by a perianastomotic venous segment stenosis, while at a histological and pathogenetic level it is due to a combination of neointimal hyperplasia and an absence of outward remodeling. At a mechanistic level, work performed by us during the current grant period has clearly demonstrated that differing hemodynamic profiles result in very different clinical (flow and diameter) and histological end points. We therefore believe that hemodynamic injury is the critical upstream event, which then results in a downstream cascade of events (the vascular biology response to injury). An important unknown, however, remains the potential impact of uremia within this cascade, especially in the context of being able to modulate the downstream biological response to upstream hemodynamic injury. The reason that uremia is likely to be important is that it is characterized by significant increases in oxidaive stress, inflammation and endothelial dysfunction, all of which are key players in the downstream biological response to hemodynamic injury. In addition we, and others have been able to demonstrate the presence of neointimal hyperplasia within venous tissue samples taken at the time of dialysis vascular access creation (even before exposure to hemodynamic changes) suggesting that uremia per se (with its linkages to inflammation, oxidative stress and endothelial dysfunction), could be an important independent risk factor for venous stenosis/remodeling. The central hypothesis of the current proposal therefore is that AVF maturation is the end result of interactions between a wide spectrum of two prominent mechanistic pathways (upstream hemodynamic injury and uremia influenced downstream vascular biology). Put another way we want to explore how the presence or absence of uremia modulates the biological response to hemodynamic injury. We plan to address this central hypothesis through three Specific Aims. In Specific Aim 1, we will expand on the hypothesis that differential hemodynamic shear stress profiles (curved versus straight AVFs) initiate a sequence of differential biological (gene expression and cellular phenotyping) profiles, which then result in different morphometric (wall thickness) and clinical (flow and diameter) end points. This Specific Aim will also provide a historically concurrent comparator for the studies in Specific Aim 2. In Specific Aim 2, we will address the hypothesis that uremia per se can influence/modulate the biological response to hemodynamic injury, through a detailed comparison of the biological, morphometric and clinical end points described in Specific Aim 1 in the setting of a uremic pig model as compared to control animals (from Specific Aim 1). Finally in Specific Aim 3, we will combine the power of next generation sequencing technology (RNA Seq. analyses) with our unique animal model of uremia in order to look to the future, with regard to the identification of novel genes, pathways and mechanisms. This information could then be used to identify novel predictive markers for AVF maturation, or alternatively, as a knowledge base for the development of future biologically relevant therapies to prevent or treat AVF maturation failure. In summary, we believe that this proposal is significant because it focuses on an important clinical problem for which there are currently no effective therapies; it is unique in that it addresses head on the complex issue of uremia per se as a modulator of AVF maturation, and finally it is innovative in that it links advanced sequencing technology and bioinformatics to a clinically relevant uremic model.

描述（由申请人提供）：尽管动静脉瘘（AVF）被广泛认为是透析血管通路的最佳形式，但它们目前存在非常严重的成熟失败问题，即无法实现足够的静脉扩张和流量来支持透析。在放射学水平上，AVF 成熟失败的特点是吻合口周围静脉段狭窄，而在组织学和发病学水平上，它是由于新内膜增生的组合所致以及缺乏外部改造。在机械层面上，我们在当前资助期内所做的工作清楚地表明，不同的血流动力学特征会导致非常不同的临床（流量和直径）和组织学终点。因此，我们认为血流动力学损伤是关键的上游事件，然后导致下游级联事件（血管生物学对损伤的反应）。然而，一个重要的未知因素仍然是尿毒症在该级联中的潜在影响，特别是在能够调节下游对上游血流动力学损伤的生物反应的情况下。尿毒症之所以重要，是因为它的特点是氧化应激、炎症和内皮功能障碍显着增加，所有这些都是血流动力学损伤的下游生物反应的关键因素。此外，我们和其他人已经能够证明在建立透析血管通路时（甚至在暴露于血流动力学变化之前）采集的静脉组织样本中存在新生内膜增生，这表明尿毒症本身（及其与炎症、氧化应激和内皮功能障碍的联系）可能是静脉狭窄/重塑的重要独立危险因素。因此，当前提议的中心假设是，AVF 成熟是两个重要机制途径（上游血流动力学损伤和尿毒症影响下游血管生物学）之间广泛相互作用的最终结果。换句话说，我们想探索尿毒症的存在或不存在如何调节对血流动力学损伤的生物反应。我们计划通过三个具体目标来解决这一中心假设。在具体目标 1 中，我们将扩展以下假设：差异血流动力学剪切应力曲线（弯曲与直 AVF）启动一系列差异生物学（基因表达和细胞表型）曲线，然后导致不同的形态（壁厚）和临床（流量和直径）终点。该特定目标还将为特定目标 2 中的研究提供历史上同时进行的比较。在特定目标 2 中，我们将通过详细比较特定目标 1 中描述的尿毒症猪模型与对照动物（来自特定目标 1）中描述的生物学、形态测量和临床终点，提出尿毒症本身可以影响/调节对血流动力学损伤的生物反应的假设。最后，在具体目标 3 中，我们将把下一代测序技术（RNA 测序分析）的力量与我们独特的尿毒症动物模型结合起来，展望未来，识别新的基因、途径和机制。然后，该信息可用于识别 AVF 成熟的新预测标记，或者作为开发未来生物学相关疗法以预防或治疗 AVF 成熟失败的知识库。总而言之，我们认为该提案意义重大，因为它关注的是目前尚无有效疗法的重要临床问题；它的独特之处在于它作为 AVF 成熟的调节剂直接解决了尿毒症本身的复杂问题，最后它的创新之处在于它将先进的测序技术和生物信息学与临床相关的尿毒症模型联系起来。