The Role of Hypoxia In Venous Neointimal Hyperplasia In Hemodialysis Grafts

缺氧在血液透析移植物静脉新生内膜增生中的作用

基本信息

批准号：
8420485
负责人：
Sanjay Misra
金额：
$ 52.7万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8420485
关键词：
Antibodies Arteriovenous fistula Avastin Blood Vessels Catheters Cell Culture Techniques Cell Line Cell Proliferation Cells Clinical Clinical Trials Data Deposition End stage renal failure Failure Fibroblasts Functional disorder Gelatinase A Gelatinase B Gelatinases Gene Expression Goals HIF1A gene Harvest Hemodialysis Hyperplasia Hypoxia In Vitro Individual Injury Knockout Mice Knowledge Maleates Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Mediating Modeling Molecular Mus Myofibroblast Nephrectomy Outcome Pathway interactions Patient Care Patients Phenotype Play Population Production Proteins Reagent Regulation Renal Replacement Therapy Research Proposals Role Secondary to Simvastatin Sirolimus Specimen Stenosis Subfamily lentivirinae Sutent Technology Testing Therapeutic Translating Tunica Adventitia Tyrosine Kinase Inhibitor Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors Venous base bevacizumab cell motility design gain of function hypoxia inducible factor 1 improved in vivo Model migration neutralizing antibody programs public health relevance receptor research study small hairpin RNA therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Project description: More than 400,000 patients in the US have end stage renal disease (ESRD), a population expected to double in the next decade. The long term goal of this current proposal and research program is to improve the care of patients with ESRD, the vast majority of who use long-term hemodialysis as their mode of renal replacement therapy. These patients require highly functioning vascular access for optimal therapeutic adequacy. Hemodialysis vascular access failure is frequently from venous stenosis secondary to neointimal hyperplasia (VNH). Preliminary data from our studies indicate that several mechanisms may be responsible for VNH formation. These include: 1) Elevated hypoxia inducible factor-1 alpha (HIF-11) which then stimulates; 2) Increased expression of vascular endothelial growth factor-A (VEGF-A) and its receptors; 3) Increased expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 (gelatinases); and 4) Proliferation and migration of fibroblasts from the adventitia and media to the intima resulting in VNH formation. We have developed state- of-the art molecular reagents and validated mouse nephrectomy with arteriovenous fistula model (AVF) and a hypoxia fibroblast cell culture model. The in vitro and in vivo models and accompanying reagents allow us to rigorously test our Central Hypothesis: Venous neointimal hyperplasia occurs when increased HIF-11 stimulates adventitial fibroblasts to differentiate into myofibroblasts (1-SMA positive cells). Increased expression of HIF-11 regulated proteins including VEGF-A, MMP-2 and MMP-9 results in the proliferation and migration of myofibroblasts into the intima leading to the formation of VNH. To test our central hypothesis we have developed three specific aims: 1). Determine the temporal and spatial role(s) of VEGF-A in VNH. 2). Determine the role(s) and regulation of MMPs in VNH. 3). Determine if the molecular mechanism of hypoxia induced fibroblast to myofibroblast differentiation is mediated by the VEGF- A/MMP axes. Successful completion of these aims will allow us to ultimately translate therapies aimed at inhibiting VNH to clinical trials thereby improving patient outcomes using commercially available anti-VEGF-A antibodies (Avastin (Bevacizumab)) and MMP inhibitors (Simvastatin or Sirolimus) which can be delivered using catheter based technology.

描述（由申请人提供）：项目描述：美国有超过 400,000 名终末期肾病 (ESRD) 患者，预计这一数字在未来十年内将增加一倍。当前提案和研究计划的长期目标是改善 ESRD 患者的护理，其中绝大多数患者使用长期血液透析作为肾脏替代治疗的方式。这些患者需要功能强大的血管通路才能获得最佳的治疗效果。血液透析血管通路失败通常是由于新生内膜增生（VNH）继发的静脉狭窄所致。我们研究的初步数据表明，多种机制可能导致 VNH 的形成。这些包括： 1) 缺氧诱导因子 1 α (HIF-11) 升高，然后刺激； 2）血管内皮生长因子-A（VEGF-A）及其受体表达增加； 3）基质金属蛋白酶-2（MMP-2）和MMP-9（明胶酶）表达增加； 4) 成纤维细胞从外膜和中膜增殖并迁移至内膜，导致 VNH 形成。我们开发了最先进的分子试剂，并通过动静脉瘘模型（AVF）和缺氧成纤维细胞培养模型验证了小鼠肾切除术。体外和体内模型以及配套试剂使我们能够严格测试我们的中心假设：当 HIF-11 增加刺激外膜成纤维细胞分化为肌成纤维细胞（1-SMA 阳性细胞）时，就会发生静脉新生内膜增生。 HIF-11 调节蛋白（包括 VEGF-A、MMP-2 和 MMP-9）表达增加导致肌成纤维细胞增殖并迁移至内膜，从而形成 VNH。为了检验我们的中心假设，我们制定了三个具体目标：1）。确定 VEGF-A 在 VNH 中的时间和空间作用。 2）。确定 MMP 在 VNH 中的作用和调节。 3）。确定缺氧诱导成纤维细胞向肌成纤维细胞分化的分子机制是否由 VEGF-A/MMP 轴介导。成功完成这些目标将使我们最终能够将旨在抑制 VNH 的疗法转化为临床试验，从而使用市售的抗 VEGF-A 抗体（阿瓦斯汀（贝伐珠单抗））和 MMP 抑制剂（辛伐他汀或西罗莫司）来改善患者的预后。使用基于导管的技术。