Manipulating the matrix to improve arteriovenous fistula patency

操纵基质以改善动静脉内瘘的通畅

• 批准号: 10648012
• 负责人: Alan Dardik
• 金额: $ 75.1万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10648012
• 关键词: Address; Arteriovenous fistula; Biology; Blood Vessels; Blood flow; Cell Proliferation; Cells; Chronic Kidney Failure; Clinical; Clinical Trials; Collagen; Data; Deposition; End stage renal failure; Endothelial Cells; Environment; Expenditure; Extracellular Matrix; Failure; Female; Fistula; Funding; Goals; Healthcare; Hemodialysis; Human; Hyperplasia; Immune; Immunity; Inflammation; Intervention; Investigation; Knockout Mice; Knowledge; Legal patent; Macrophage; Mechanics; Mediating; Mediator; Methodology; Modeling; Mus; Needles; Nephrectomy; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Physiology; Procedures; Proteins; Puncture procedure; Resources; Sex Differences; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Specimen; T-Lymphocyte Subsets; Techniques; Tenascin; Testing; Transforming Growth Factor beta; Veins; Venous; Wild Type Mouse; Woman; Work; clinical translation; density; experience; hemodynamics; human disease; immunoregulation; improved; in vivo; in vivo Model; innovation; local drug delivery; male; men; mouse model; nanoparticle; next generation; novel; novel strategies; shear stress; tool; transcriptomics

The preferred vascular access for hemodialysis uses an arteriovenous fistula (AVF) to increase blood flow through a vein. Successful adaptation of the venous conduit to the arterial-like fistula environment requires remodeling of the vein wall without excessive wall thickening, enabling mechanical strength to resist hemodialysis procedures that puncture the AVF wall with large bore needles 3 times a week. However, the poor maturation and patency of AVF, especially in women and requiring additional re-do procedures and surgery, reflects our imperfect understanding of the biology of venous remodeling that leads to successful venous adaptation to the fistula environment. This knowledge gap creates an unmet need for novel approaches to enhance venous remodeling and thereby increase successful clinical use of venous conduits. During the funding period, we used an innovative mouse AVF model to show that TGF-β signaling regulates venous adaptive remodeling to improve AVF patency; activation of both the smad2/3 (canonical) and tak1 (noncanonical) pathways regulate venous remodeling; and endothelial cell-targeted TGF-β inhibition regulates both collagen density and smooth muscle cell proliferation to improve AVF patency. We present exciting new data that: 1) expression of the matricellular protein tenascin-C (TnC) is greatly increased and colocalizes with the remodeling venous wall; 2) TnC regulates AVF patency and TGF-β signaling during venous remodeling; 3) TnC expression is not downregulated in failed AVF; and 4) TnC knockout mice have altered proportions of immune cells in the AVF wall. In addition, we have developed the mouse model further to incorporate chronic kidney disease (CKD) via 5/6-nephrectomy and these AVF faithfully recapitulate human AVF maturation. We hypothesize that modulating tenascin-C activity will alter venous remodeling, thereby improving AVF maturation and patency. We will use our translationally relevant in vivo model, an innovative tool using nanoparticles for local drug delivery, innovative methodology to analyze the cell composition within the AVF wall, as well as advanced next-generation analyses using transcriptomics techniques that are available at Yale, to test our innovative hypothesis with the following specific aims: Aim I: Determine sex differences in TnC expression during human AVF remodeling in vivo. Aim II: Determine whether TnC function mediates venous remodeling in mice with CKD. Aim III: Determine whether regulation of immune cells is a mechanism of TnC-mediated venous remodeling. A successful outcome of this investigation will have lasting impact by establishing whether TnC mediates venous remodeling, and thus whether regulating TnC activity is a valuable strategy for clinical translation to enhance AVF maturation. We will also determine whether reduced AVF maturation in women is due to sex differences in TnC function as well as in inflammation and/or immunity. We use an innovative strategy and novel tools and models to alter venous remodeling and thereby improve AVF maturation.

血液透析首选的血管通道使用动静脉瘘（AVF）增加血液 流过静脉。成功适应静脉导管对动脉状的瘘管环境需要 对静脉壁的重塑而没有过多的壁增厚，从而能够抵抗机械强度 血液透析程序每周用大孔针约3次，将AVF墙穿刺。但是， AVF的成熟和通畅率较差，尤其是在女性中，需要其他重新进行程序， 手术，反映了我们对导致成功的静脉重塑生物学的不完善的理解 静脉适应瘘管环境。这种知识差距创造了对小说的未满足的需求 增强静脉重塑的方法，从而增加静脉导管的临床使用。 在资金期间，我们使用创新的小鼠AVF模型来表明TGF-β信号传导 调节静脉自适应重塑以提高AVF通畅； Smad2/3（规范）和 TAK1（非规范）途径调节静脉重塑；和内皮细胞靶向的TGF-β 调节胶原蛋白密度和平滑肌细胞增殖，以提高AVF通畅性。我们在场 令人兴奋的新数据：1）基质蛋白Tenascin-C（TNC）的表达大大增加，并且 与重塑静脉壁共定位； 2）TNC调节AVF通畅性和TGF-β信号传导 静脉重塑； 3）在失败的AVF中，TNC表达不会下调； 4）TNC淘汰小鼠有 AVF壁中免疫细胞的比例改变。此外，我们还将鼠标模型进一步开发到 通过5/6-否则切除术纳入慢性肾脏疾病（CKD），这些AVF忠实地概括了人类 AVF成熟。我们假设调节Tenascin-C活性会改变静脉重塑，从而 改善AVF的成熟和通畅。我们将使用我们的翻译相关体内模型，这是一种创新的 使用纳米颗粒进行局部药物输送的工具，以分析细胞组成的创新方法 AVF墙以及使用转录组学技术的高级下一代分析 可在耶鲁大学获得，以测试我们的创新假设，以以下特定目的： 目标I：确定人体AVF重塑过程中TNC表达的性别差异。 AIM II：确定 TNC功能是否介导使用CKD的小鼠中的静脉重塑。 AIM III：确定是否规定 免疫细胞是TNC介导的静脉重塑的机制。 这项调查的成功结果将通过确定TNC是否会产生持久的影响 介导静脉重塑，从而调节TNC活动是否是临床的宝贵策略 翻译以增强AVF成熟。我们还将确定女性的AVF成熟是否降低是 由于TNC功能以及注射和/或免疫力的性别差异。我们使用创新 策略，新颖的工具和模型，以改变静脉重塑，从而改善AVF成熟。

项目成果

Hypoxia and hypoxia-inducible factors promote the development of neointimal hyperplasia in arteriovenous fistula.

• DOI: 10.1113/jp281218
• 发表时间: 2021-04
• 期刊: The Journal of physiology
• 作者: Sadaghianloo N;Contenti J;Declemy S;Ambrosetti D;Zdralevic M;Tannour-Louet M;Fabbri L;Pagès G;Bost F;Hassen-Khodja R;Pouysségur J;Jean-Baptiste E;Dardik A;Mazure NM
• 通讯作者: Mazure NM

Endothelial Cell TGF-β (Transforming Growth Factor-Beta) Signaling Regulates Venous Adaptive Remodeling to Improve Arteriovenous Fistula Patency.

• DOI: 10.1161/atvbaha.122.317676
• 发表时间: 2022-07
• 期刊: ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
• 影响因子: 8.7
• 作者: Taniguchi, Ryosuke;Ohashi, Yuichi;Lee, Jung Seok;Hu, Haidi;Gonzalez, Luis;Zhang, Weichang;Langford, John;Matsubara, Yutaka;Yatsula, Bogdan;Tellides, George;Fahmy, Tarek M.;Hoshina, Katsuyuki;Dardik, Alan
• 通讯作者: Dardik, Alan

The Society for Vascular Surgery 2023 von Liebig lecture: The joys of being a surgeon-scientist.

• DOI: 10.1016/j.jvssci.2023.100121
• 发表时间: 2023
• 期刊: JVS-vascular science
• 作者: Dardik, Alan

Sex differences in arterial identity correlate with neointimal hyperplasia after balloon injury.

• DOI: 10.1007/s11033-022-07644-2
• 发表时间: 2022-09
• 期刊: MOLECULAR BIOLOGY REPORTS
• 影响因子: 2.8
• 作者: Gao, Mingjie;Gao, Xixiang;Taniguchi, Ryosuke;Brahmandam, Anand;Matsubara, Yutaka;Liu, Jia;Liu, Hao;Zhang, Weichang;Dardik, Alan
• 通讯作者: Dardik, Alan

EphB4 monomer inhibits chronic graft vasculopathy in an aortic transplant model.

• DOI: 10.1016/j.jvssci.2023.100109
• 发表时间: 2023
• 期刊: JVS-vascular science
• 作者: Langford, John T;Gonzalez, Luis;Taniguchi, Ryosuke;Brahmandam, Anand;Zhang, Weichang;Dardik, Alan
• 通讯作者: Dardik, Alan