Novel Molecular Target to Prevent Maturation Failure of Arteriovenous Fistula

预防动静脉瘘成熟失败的新分子靶点

基本信息

批准号：
10457852
负责人：
Devendra K. Agrawal
金额：
$ 70.5万
依托单位：
WESTERN UNIVERSITY OF HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10457852
关键词：
Accounting Anatomy Angiography Antibodies Apoptosis Arterial Occlusive Diseases Arteriovenous fistula Autologous Biological Blood Blood Vessels Blood flow Calcitriol Caliber Carotid Arteries Cathepsin L Cells Chronic Kidney Failure Collagen Color Data Defect Development Doppler Ultrasound Elastases Elastin Failure Family suidae Femoral vein Fibrosis Fistula Functional disorder Gene Expression Growth Factor HMGB1 gene Hemodialysis Histology Human Hyperplasia IL8 gene Immunology Infiltration Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Kidney Failure Knowledge Lentivirus Vector Leukocytes Link MME gene Matrix Metalloproteinases Measures Mediating Mediator of activation protein Modeling Molecular Biology Molecular Target Morbidity - disease rate Myeloid Cells Myofibroblast Nephrology Nitroglycerin Operative Surgical Procedures Optical Coherence Tomography Outcome Pathology Patients Peptides Phase I Clinical Trials Phenotype Placebos Proteins Research Sirolimus Site Smooth Muscle Myocytes Stenosis TLR4 gene TNF gene Testing Therapeutic Therapeutic Intervention Tumor-infiltrating immune cells Vascular Smooth Muscle Vascular remodeling Veins Venous antagonist base bevacizumab cell motility coronary artery occlusion cytokine design experience experimental group extracellular femoral artery hemodynamics iliac artery improved inhibitor macrophage migration monocyte mortality neutrophil new therapeutic target novel porcine model prevent receptor response vascular smooth muscle cell proliferation

项目摘要

ABSTRACT Autologous arteriovenous fistula (AVF) is the preferred vascular access in hemodialysis. However, high rate of maturation failure due to inadequate blood flow in the outflow vein renders the fistula not useful for hemodialysis. Neointimal hyperplasia and failure of outward remodeling are the major causes of AVF maturation failure which is due to inflammation, proliferation, migration, and phenotypic changes of vascular smooth muscle cells (VSMCs), and extracellular remodeling due to increased matrix metalloproteinases (MMPs). We discovered increased expression of triggering receptor expressed on myeloid cells-1 (TREM-1), TLR4 and related proteins in the immature AV fistula. Based on our novel findings, the central hypothesis is that hemodynamic injury during AVF creation induces inflammation to upregulate TREM-1 and TLR4 to enhance neointimal hyperplasia and vascular remodeling, and antagonizing TREM-1 and TLR4 will enhance AVF maturation. This hypothesis will be tested with the following Aims: Aim 1: Our corollary hypothesis predicts that the administration of TREM-1 and TLR4 antagonists will prevent maturation failure of AVF in swine. We will examine the effect of a potent inhibitory TREM-1 peptide in the AVF model in pigs. Since TREM-1 could synergize with TLR4 to mediate the pathology of AVF maturation failure, effect of a potent TLR4 antagonist will also be examined to prevent maturation failure of AVF. The outcome parameters will include neointimal hyperplasia in the inflow and outflow segments in the AVF, angiography of the AVF, color Doppler ultrasound, optical coherence tomography, and histology, immunostaining to analyze inflammation, expression of various mediators and infiltration of macrophages and neutrophils, VSMC apoptosis, and vascular remodeling. Aim 2: Our corollary hypothesis predicts that the TREM-1 and TLR4 antagonism inhibits inflammation and thus prevents maturation failure of AVF by reducing the development of intimal hyperplasia and vascular remodeling primarily due to inflammatory cells, cathepsin L, IL-8 and MMP-12. These studies will be performed in the blood and isolated VSMCs of femoral artery and femoral vein of the pigs from Aim 1. Mechanistic studies will examine the effect of TREM-1 and TLR4 inhibition in the presence of IL-8 on neutrophils, monocyte-differentiated macrophages and VSMCs, and cathepsin L-mediated elastin and collagen degradation in VSMCs, and the effect of elastin-derived peptides on monocyte differentiation into macrophages and VSMC proliferation and migration. Additional mechanistic studies will include the link between TLR4 and TREM-1 in promoting matrix remodeling, release of inflammatory cytokines from neutrophils and macrophages in the cross- talk inducing phenotype switch in VSMCs and macrophage polarization. The findings from this study will confirm if TREM-1 is a novel target for therapeutic intervention and extend the knowledge to develop better molecules to antagonize TREM-1 and design phase I clinical trials.

抽象的自体动静脉内瘘（AVF）是血液透析的首选血管通路。然而，高比率由于流出静脉血流不足导致成熟失败，使得瘘管无法用于血液透析。新内膜增生和外向重塑失败是 AVF 成熟失败的主要原因是由于血管平滑肌细胞的炎症、增殖、迁移和表型变化所致（VSMC），以及由于基质金属蛋白酶（MMP）增加而导致的细胞外重塑。我们发现骨髓细胞 1 (TREM-1)、TLR4 和相关蛋白上表达的触发受体表达增加在未成熟的动静脉瘘中。根据我们的新发现，中心假设是血流动力学损伤在 AVF 形成期间诱导炎症上调 TREM-1 和 TLR4，以增强新生内膜增生和血管重塑，拮抗 TREM-1 和 TLR4 将促进 AVF 成熟。该假设将通过以下目标进行检验：目标 1：我们的推论假设预测施用 TREM-1 和 TLR4 拮抗剂将防止猪 AVF 成熟失败。我们将检查强效抑制性 TREM-1 肽在猪 AVF 模型中的作用。由于 TREM-1 可以与 TLR4 协同介导 AVF 成熟失败的病理学，有效的 TLR4 拮抗剂的作用将还应进行检查以防止 AVF 成熟失败。结果参数将包括新内膜 AVF 流入和流出段增生、AVF 血管造影、彩色多普勒超声、光学相干断层扫描、组织学、免疫染色分析炎症、各种表达巨噬细胞和中性粒细胞的介质和浸润、VSMC 凋亡和血管重塑。目标 2：我们的推论假设预测 TREM-1 和 TLR4 拮抗作用会抑制炎症，从而通过减少内膜增生和血管的发展来防止 AVF 成熟失败重塑主要由炎症细胞、组织蛋白酶 L、IL-8 和 MMP-12 引起。这些研究将在目标 1 中的猪股动脉和股静脉的血液和分离的 VSMC 中进行。机制研究将检查 IL-8 存在下 TREM-1 和 TLR4 抑制对中性粒细胞的影响，单核细胞分化的巨噬细胞和 VSMC，以及组织蛋白酶 L 介导的弹性蛋白和胶原蛋白降解 VSMC 中的作用，以及弹性蛋白衍生肽对单核细胞分化为巨噬细胞和 VSMC 的影响扩散和迁移。其他机制研究将包括 TLR4 和 TREM-1 之间的联系促进基质重塑，中性粒细胞和巨噬细胞释放炎症细胞因子谈话诱导 VSMC 中的表型转换和巨噬细胞极化。这项研究的结果将证实 TREM-1 是否是治疗干预的新靶点并扩展开发更好的分子来拮抗 TREM-1 和设计 I 期临床试验的知识。

项目成果

期刊论文数量（27）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Implications of Obstructive Sleep-related Breathing Disorder in Dentistry: Focus on Snoring and Obstructive Sleep Apnea.

阻塞性睡眠相关呼吸障碍对牙科的影响：关注打鼾和阻塞性睡眠呼吸暂停。

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Lee; Yeon
通讯作者：
Yeon

CHL1-Deficient and Wild-Type Male Mice do Not Differ in Locomotor Recovery from Spinal Cord Injury.

CHL1 缺陷型和野生型雄性小鼠在脊髓损伤后的运动恢复方面没有差异。

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Theis, Thomas;Ayala, Carlos;Tschang, Monica;Philip, Michele;Nagaraj, Vini;Shrirao, Anil;Voronin, Gregory;Young, Wise;Schachner, Melitta
通讯作者：
Schachner, Melitta

Anatomical Injury Clusters in Polytrauma Patients.

多发伤患者的解剖损伤集群。

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Birri, Tanja;Pape, Hans;Dennler, Cyrill;Simmen, Hans;Vomela, Jindrich;Chaloupka, Richard;Mica, Ladislav
通讯作者：
Mica, Ladislav

Patient-Specific Cardiac Magnetic Resonance Feature Tracking Approach for Scar Detection in Concomitant Ischemic and Non-Ischemic Heart Disease.

用于伴发缺血性和非缺血性心脏病的疤痕检测的患者特异性心脏磁共振特征跟踪方法。