Novel Approach to Stabilize Atherosclerotic Plaque in Carotid Artery

稳定颈动脉粥样硬化斑块的新方法

基本信息

批准号：
9920604
负责人：
Devendra K. Agrawal
金额：
$ 69.02万
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：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9920604
关键词：
Anatomy Angioplasty Aphasia Apoptosis Apoptotic Arterial Fatty Streak Arterial Occlusive Diseases Arteries Attenuated Biochemical Biological Brain Carotid Arteries Carotid Artery Diseases Carotid Artery Plaques Carotid Artery Ulcerating Plaque Carotid Endarterectomy Carotid Stenosis Cell Nucleus Cells Cellular biology Cholesterol Clinical Collagen Data Defect Development Diet Disease Doppler Ultrasound Extracellular Matrix Degradation Family suidae Foam Cells Foamy Macrophage Functional disorder Gelatinase B Gene Expression Hemorrhage Histologic Histology Human Immune response Immunofluorescence Immunologic Immunohistochemistry Immunology In Vitro Inflammation Inflammatory Interstitial Collagenase Knowledge Lentivirus Vector Link Lipids Lipopolysaccharides Matrix Metalloproteinases Measures Mediating Messenger RNA Modeling Molecular Biology Morbidity - disease rate Morphology Motor Myeloid Cells Neck Necrosis Operative Surgical Procedures Optical Coherence Tomography Pathology Patients Peptide Hydrolases Peptides Phase I Clinical Trials Placebos Process Research Role Rupture Smooth Muscle Myocytes Stroke Symptoms TLR4 gene TNF gene Testing Therapeutic Therapeutic Intervention Thinness Thrombosis Tissues Transcript Transient Ischemic Attack Tumor-infiltrating immune cells Ulcer Vascular Smooth Muscle Vascular remodeling arterial remodeling base calcification cholesterol control coronary artery occlusion cytokine design experience experimental group iliac artery in vivo inhibitor/antagonist mRNA Expression macrophage monocyte mortality neovascularization new therapeutic target novel novel strategies oxidized low density lipoprotein prevent protein expression receptor response

项目摘要

ABSTRACT Unstable/vulnerable plaques, that are characterized by a thin cap fibroatheroma, necrotic core due to lipid pools by macrophages, may result in serious clinical conditions, including transient ischemic attack, stroke, aphasia, and other motor defects. Inflammation, apoptosis of plaque vascular smooth muscle cells (VSMCs) and increased degradation of extracellular matrices are the primary underlying cause of plaque instability. Despite extensive research, the causative factor(s) in the initiation of vulnerable plaque is unknown. Based on our novel findings, we hypothesize that lipopolysaccharide (LPS) or minimally oxLDL induce vulnerable/unstable carotid plaque and antagonizing TREM-1 and TLR4 stabilizes atherosclerotic plaque in carotid arteries. These studies will be performed in atherosclerotic Yucatan microswine model with occlusion of carotid arteries that resemble to occlusive carotid artery disease in human. This model will mimic the real situation in patients with carotid artery disease, and thus, will make a direct contribution to understanding the pathophysiology of the disease process and allow us to develop better therapeutic approaches to stabilize vulnerable plaques. Aim 1: The hypothesis predicts that the administration of LPS or minimally oxLDL in the carotid artery of atherosclerotic Yucatan microswine induces histological, morphological and biochemical features of carotid plaque like human unstable plaque by increasing the expression of TREM-1, MMP-1, MMP-9, TLR4 and M1 macrophages and decreasing collagen, TREM-2, and M2 macrophages. We will probe the effect of LPS-induced plaque instability by gray scale and Doppler ultrasound, Optical coherence tomography and the histology, immunohistochemistry and immunofluorescence to analyze thinned fibrous cap, inflammation, necrotic core, intimal proliferation with foamy macrophages, VSMCs apoptosis, lipid core, necrosis, intraplaque hemorrhage, and vascular remodeling. These findings will be compared in-vivo and in-vitro in the stable and unstable carotid plaques. We will also examine and compare the mRNA transcripts and protein expression of TREM-1, TREM-2, MMP-1, MMP-9, collagen I(α1), collagen III(α1), M1-M2 macrophages, VSMCs, expression and interaction of TLRs with TREM-1, in addition to the effect of TREM-1 on foam cell formation, release of inflammatory cytokines, and in the cross-talk between VSMCs and macrophages. Aim 2: The hypothesis predicts that the administration of TREM-1 and TLR4 antagonists will prevent the development of unstable plaque in the carotid artery of atherosclerotic swine. Effect of an inhibitory TREM-1 peptide, LR12, a scrambled peptide (placebo), and TAK-242, a TLR4 antagonist, will be examined in carotid arteries following LPS/oxLDL administration. Also, in-vivo and in-vitro functional/biochemical parameters will be examined. 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.

抽象的不稳定/脆弱斑块，其特征是薄帽纤维粥样斑块、脂质池导致的坏死核心巨噬细胞可能导致严重的临床症状，包括短暂性脑缺血发作、中风、失语症、和其他运动缺陷。斑块血管平滑肌细胞（VSMC）的凋亡和细胞外基质降解的增加是斑块不稳定的主要原因。尽管进行了广泛的研究，但易损斑块形成的致病因素尚不清楚。根据我们的新发现，我们追求脂多糖 (LPS) 或最低限度的 oxLDL 诱导脆弱/不稳定的颈动脉斑块和拮抗 TREM-1 和 TLR4 可稳定动脉粥样硬化这些研究将在动脉粥样硬化尤卡坦微型猪模型中进行。该模型具有类似于人类颈动脉闭塞性疾病的颈动脉闭塞。模仿颈动脉疾病患者的真实情况，因此将直接做出贡献了解疾病过程的病理生理学，使我们能够开发更好的治疗方法目标 1：该假设预测施用 LPS 或微量 oxLDL 在动脉粥样硬化尤卡坦微型猪的颈动脉中诱导颈动脉斑块的组织学、形态学和生化特征，类似于人类不稳定斑块通过增加 TREM-1、MMP-1、MMP-9、TLR4 和 M1 巨噬细胞的表达并减少我们将探讨 LPS 诱导的斑块不稳定性的影响。灰阶和多普勒超声、光学相干断层扫描和组织学、免疫组织化学和免疫荧光分析变薄的纤维帽、炎症、坏死核心、内膜增殖泡沫状巨噬细胞、VSMC 凋亡、脂质核心、坏死、斑块内出血和血管这些发现将在稳定和不稳定颈动脉斑块的体内和体外进行比较。我们还将检查和比较 TREM-1、TREM-2、 MMP-1、MMP-9、胶原蛋白 I(α1)、胶原蛋白 III(α1)、M1-M2 巨噬细胞、VSMC、表达和相互作用 TREM-1 与 TLR 的相互作用，除了 TREM-1 对泡沫细胞形成、炎症释放的影响之外目标 2：假设预测： TREM-1 和 TLR4 拮抗剂的施用将防止不稳定斑块的发展抑制性 TREM-1 肽 LR12（一种乱序）对动脉粥样硬化猪的颈动脉的影响。肽（安慰剂）和 TAK-242（一种 TLR4 拮抗剂）将在颈动脉中进行检查此外，还将检查体内和体外功能/生化参数。这项研究的结果将证实 TREM-1 是否是治疗干预的新靶标扩展知识以开发更好的分子来拮抗 TREM-1 并设计 I 期临床试验。