Novel Approach to Stabilize Atherosclerotic Plaque in Carotid Artery

稳定颈动脉粥样硬化斑块的新方法

• 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
• 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; 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

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/脆弱的斑块，其特征是薄帽纤维瘤，由于脂质池引起的坏死核 通过巨噬细胞，可能导致严重的临床状况，包括短暂的缺血性发作，中风，失语症， 和其他运动缺陷。炎症，斑块血管平滑肌细胞的凋亡（VSMC）和 细胞外物质的降解增加是斑块不稳定的主要根本原因。 尽管进行了广泛的研究，但在脆弱斑块的倡议中的原因是未知。基于 在我们的新发现中，我们假设脂多糖（LPS）或最小Oxldl影响 脆弱/不稳定的颈动脉斑块和对抗TREM-1和TLR4稳定动脉粥样硬化 颈动脉中的斑块。这些研究将在动脉粥样硬化的尤卡坦微酮模型中进行 随着颈动脉的阻塞，类似于人类的颈动脉疾病。这个模型将 模仿颈动脉疾病患者的实际情况，因此将直接贡献 了解疾病过程的病理生理学，并使我们能够发展更好的治疗 稳定脆弱斑块的方法。目的1：假设的预测 LPS或最小OXLDL在动脉粥样硬化尤卡坦微酮影响的颈动脉中 颈动脉斑块的组织学，形态学和生化特征如人类不稳定斑块 通过增加TREM-1，MMP-1，MMP-9，TLR4和M1巨噬细胞的表达并减少 胶原蛋白，TREM-2和M2巨噬细胞。我们将通过 灰度和多普勒超声，光学相干断层扫描和组织学，免疫组织化学 和免疫荧光以分析细薄的纤维帽，感染，坏死核，内膜增殖 与泡沫巨噬细胞，VSMC凋亡，脂质核心，坏死，内部出血和血管 重塑。这些发现将在稳定且不稳定的颈动脉斑块中比较体内和体外。 我们还将检查和比较trem-1，trem-2， MMP-1，MMP-9，胶原I（α1），胶原蛋白III（α1），M1-M2巨噬细胞，VSMC，表达和相互作用 除了TREM-1对泡沫细胞形成的影响，炎症的释放外，具有TREM-1的TLR 细胞因子，以及VSMC和巨噬细胞之间的串扰。目标2：假设预测 TREM-1和TLR4拮抗剂的给药将防止发展不稳定的斑块 在动脉粥样硬化游泳的颈动脉中。抑制性trem-1胡椒，lr12的效果 肽（安慰剂）和TLR4拮抗剂TAK-242将在颈动脉中检查 LPS/OXLDL给药。同样，还将检查体内和体外功能/生化参数。 这项研究的发现将确认TREM-1是否是治疗干预和 扩展知识以发展更好的分子以拮抗TREM-1和设计I期临床试验。