APOPTOSIS OF SMOOTH MUSCLE CELLS IN CAROTID PLAQUES

颈动脉斑块中平滑肌细胞的凋亡

• 批准号: 8391243
• 负责人: Devendra K. Agrawal
• 金额: $ 30.64万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-08 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391243
• 关键词: Abbreviations; Address; Affinity; Aphasia; Apoptosis; Arterial Fatty Streak; Arteries; Attenuated; Blood; Blood Vessels; Boxing; CCR; CCR5 gene; CD11 Antigens; CD40 Antigens; CD80 gene; Carotid Arteries; Carotid Artery Plaques; Carotid Endarterectomy; Carotid Stenosis; Cell surface; Cells; Cessation of life; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Defect; Dendritic Cells; Disease; Fibroblast Growth Factor 2; Funding; Goals; Human; IL2RA gene; IL3RA gene; Immune response; In Vitro; Inflammation; Inflammatory; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Insulin-Like Growth-Factor-Binding Proteins; Interferon Type II; Interleukin-10; Interleukin-12; Investigation; Ligands; Low-Density Lipoproteins; Mediating; Messenger RNA; Molecular; Motor; Myelogenous; Neck; Neurologic; Norepinephrine; Operative Surgical Procedures; Patients; Phenotype; Process; Production; Proteins; Regulatory T-Lymphocyte; Role; Rupture; Small Interfering RNA; Smooth Muscle Myocytes; Stroke; Stroke prevention; Symptoms; T-Lymphocyte; TNF gene; TNFRSF11B gene; Therapeutic; Time; Tissues; Transcript; Transient Ischemic Attack; Wing; cell mediated immune response; chemokine; chemokine receptor; cytokine; density; fascin; follow-up; immunoreactivity; inhibitor/antagonist; insight; mRNA Expression; macrophage; nervous system disorder; neuropeptide Y; neuropeptide Y-Y1 receptor; neuropeptide Y2 receptor; novel; oxidized low density lipoprotein; prevent; programs; public health relevance; receptor; receptor expression; research study; response; vascular smooth muscle cell migration; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): Rupture of atherosclerotic plaques in the carotid artery results in neurological problems. Inflammatory cytokines in the plaque induce apoptosis of vascular smooth muscle cells (VSMCs), thus thinning the fibrous cap and resulting in plaque destabilization and rupture. During the initial funding cycle, we made novel observations that IGF-1 is more potent in inducing the survival of VSMCs in carotid endarterectomy tissues of asymptomatic than symptomatic patients. Also, atheroma-associated cytokines decrease IGF-1-induced survival and proliferation of VSMCs. In our follow-up studies we observed specific differences in the profile of dendritic cells (DCs), T-regulatory cells, and NPY and NPY receptors in symptomatic (unstable) and asymptomatic (stable) plaques. Also, stronger immunoreactivity of Foxp3, IL-10 and CD25 with preponderance of CD4? T cells in carotid plaques of asymptomatic than symptomatic patients. IGF-1 increased mRNA transcripts of NPY-Y2 and NPY-Y5 receptors in asymptomatic but not in symptomatic plaque SMCs. These novel findings suggest a cell-mediated immune response in carotid plaques which is regulated by NPY. Our central hypothesis is that the inflammation in the carotid plaque is modulated by interaction of NPY with DCs and T cells leading to increased inflammation and apoptosis of VSMCs in carotid plaques of symptomatic patients with carotid stenosis, and that atheroma-associated cytokines modulate NPY receptors and their function in VSMCs of carotid plaques. In Aim 1, we will examine the phenotypes of dendritic cells and the effect of NPY, in the presence and absence of IGF-1, on the cell surface expression of co-stimulatory molecules in DCs in the carotid plaques of symptomatic and asymptomatic patients with carotid stenosis. In Aim 2, we will examine the phenotype of T-regulatory cells (inducible CD4? T-regs and naturally-occurring CD4???? T-regs) and the effect of NPY, in the presence and absence of IGF-1, on the cell surface expression of the receptors for co-stimulatory molecules (PD-1, CTLA- 4) in T-regs from the carotid plaques of symptomatic and asymptomatic patients with carotid stenosis. We will also determine the effect of NPY, in the presence and absence of atheroma-associated cytokines, on the differentiation of naive T cells into T-regulatory cells. In Aim 3, we will examine the effect of NPY, in the presence and absence of inflammatory cytokines, on the survival and apoptosis of VSMCs isolated from the carotid plaques of symptomatic and asymptomatic patients with carotid stenosis. The long-term goal of this study is to determine the cellular and molecular mechanisms responsible for the instability and rupture of carotid plaques in patients with carotid stenosis. Such investigations would provide unique insights to the pathophysiologic process of neurological diseases associated with the rupture of atherosclerotic plaques and the means to prevent the disease in patients with carotid stenosis.

描述（由申请人提供）：颈动脉动脉粥样硬化斑块破裂会导致神经系统问题。斑块中的炎性细胞因子会诱导血管平滑肌细胞（VSMC）的凋亡，从而使纤维帽变薄并导致牙菌斑破坏和破裂。在最初的资金周期中，我们对IGF-1的诱导症患者比有症状的患者更有效地观察到，IGF-1在诱导无症状的颈动脉内膜切除术组织中更有效。此外，动脉瘤相关的细胞因子降低了IGF-1诱导的VSMC的生存和增殖。在我们的后续研究中，我们观察到在有症状（不稳定）和无症状（稳定）斑块中树突状细胞（DC），T调节细胞以及NPY和NPY受体的特定差异。另外，具有CD4优势的FOXP3，IL-10和CD25的更强免疫反应性？与有症状的患者相比，无症状的颈动脉斑块中的T细胞。 IGF-1增加了无症状的NPY-Y2和NPY-Y5受体的mRNA转录本，但在有症状的斑块中没有。这些新的发现表明细胞介导的颈动脉斑块中的免疫反应受N​​PY调节。 Our central hypothesis is that the inflammation in the carotid plaque is modulated by interaction of NPY with DCs and T cells leading to increased inflammation and apoptosis of VSMCs in carotid plaques of symptomatic patients with carotid stenosis, and that atheroma-associated cytokines modulate NPY receptors and their function in VSMCs of carotid plaques.在AIM 1中，我们将检查树突状细胞的表型以及在存在和不存在IGF-1的情况下，NPY对颈动体患者的颈动脉斑块中DC中共刺激分子的细胞表面表达的影响。 In Aim 2, we will examine the phenotype of T-regulatory cells (inducible CD4? T-regs and naturally-occurring CD4???? T-regs) and the effect of NPY, in the presence and absence of IGF-1, on the cell surface expression of the receptors for co-stimulatory molecules (PD-1, CTLA- 4) in T-regs from the carotid plaques of symptomatic and无症状的颈动脉狭窄患者。在存在和不存在与动脉瘤相关的细胞因子的情况下，我们还将确定NPY对幼稚T细胞分化为T调节细胞的影响。在AIM 3中，我们将在存在和不存在炎症细胞因子的情况下检查NPY的影响，对从颈动脉狭窄的有症状和无症状患者的颈动脉斑块中分离出的VSMC的生存和凋亡。这项研究的长期目标是确定导致颈动脉狭窄患者颈动脉斑块不稳定和破裂的细胞和分子机制。这样的研究将为与动脉粥样硬化斑块破裂相关的神经系统疾病的病理生理过程提供独特的见解，并为颈动脉狭窄患者预防这种疾病的手段。

项目成果

Triggering Receptor Expressed on Myeloid Cells in Cutaneous Melanoma.

• DOI: 10.1111/cts.12308
• 发表时间: 2015-10
• 期刊: Clinical and translational science
• 作者: Nguyen AH;Koenck C;Quirk SK;Lim VM;Mitkov MV;Trowbridge RM;Hunter WJ 3rd;Agrawal DK
• 通讯作者: Agrawal DK

Immunomodulation in asthma: a distant dream or a close reality?

• DOI: 10.1016/j.intimp.2004.02.001
• 发表时间: 2004-04-01
• 期刊: INTERNATIONAL IMMUNOPHARMACOLOGY
• 影响因子: 5.6
• 作者: Bharadwaj, A;Agrawal, DK
• 通讯作者: Agrawal, DK

Data on TREM-1 activation destabilizing carotid plaques.

TREM-1 激活使颈动脉斑块不稳定的数据。

• DOI: 10.1016/j.dib.2016.05.047
• 发表时间: 2016
• 期刊: Data in brief
• 影响因子: 1.2
• 作者: Rao,VelidiH;Rai,Vikrant;Stoupa,Samantha;Subramanian,Saravanan;Agrawal,DevendraK
• 通讯作者: Agrawal,DevendraK

Treatment with Flt3 ligand plasmid reverses allergic airway inflammation in ovalbumin-sensitized and -challenged mice.

Flt3配体质粒治疗可逆转卵清蛋白致敏和攻击小鼠的过敏性气道炎症。

• DOI: 10.1016/j.intimp.2004.10.002
• 发表时间: 2005
• 期刊: International immunopharmacology.
• 作者: Edwan,JehadH;Talmadge,JamesE;Agrawal,DevendraK
• 通讯作者: Agrawal,DevendraK

NPY and NPY receptors in airway structural and inflammatory cells in allergic asthma.

过敏性哮喘气道结构和炎症细胞中的 NPY 和 NPY 受体。

• DOI: 10.1016/j.yexmp.2012.05.009
• 发表时间: 2013
• 期刊: Experimental and molecular pathology
• 影响因子: 3.6
• 作者: Makinde,ToluwalopeO;Steininger,Robert;Agrawal,DevendraK
• 通讯作者: Agrawal,DevendraK