Inflammation in Vein Graft Disease: A Genetic Approach

静脉移植疾病中的炎症：遗传方法

• 批准号: 7273694
• 负责人: KARSTEN PEPPEL
• 金额: $ 36.74万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7273694
• 关键词: Adenoviruses; American; Apolipoprotein E; Arteries; Atherosclerosis; Attenuated; Blood Circulation; Blood Vessels; Carotid Arteries; Cell Proliferation; Cells; Chimeric Proteins; Cholesterol; Chronic; Clinical; Condition; Coronary Artery Bypass; Coronary Vessels; Coronary artery; Development; Diabetes Mellitus; Disease; Evaluation; Extracellular Domain; Failure; Foam Cells; Genes; Genetic; Hand; Hyperlipidemia; Immunoglobulin G; Implant; In Vitro; Individual; Inferior vena cava structure; Infiltration; Inflammation; Inflammatory; Legal patent; Lesion; Lipids; Medial; Mediator of activation protein; Modeling; Molecular; Mouse Strains; Mus; Nature; Operative Surgical Procedures; Patients; Predisposition; Procedures; Process; Rate; Recombinants; Risk Factors; Role; Rosa; Saphenous Vein; Signal Transduction; Smooth Muscle Myocytes; Stenosis; TNF gene; TNFRSF1A gene; Testing; Therapeutic; Thinking; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Veins; beta-Galactosidase; cigarette smoking; congenic; cytokine; graft failure; human MPP1 protein; in vivo; inhibitor/antagonist; macrophage; migration; neointima formation

DESCRIPTION (provided by applicant): Aortocoronary vein graft atherosclerosis afflicts over two million Americans. While it shares many features with atherosclerosis of native arteries, vein graft atherosclerosis progresses considerably more rapidly. Inasmuch as atherosclerosis is a chronic inflammatory disorder, inflammatory cytokines such as Tumor Necrosis Factor alpha (TNFalpha) might contribute to vascular lesion development. Preliminary studies demonstrate a strong proatherogenic activity of TNF on vascular smooth muscle cells (SMCs) in vitro. Our Central Hypothesis is that TNF contributes substantially to vein graft failure in vivo. While both activated macrophages and SMCs can produce TNF, the contribution of this cytokine to vein graft disease, and the cellular and molecular mechanisms by which TNF may accentuate vein graft atherosclerosis, are incompletely understood. To study these issues, we recently developed a new murine vein graft model that uses congenic inferior vena cavae to carotid artery interposition grafts. As a result, we can manipulate the genetic background of the vein graft wall independently from that of the recipient's circulating cells. Our preliminary studies show a significant reduction (40%) of vein graft neointima formation in grafts that are deficient in TNF receptor 1 signaling (TNFR1-/-), when placed into normolipidemic TNFR1-/- recipients. Our first aim is to determine the role of TNFalpha in vein graft atherosclerosis under normal and hyperlipidemic conditions in vivo. To achieve this aim, we will use wild type (C57Bl/6) or congenic apolipoprotein E deficient (ApoE-/-) mice as pro-atherogenic recipients of congenic vein grafts. The vein grafts will be derived from either wild type or TNF receptor-1-deficient (TNFR1-/-) mice. All of the recipient mice will also express the beta-galactosidase marker gene (from the Rosa 26 mouse strain) to allow for evaluation of vein graft infiltration by recipient-derived cells. Our second aim is to assess the potential for a recombinant TNF Inhibitor to attenuate vein graft neointima formation in mice with normal or elevated lipid levels. This will be achieved by examining vein graft remodeling in wild-type or ApoE-/- mice, that have been infected with a recombinant adenovirus expressing a p55TNFR1-IgG fusion protein that we have created. Defining cellular mechanisms by which TNF promotes vein graft atherosclerosis may have therapeutic implications for the many patients with vein graft disease.

描述(由申请人提供)： 动脉冠状静脉移植动脉粥样硬化困扰着200多万美国人。尽管静脉移植物的动脉粥样硬化与天然动脉的动脉粥样硬化有许多相似之处，但它的进展要快得多。由于动脉粥样硬化是一种慢性炎症性疾病，炎性细胞因子如肿瘤坏死因子α(TNFpha)可能有助于血管病变的发展。初步研究表明，肿瘤坏死因子对体外培养的血管平滑肌细胞具有较强的致动脉粥样硬化作用。我们的中心假设是，在活体内，肿瘤坏死因子在静脉移植失败中起着重要作用。虽然激活的巨噬细胞和SMCs都能产生肿瘤坏死因子，但这种细胞因子在静脉移植物疾病中的作用以及肿瘤坏死因子加重静脉移植物动脉粥样硬化的细胞和分子机制尚不完全清楚。为了研究这些问题，我们最近开发了一种新的小鼠静脉移植模型，该模型使用同种下腔静脉到颈动脉间置移植物。因此，我们可以独立于受体的循环细胞来操纵移植静脉壁的遗传背景。我们的初步研究表明，当移植到正常血脂水平的TNFR1-/-受体时，移植静脉中肿瘤坏死因子受体1信号(TNFR1-/-)缺陷的移植静脉新生内膜形成显著减少(40%)。我们的第一个目标是确定在体内正常和高脂条件下，肿瘤坏死因子α在静脉移植物动脉粥样硬化中的作用。为了达到这一目的，我们将使用野生型(C57BL/6)或同源载脂蛋白E缺陷(ApoE-/-)小鼠作为同种静脉移植物的致动脉粥样硬化受体。静脉移植物将来自野生型或肿瘤坏死因子受体-1缺陷(TNFR1-/-)小鼠。所有受体小鼠也将表达β-半乳糖苷酶标记基因(来自ROSA 26小鼠品系)，以评估受体来源细胞对静脉移植物的渗透。我们的第二个目标是评估重组的肿瘤坏死因子抑制剂对血脂水平正常或升高的小鼠静脉移植物新生内膜形成的抑制作用。这将通过检测野生型或ApoE-/-小鼠的静脉移植重建来实现，这些小鼠已经感染了我们创建的表达p55TNFR1-Ig G融合蛋白的重组腺病毒。明确肿瘤坏死因子促进静脉移植物动脉粥样硬化的细胞机制可能对许多静脉移植物疾病患者具有治疗意义。

项目成果

Expression of tumor necrosis factor receptor-1 in arterial wall cells promotes atherosclerosis.

动脉壁细胞中肿瘤坏死因子受体1的表达促进动脉粥样硬化。

• DOI: 10.1161/atvbaha.0000261548.49790.63
• 发表时间: 2007
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Zhang,Lisheng;Peppel,Karsten;Sivashanmugam,Perumal;Orman,EricS;Brian,Leigh;Exum,SabrinaT;Freedman,NeilJ
• 通讯作者: Freedman,NeilJ

G protein-coupled receptor kinase-5 attenuates atherosclerosis by regulating receptor tyrosine kinases and 7-transmembrane receptors.

• DOI: 10.1161/atvbaha.111.239608
• 发表时间: 2012-02
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Wu JH;Zhang L;Fanaroff AC;Cai X;Sharma KC;Brian L;Exum ST;Shenoy SK;Peppel K;Freedman NJ
• 通讯作者: Freedman NJ

Induction of microRNA-138 by pro-inflammatory cytokines causes endothelial cell dysfunction.

• DOI: 10.1016/j.febslet.2014.01.033
• 发表时间: 2014-03-18
• 期刊: FEBS letters
• 影响因子: 3.5
• 作者: Sen A;Most P;Peppel K
• 通讯作者: Peppel K