The Role of Hydrogen Peroxide in RAGE Expression in Collateral Vessel Formation

过氧化氢在侧枝血管形成中 RAGE 表达中的作用

• 批准号: 8908489
• 负责人: Laura Marie Hansen
• 金额: $ 5.42万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-02 至 2018-04-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8908489
• 关键词: Advanced Glycosylation End Products; Arteries; Blood Vessels; Blood flow; CCL2 gene; Cell Culture Techniques; Cell Extracts; Cell Proliferation; Cell Separation; Cells; Clinical; Coculture Techniques; Complex; Coronary Arteriosclerosis; Coronary artery; Cytokine Signaling; Data; Development; Disease; Endothelial Cells; Equilibrium; Future; Generations; Goals; Growth; Health; Hydrogen Peroxide; Hypoxia; Image; Immunohistochemistry; In Situ Hybridization; Inflammation; Inflammatory; Inflammatory Response; Ischemia; Knock-out; Lasers; Lead; Leg; Ligands; Limb structure; Measures; Mediating; Modeling; Mus; Outcome; Oxides; Patients; Perfusion; Peripheral; Peripheral Vascular Diseases; Peripheral arterial disease; Physiology; Procedures; Process; Production; Recovery of Function; Regulation; Reperfusion Therapy; Role; Running; Signal Transduction; Signaling Molecule; Smooth Muscle Myocytes; Source; Stimulus; Testing; Therapeutic; Tissues; Transgenic Mice; United States; Vascular Endothelial Growth Factors; angiogenesis; artery occlusion; catalase; cell motility; cell type; density; diabetic; effective therapy; improved; in vitro Model; in vivo; magnetic beads; microCT; neovascularization; non-diabetic; osteopontin; overexpression; public health relevance; receptor; receptor for advanced glycation endproducts; response; satellite cell; scavenger receptor; vasculogenesis

 DESCRIPTION (provided by applicant): Both coronary artery and peripheral vascular disease are growing health concerns that can lead to impaired blood flow and tissue ischemia, though neovascularization and growth of collateral vessels can help to restore blood flow and preserve the tissue improving outcomes. Collateral formation includes both angiogenesis and arteriogenesis and is a complex process with many coordinating parts including inflammatory signaling and cell proliferation and migration. The balance of these inflammatory responses is important since too little or too much can impair vessel growth. One factor that has been associated with negative effects on collateral growth and may exacerbate the negative effects of inflammatory signals is the receptor for advanced glycation end products (RAGE); however, the cellular source and the mechanism of its regulation in ischemic regions is not fully understood. The preliminary data show increases in RAGE expression mediated by hydrogen peroxide (H2O2) in an ischemia model and that RAGE has a negative effect on collateral formation in a non-diabetic state. We hypothesized that satellite cells are a major source of RAGE in ischemia and that RAGE expression is H2O2-mediated. To test this hypothesis we plan to use both in vivo and in vitro models. Aim 1 will use a mouse hind limb ischemia (HLI) model to confirm if increased RAGE expression is upregulated in response to H2O2 and confirm that satellite cells express RAGE in response to H2O2. This aim will also investigate the mechanisms by which H2O2 mediates RAGE expression. In Aim 2, we will investigate differences in the production of several factors that mediate collateral growth in wildtype and RAGE knockout satellite cells. The effects of the different cell types on cell migration and proliferation will be studied as well. Fially in Aim 3, we will study the specific role of H2O2-mediated RAGE expression in the satellite cells using a transgenic mouse with satellite cell specific overexpression of catalase a H2O2 scavenger (TgCat-pax7). These studies will advance the understanding of the role of RAGE and its regulation. It is critical to understand how RAGE expression is regulated in non-diabetic ischemia and what the cellular sources of RAGE are in the ischemic setting because manipulating its regulation could help improve collateral formation and improve blood flow and clinical outcomes for patients with ischemic disease.

 描述（由申请人提供）：冠状动脉和外周血管疾病都是日益严重的健康问题，可导致血流受损和组织缺血，尽管新血管形成和侧支血管生长有助于恢复血流和保护组织，改善结局。侧支形成包括血管生成和动脉生成，是一个复杂的过程，有许多协调部分，包括炎症信号传导和细胞增殖和迁移。这些炎症反应的平衡很重要，因为太少或太多都会损害血管生长。与侧支生长的负面影响相关并可能加剧炎症信号负面影响的一个因素是晚期糖基化终末产物（AGEs）的受体;然而，缺血区域的细胞来源及其调节机制尚未完全了解。初步数据显示，在缺血模型中，过氧化氢（H2 O2）介导的H2O表达增加，并且H2O对非糖尿病状态下的侧支形成具有负面影响。我们假设卫星细胞是缺血性脑卒中的一个主要来源，并且脑卒中的表达是H2 O2介导的。为了验证这一假设，我们计划使用体内和体外模型。目的1将使用小鼠后肢缺血（HLI）模型来确认增加的H2 O2表达是否响应于H2 O2而上调，并确认卫星细胞响应于H2 O2而表达H2 O2。这一目标也将调查的机制，其中H2 O2介导的表达。在目标2中，我们将研究在野生型和β-敲除卫星细胞中介导侧枝生长的几种因子的产生差异。还将研究不同细胞类型对细胞迁移和增殖的影响。在目的3中，我们将使用具有卫星细胞特异性过表达过氧化氢酶（H2 O2清除剂）（TgCat-pax 7）的转基因小鼠来研究H2 O2介导的H2 O2在卫星细胞中表达的特异性作用。这些研究将促进对β-淀粉样蛋白的作用及其调节的理解。了解在非糖尿病性缺血中如何调节β-淀粉样蛋白表达以及在缺血环境中β-淀粉样蛋白的细胞来源是至关重要的，因为操纵其调节可以帮助改善侧支形成，改善缺血性疾病患者的血流和临床结局。