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日益成为健康问题，可能导致血流受损和组织缺血，尽管新生血管形成和侧支血管生长有助于恢复血流并保护组织，从而改善预后。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。晚期糖基化终末产物 (RAGE) 受体是与侧枝生长负面影响相关并可能加剧炎症信号负面影响的因素之一。然而，其细胞来源及其在缺血区域的调节机制尚不完全清楚。初步数据显示，在缺血模型中，过氧化氢 (H2O2) 介导的 RAGE 表达增加，并且 RAGE 在非糖尿病状态下对侧支循环形成具有负面影响。我们假设卫星细胞是缺血中 RAGE 的主要来源，并且 RAGE 表达是 H2O2 介导的。为了检验这一假设，我们计划使用体内和体外模型。目标 1 将使用小鼠后肢缺血 (HLI) 模型来确认增加的 RAGE 表达是否会响应 H2O2 上调，并确认卫星细胞响应 H2O2 表达 RAGE。该目标还将研究 H2O2 介导 RAGE 表达的机制。在目标 2 中，我们将研究介导野生型和 RAGE 敲除卫星细胞中附带生长的几种因子产生的差异。还将研究不同细胞类型对细胞迁移和增殖的影响。最后，在目标 3 中，我们将使用卫星细胞特异性过度表达过氧化氢酶（一种 H2O2 清道夫，TgCat-pax7）的转基因小鼠来研究 H2O2 介导的 RAGE 表达在卫星细胞中的具体作用。这些研究将增进对 RAGE 作用及其调节的理解。了解非糖尿病缺血中 RAGE 表达的调节方式以及缺血环境中 RAGE 的细胞来源至关重要，因为操纵其调节有助于改善侧支循环形成，改善缺血性疾病患者的血流和临床结果。