MONOCYTE RECRUITMENT: A STRATEGIC TARGET IN ANGIOGENESIS

单核细胞募集：血管生成的战略目标

• 批准号: 6527673
• 负责人: NICANOR I. MOLDOVAN
• 金额: $ 29.5万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6527673
• 关键词: angiogenesis; genetically modified animals; laboratory mouse; macrophage; membrane channels; monocyte

(Applicant's Description) Therapeutic angiogenesis attempts to change the course of diseases by altering the microvascular blood supply to the organs, either by reducing it in tumors. or increasing it in ischemic tissues. A new arsenal of methods is being developed including gene therapy for localized administration of angiogenic factors, efficient monoclonal antibodies against adhesion molecules; or cloned peptides mimicking the natural angiostatic mechanisms. However, the basic mechanisms governing the efficiency of these approaches are poorly understood. Here we suggest that a potent system for controlling angiogenesis is the monocyte/macrophage activity, which is essential for the progression of angiogenesis and tissue remodeling. We discovered that, when present in ischemic tissues, these cells produce long-lasting channels in the tissues they infiltrate. Our hypothesis is that these channels represent a prerequisite for angiogenesis in vivo, therefore are an ideal therapeutic target. In order to prove this new concept, and to bring it to practical applicability, the following specific aims will be pursued: 1) Model in vitro the formation of channels by monocytes/macrophages, and find the molecular factors on which this process depends. 2) Determine the influence that specific physiologic and pathologic conditions, thought to be associated with angiogenesis, have on the formation of channels by monocytes/macrophages in vitro. 3) Test the role the channel formation has in progression of angiogenesis in vitro. 4) reproduce in vivo and analyze the formation of channels in matrices of controlled composition. 5) test the possibility for therapeutic manipulation of angiogenesis in selected transgenic animals, by either using inhibitors of channel formation, or modifying tissue concentrations and/or distribution of monocytes (changing the distribution of chemotactic factors, or injecting concentrates of monocytes). To this end, we developed assays which will be used in vitro and in vivo for: a) characterization of molecular mechanisms of channel formation; b) the impact of channels system on angiogenesis; c) identification of compounds targeting the monocytes and macrophages, likely to influence the course of angiogenesis. The new approach for management of angiogenesis we suggest here, complements the current efforts in the field, bringing a broader understanding of basic mechanisms of angiogenesis and expending the spectrum of available therapeutic options.

（申请人的描述） 治疗性血管生成试图通过改变 通过减少肿瘤中的微血管血液供应来减少器官的微血管血液供应。 或在缺血组织中增加它。一个新的方法库正在被开发 开发了包括用于局部施用血管生成的基因疗法 因素，针对粘附分子的高效单克隆抗体；或克隆 模拟天然血管抑制机制的肽。然而，基本的 人们对控制这些方法的效率的机制知之甚少。 在这里，我们建议控制血管生成的有效系统是 单核细胞/巨噬细胞活性，这对于疾病进展至关重要 血管生成和组织重塑。我们发现，当存在于 缺血组织中，这些细胞在组织中产生持久的通道 他们渗透。我们的假设是这些渠道代表 体内血管生成的先决条件，因此是理想的治疗方法 目标。为了证明这个新概念，并将其付诸实践 适用性，将追求以下具体目标：1）体外模型 单核细胞/巨噬细胞通道的形成，并找到分子 该过程所依赖的因素。 2) 确定影响 特定的生理和病理条件，被认为与 血管生成，对单核细胞/巨噬细胞通道的形成有影响 体外。 3) 测试通道形成在进展中的作用 体外血管生成。 4）体内再现并分析形成 受控成分矩阵中的通道。 5）测试可能性 在选定的转基因动物中进行血管生成的治疗操作，通过 使用通道形成抑制剂或改变组织 单核细胞的浓度和/或分布（改变单核细胞的分布 趋化因子，或注射单核细胞浓缩物）。为此，我们 开发的检测方法将用于体外和体内：a) 通道形成的分子机制的表征； b) 影响 血管生成的通道系统； c) 鉴定目标化合物 单核细胞和巨噬细胞，可能影响血管生成的过程。 我们在此建议的血管生成管理新方法是对 当前该领域的努力，使人们对基本知识有了更广泛的了解 血管生成机制并扩大可用治疗范围 选项。