MONOCYTE RECRUITMENT: A STRATEGIC TARGET IN ANGIOGENESIS

（申请人的描述） 治疗性血管生成试图通过改变血管生成因子来改变疾病的进程。 器官的微血管血液供应，或者通过减少肿瘤中的微血管血液供应。 或在缺血组织中增加它。一种新的方法正在被 包括用于局部施用血管生成药物的基因疗法 因子，针对粘附分子的有效单克隆抗体;或克隆 模拟天然血管抑制机制的肽。但其基本 人们对这些方法的效率机制知之甚少。 在这里，我们认为，一个有效的系统，控制血管生成是 单核细胞/巨噬细胞活性，这是必不可少的进展， 血管生成和组织重塑。我们发现，当存在于 这些细胞在组织中产生持久的通道 他们渗透。我们的假设是这些通道代表了 是体内血管生成的先决条件，因此是一种理想的治疗方法， 目标为了验证这一新概念，并将其应用于实际， 本研究的具体目标如下：1）体外模型 单核细胞/巨噬细胞通道的形成，并找到分子 这一过程所依赖的因素。2)确定影响， 特定的生理和病理状况，被认为与 血管生成，对单核细胞/巨噬细胞形成通道， 体外3)测试通道形成在以下过程中的作用： 体外血管生成。4)在体内繁殖并分析 控制成分的矩阵中的通道。5)测试…的可能性 在选择的转基因动物中治疗性地操纵血管生成， 或者使用通道形成的抑制剂， 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 开发了将在体外和体内用于以下的测定：a） 通道形成的分子机制的表征; B）影响 c）鉴定靶向血管生成的化合物 单核细胞和巨噬细胞，可能影响血管生成的过程。 我们在这里建议的新的血管生成管理方法， 目前在这一领域的努力，使人们更广泛地了解 血管生成的机制和扩大可用的治疗谱 选项.

(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.