MONOCYTE RECRUITMENT: A STRATEGIC TARGET IN ANGIOGENESIS

(申请人描述) 治疗性血管生成试图通过改变 器官的微血管供血，或者通过减少肿瘤中的微血管供血。 或者在缺血组织中增加它。一个新的方法武器库正在进行 开发包括基因治疗的局部给药血管生成 因子，高效抗黏附分子的单抗；或克隆 模拟天然血管抑制机制的多肽。然而，基本的 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控制血管生成的系统是 单核/巨噬细胞活性，这是发展过程中必不可少的 血管生成和组织重塑。我们发现，当存在于 缺血组织，这些细胞在组织中产生持续时间长的通道 他们渗透进来。我们的假设是，这些渠道代表着 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。为了证明这一新概念，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/巨噬细胞的通道形成，并寻找分子 这一过程所依赖的因素。2)确定 特殊的生理和病理条件，被认为与 血管生成对单核/巨噬细胞通道形成的影响 体外培养。3)测试渠道形成在疾病进展中的作用 体外血管生成。4)体内繁殖并分析其形成 受控合成矩阵中的通道。5)测试以下项目的可能性 在选定的转基因动物中进行血管生成的治疗性操作 要么使用通道形成的抑制剂，要么修改组织 单核细胞的浓度和/或分布(改变 趋化因子，或单核细胞注射浓缩物)。为此，我们 已开发的检测方法将在体外和体内用于：a) 渠道形成的分子机制的表征；b)影响 关于血管生成的通道系统；c)靶向化合物的鉴定 单核细胞和巨噬细胞，可能影响血管生成的进程。 我们在这里建议的管理血管生成的新方法是补充 目前在该领域的努力，带来了对基本情况的更广泛的理解 血管生成的机制及有效治疗方法的拓展 选择。

(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.