Role of macrophages in hemangioendothelioma development

描述（由申请人提供）： 血管瘤是儿童最常见的软组织肿瘤，血管内皮瘤（HE）是其临床亚型。HE染色与巨噬细胞浸润和MCP-1表达有关。在增殖性肿瘤中看到的巨噬细胞，如在HE中看到的巨噬细胞，被称为肿瘤相关巨噬细胞（TAM），其生物学作用尚未确定。假设TAM促进血管生成以支持HE发展。巨噬细胞具有NADPH氧化酶，其产生大量的诱导活性氧（ROS），其现在被认为是关键的信号传导介质。具体而言，ROS已被描述为促进血管生成因子和新血管形成的表达的关键参与者。因此，巨噬细胞源性ROS可能驱动血管内皮瘤的发展。在拟议的研究中，候选人将测试MCP-1招募TAM及其ROS衍生物在促进血管生成和血管内皮瘤（HE）发展中起关键作用的假设。将分别使用HE和培养EOMA细胞的鼠模型进行体内和体外实验。该提议基于一个惊人的发现，即MCP-1和NADPH氧化酶是HE发展的关键因素。这些结果来自于使用适当的敲除动物模型。 为了检验所述假设，将解决以下三个具体目标：目标#1：确定巨噬细胞在HE发展中的意义。目标二：体外表征巨噬细胞来源的ROS是否影响EOMA细胞的血管生成特征行为，以及H2 O2是否是介导ROS作用的主要信号传导分子;以及目标#3：体内测试巨噬细胞来源的ROS对HE发育的意义。 长期目标是在临床相关的血管生成和潜在机制领域发展研究事业。目前的建议包括教学和研究培训的元素，对西班牙裔女性整形外科医生的外科科学家的职业生涯的发展。

DESCRIPTION (provided by applicant): Hemangiomas represent the most common soft tissue tumor in children and hemangioendothelioma (HE) are a clinical subtype. Proliferating HE are associated with macrophage infiltration and MCP-1 expression. Macrophages seen in proliferating neoplasms, such as those seen in HE are referred to as tumor associated macrophages (TAM) and their biological role has not been defined. It is hypothesized that TAM facilitate angiogenesis to support HE development. Macrophages possess NADPH oxidase that generates substantial amounts of inducible reactive oxygen species (ROS), which are now recognized as key signaling mediators. Specifically, ROS have been described to be a key player in facilitating the expression of angiogenic factor and neovascularization as well. Therefore, it is possible that macrophage-derived ROS may drive hemangioendothelioma development. In the proposed study, the candidate will test the hypothesis that MCP-1 recruited TAM and its ROS derivative play a critical role in promoting angiogenesis and hemangioendothelioma (HE) development. In vivo and in vitro experiments will be conducted using a murine model of HE and culture EOMA cells, respectively. The proposal rests on a striking finding that MCP-1 and NADPH oxidase are key contributors to HE development. These results were derived from the use of appropriate knock-out animal models. To test the stated hypothesis, the following three specific aims will be addressed: Aim #1: Determine the significance of macrophages in HE development. Aim #2: Characterize in vitro whether macrophage-derived ROS influences the angiogenic characteristics behavior of EOMA cells and whether H202 is the primary signaling molecule mediating the effect of ROS; and Aim #3: Test in vivo the significance of macrophage-derived ROS on HE development. The long-term goal is to develop a research career in the field of clinically relevant angiogenesis and underlying mechanisms. The current proposal includes didactic and research training elements towards the development of a surgical scientist career of a hispanic woman plastic surgeon.