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)是临床亚型。增殖性HE与巨噬细胞浸润和MCP-1表达密切相关。在增生性肿瘤中见到的巨噬细胞，如在HE中见到的巨噬细胞，被称为肿瘤相关巨噬细胞()，其生物学作用尚未确定。推测通过促进血管生成来支持HE的发生发展。巨噬细胞具有NADPH氧化酶，可产生大量的可诱导的活性氧物种(ROS)，现在被认为是关键的信号媒介。具体地说，ROS被认为是促进血管生成因子表达和新生血管形成的关键因素。因此，巨噬细胞来源的ROS可能推动血管内皮瘤的发展。在拟议的研究中，候选人将检验这样一种假设，即招募的单核细胞趋化蛋白-1及其ROS衍生物在促进血管生成和血管内皮瘤(HE)发展方面发挥关键作用。体内和体外实验将分别使用HE小鼠模型和培养的EOMA细胞。这一建议基于一项惊人的发现，即MCP-1和NADPH氧化酶是HE发生的关键贡献者。这些结果是通过使用适当的基因敲除动物模型得出的。 为了验证所陈述的假设，将解决以下三个具体目标：目标1：确定巨噬细胞在HE发育中的重要性。目的#2：体外研究巨噬细胞来源的ROS是否影响EOMA细胞的血管生成特性，以及H202是否是介导ROS作用的主要信号分子；目的#3：在体内检测巨噬细胞来源的ROS在HE发生中的意义。 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。目前的提案包括教学和研究培训内容，以发展西班牙裔女性整形外科医生的外科科学家职业生涯。

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.