Role of macrophages in hemangioendothelioma development

巨噬细胞在血管内皮瘤发展中的作用

• 批准号: 6777280
• 负责人: Gayle M Gordillo
• 金额: $ 12.52万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6777280
• 关键词: NAD(H) phosphate; angiogenesis; biological signal transduction; cell line; free radical oxygen; genetically modified animals; hemangioma; hydrogen peroxide; laboratory mouse; macrophage; microarray technology; monocyte chemoattractant protein 1; neoplasm /cancer genetics; neoplastic growth; preneoplastic state

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.

描述（由申请人提供）： 血管瘤是儿童中最常见的软组织肿瘤，而血管内皮瘤（HE）是临床亚型。增殖他与巨噬细胞浸润和MCP-1表达有关。在增殖的肿瘤中看到的巨噬细胞，例如在他中看到的巨噬细胞被称为肿瘤相关的巨噬细胞（TAM）及其生物学作用尚未定义。假设TAM促进了血管生成以支持他发育。巨噬细胞具有NADPH氧化酶，该氧化酶产生大量可诱导的活性氧（ROS），现在被认为是关键信号介体。具体而言，ROS被描述为促进血管生成因子和新血管形成的表达方面的关键参与者。因此，巨噬细胞衍生的ROS可能会促进血管内皮瘤的发育。在拟议的研究中，候选人将检验以下假设：MCP-1募集TAM及其ROS衍生物在促进血管生成和血管内皮瘤（HE）发育中起关键作用。体内和体外实验将分别使用He和培养的Eoma细胞的鼠模型进行。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。这些结果来自使用适当的敲除动物模型。 为了检验既定假设，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。 AIM＃2：在体外表征巨噬细胞衍生的ROS是否影响Eoma细胞的血管生成特征行为以及H202是否是介导ROS效应的主要信号分子； AIM＃3：在体内测试巨噬细胞衍生的ROS对HE发育的重要性。 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职业。当前的建议包括教学培训元素，以发展西班牙裔女性整形外科医生的外科科学家职业。