Mechanisms Regulating Hemangioendothelioma: A Plastic Surgeon's Challenge

描述（由申请人提供）：这个题为“调节血管内皮瘤的机制：整形外科医生的挑战”的提案的总体目标是确定nox-4如何调节发展成肿瘤的内皮细胞的生长，并确定由nox-4衍生的氧化剂产生的生物制品是否可以用作生物标志物。Nox-4是NADPH氧化酶的催化亚基，它将分子氧转化为超氧化物，这是内源性活性氧产生的第一步，在细胞中具有许多功能。我们使用了一个已建立的小鼠模型，其中注射内皮细胞（EOMA）导致血管内皮瘤的形成，并表明血管内皮瘤的形成依赖于nox-4。该提案结合了多学科研究小组的专业知识，包括外科医生、科学家、分子生物学家和放射科医生。总的来说,我们将利用全国儿童医院血管瘤和血管畸形诊所的独特资源和基础设施，以及俄亥俄州立大学医学中心戴维斯心肺研究所的激光捕获显微镜核心，这些实体由临床转化科学奖资助的临床和转化科学中心联系起来，创造一种新的转化方法来研究血管瘤和血管内皮瘤的孩子。这些是儿童中最常见的软组织肿瘤，它们可能会严重毁容，最有效的治疗方案都有危及生命的副作用。改善受影响儿童临床结果的一个关键障碍是缺乏低风险治疗方案。该提案的目标是通过确定潜在的新治疗靶点和建立可用于设计和执行科学严格的临床试验的生物标志物来解决这一关键障碍。该基金的目标将通过以下3个具体目标来实现：1)确定nox-4衍生氧化剂诱导EOMA形成血管内皮瘤的机制。2)表征let 7f microRNA下调在EOMA中释放nox-4高表达中的意义。3)确定nox-4衍生氧化剂诱导的尿8-OHdG和血清MCP-1水平是否可以作为监测儿童HE生长和退化的生物标志物。该建议的成功实施将通过发现负责介导nox-4衍生氧化剂产生对血管内皮瘤形成的影响的新治疗靶点，提供沉默nox-4的microRNA的第一个证据，并在该患者群体中进行首次前瞻性纵向研究以确定生物标志物，从而推进血管内皮瘤的知识基础。这将导致临床和基础科学研究方法的范式转变，强调内源性氧化剂产生在血管内皮瘤形成中的重要性，并引入微rna导向治疗血管内皮瘤的概念。

DESCRIPTION (provided by applicant): The overall objective of this proposal entitled, "Mechanisms Regulating Hemangioendothelioma: A Plastic Surgeon's Challenge", is to determine how nox-4 regulates the growth of endothelial cells that develop into tumors and to determine whether the biological products that result from nox-4 derived oxidants can be used as biomarkers. Nox-4 is the catalytic subunit of the enzyme NADPH oxidase that converts molecular oxygen to superoxide as the first step in endogenous reactive oxygen species production that serves many functions in the cell. We have used an established murine model where injection of endothelial (EOMA) cells results in formation of a hemangioendothelioma, and have shown that hemangioendothelioma formation is nox-4 dependent. This proposal combines the expertise of a multidisciplinary group of investigators including a surgeon-scientist, molecular biologist, and radiologist. Collectively, we will utilize the unique resources and infrastructure of the Hemangioma and Vascular Malformation Clinic at Nationwide Children's Hospital and the Laser Capture Microscopy Core housed in the Davis Heart Lung Research Institute at Ohio State University Medical Center and these entities are linked by the Clinical Translational Science Award funded Center for Clinical and Translational Science to create a novel translational approach to investigating hemangiomas and hemangioendotheliomas in children. These are the most common soft tissue tumors in children, they can be extremely disfiguring and the most effective treatment options all have life-threatening side effect profiles. A critical barrier to improving the clinical outcomes for affected children is the lack of low risk treatment options. The goal of this proposal is to address that critical barrier by identifying potential new treatment targets and establishing biomarkers that can be used to design and execute scientifically rigorous clinical trials. The goals and objectives for this grant will be achieved through the following 3 specific aims: 1) Determine the mechanisms through which nox-4 derived oxidants induce EOMA to form hemangioendothelioma. 2) Characterize the significance of let 7f microRNA down regulation in unleashing high nox-4 expression in EOMA. 3) Determine whether nox-4 derived oxidant inducible urinary 8-OHdG and serum MCP-1 levels can be used as biomarkers to monitor growth and involution of HE in children. Successful execution of this proposal will advance the knowledge base for hemangioendothelioma by discovering new therapeutic targets responsible for mediating the effects of nox-4 derived oxidant production on hemangioendothelioma formation, providing first evidence of microRNA that silence nox-4, and performing the first prospective longitudinal study in this patient population to identify biomarkers. This would result in a paradigm shift in both the clinical and basic science investigative approaches by emphasizing the importance of endogenous oxidant production in hemangioendothelioma formation and by introducing the concept of microRNA directed therapeutics to treat hemangioendotheliomas.