Mechanisms Regulating Hemangioendothelioma: A Plastic Surgeon's Challenge

描述(由申请人提供)：这项题为“血管内皮瘤的调控机制：整形外科医生的挑战”的提案的总体目标是确定NOx-4如何调控发展为肿瘤的内皮细胞的生长，并确定NOx-4衍生氧化剂产生的生物制品是否可以用作生物标记物。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，在细胞中起着多种功能。我们使用了一个已建立的小鼠模型，其中注射内皮细胞(EOMA)会导致血管内皮瘤的形成，并表明血管内皮瘤的形成是NOx-4依赖的。这项建议结合了包括外科科学家、分子生物学家和放射科医生在内的多学科研究人员的专业知识。总的来说，我们将利用国立儿童医院血管瘤和血管畸形诊所的独特资源和基础设施，以及位于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，这些实体通过临床翻译科学奖资助的临床和翻译科学中心联系在一起，创建一种新的翻译方法来研究儿童血管瘤和血管内皮瘤。这些是儿童中最常见的软组织肿瘤，它们可以极大地毁容，最有效的治疗方案都有危及生命的副作用。改善受影响儿童的临床结果的一个关键障碍是缺乏低风险的治疗选择。这项提案的目标是通过确定潜在的新治疗目标和建立可用于设计和执行科学严格的临床试验的生物标记物来解决这一关键障碍。这笔赠款的目标和目的将通过以下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)探讨let 7f microRNA下调EOMA中NOx-4高表达的意义。3)确定NOx-4氧化诱导性尿8-OHdG和血清MCP-1水平是否可作为监测儿童HE生长和消退的生物标志物。这项提议的成功执行将通过发现新的治疗靶点来推进血管内皮瘤的知识库，这些治疗靶点负责调节NOx-4衍生的氧化剂产生对血管内皮瘤形成的影响，提供第一个证据表明microRNA可以沉默NOx-4，并在这一患者群体中进行第一次前瞻性纵向研究以确定生物标记物。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，并通过引入microRNA导向疗法的概念来治疗血管内皮瘤。 公共卫生相关性：血管内皮瘤和血管瘤都是内皮细胞肿瘤，是儿童最常见的软组织肿瘤。它们经常毁容，并可能危及生命，给受影响儿童的家庭带来严重痛苦。最有效的治疗方案都有危及生命的副作用，这些副作用限制了它们的使用，并成为改善临床结果的关键障碍。这项提案寻求确定新的治疗目标和生物标志物，可用于设计临床试验，以加快向患有血管内皮瘤的儿童提供新的治疗替代方案。

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. PUBLIC HEALTH RELEVANCE: Hemangioendothelioma as well as hemangiomas are both endothelial cell tumors, which are the most common soft tissue tumor in children. They are frequently disfiguring and can be life-threatening resulting in significant distress for the families of affected children. The most effective treatment options all have life-threatening side effects that limit their use and represent a critical barrier to improving clinical outcomes. This proposal seeks to identify new treatment targets and biomarkers that can be used to design clinical trials to accelerate the delivery of new treatment alternatives to children with hemangioendothelioma.