Molecular and Cellular Mechanisms of Vascular Anomalies

该项目申请题为“血管异常的分子和细胞机制”，要求继续资助三个研究小组的合作努力，两个在波士顿，一个在比利时布鲁塞尔，阐明人类血管异常的发病机制，生成小鼠模型和确定治疗靶点。这些常见的血管疾病属于通常被称为血管胎记的儿童疾病组。大约每100个出生的孩子中就有一个有血管胎记，尽管在确定这些异常的许多更罕见形式的遗传基础方面取得了重大进展，但它们经常被误诊，而且没有有效的治疗方法。为了进一步了解血管异常的发病机制，为更好的分子诊断工具和开发新的合理治疗方法提供基础，研究者建议通过由三个项目和三个核心组成的高度互动的项目，继续对婴儿血管瘤和静脉畸形进行研究。婴儿血管瘤是一种1岁高加索儿童中发现的血管肿瘤，占10%。血管瘤通常在出生后几天出现，快速生长几周到几个月，然后在5-10年的时间内缓慢消退。畸形不会消退，但会随着孩子的成长而成长，并可能危及生命。基于第一次拨款期间的发现，并利用波士顿和布鲁塞尔两个中心收集的特殊患者数据、组织、细胞和核酸资源，研究人员建议使用遗传学、细胞生物学和蛋白质化学技术来更深入地了解与血管瘤和静脉畸形相关的基因突变如何影响内皮和平滑肌细胞的分化和功能。将人类细胞移植到免疫功能受损小鼠和携带血管瘤和静脉畸形相关突变的转基因小鼠体内的动物模型将被表征并用于测试假设，并探索用于疾病改善药物的临床前试验。

This Program Project application, entitled "Molecular and Cellular Mechanisms of Vascular Anomalies" requests continued funding for collaborative efforts of three research groups, two in Boston, and one in Brussels, Belgium to elucidate pathogenetic mechanisms of human vascular anomalies, to generate mouse models and identify therapeutic targets. These common vascular disorders belong to the group of childhood conditions popularly known as vascular birthmarks. One in about 100 children born have a vascular birthmark, and although significant progress has been made in identifying the genetic basis for many of the more rare forms of these anomalies, they are frequently misdiagnosed and effective therapies are unavailable. To advance pathogenetic understanding of vascular anomalies, provide the basis for better molecular diagnostic tools and development of new rational therapies, the investigators propose to continue their research on infantile hemangioma, a vascular tumor found in 10% of Caucasian children at 1 year of age, and venous malformations through highly interactive program consisting of three Projects and three Cores. Hemangiomas usually appear a few days after birth, grow rapidly for a few weeks to months, and then slowly regress over a 5-10-year period. Malformations do not regress, but grow with the child and can become life-threatening. Building on discoveries made during the first grant period and taking advantage of exceptional patient-data, tissue, cell and nucleic acid resources that have been collected in two Cores, one in Boston and one in Brussels, the investigators propose to use genetic, cell biological, and protein chemistry techniques to gain deeper understanding of how gene mutations that are associated with hemangioma and venous malformations affect endothelial and smooth muscle cell differentiation and function. Animal models comprising human cells transplanted into immunocompromised mice and genetically modified mice carrying hemangioma- and venous malformation-associated mutations will be characterized and used for testing hypotheses and explored for preclinical trials of disease-modifying drugs.