Molecular and Cellular Mechanisms of Vascular Anomalies

描述(由申请者提供)：该项目名为“血管异常的分子和细胞机制”，代表了三个研究小组的共同努力，其中两个在波士顿，一个在比利时布鲁塞尔，旨在阐明导致皮肤血管异常的原因和异常机制。这些异常通常被称为胎记，包括婴儿血管瘤，一种在1岁时5-10%的高加索儿童中发现的血管肿瘤，以及血管畸形。血管瘤通常在出生后几天出现，迅速生长几周到几个月，然后在5-10年内缓慢消退。在大多数情况下，不需要治疗，但有时至关重要的结构可能会受阻或扭曲，造成严重问题。与血管瘤不同的是，畸形不会退化，而是随着孩子的成长而生长，可能会危及生命。 研究人员最近发现，血管瘤包含异常内皮细胞的克隆性扩张，他们发现了两种类型的突变，导致静脉畸形和球静脉畸形患者的皮肤局部异常。在由三个核心支持的三个研究项目中，项目调查人员建议检验和测试以下假设：血管瘤是由控制前体细胞的内皮细胞增殖和/或成熟的基因的体细胞突变导致的，导致异常毛细血管的快速生长。除了识别这些基因和突变外，还建议识别导致罕见遗传性血管瘤的基因，并建立小鼠模型，以便进一步研究详细的病理机制。最后，他们现在建议建立静脉和肾静脉畸形的小鼠模型，表征致病突变的细胞和分子后果，并在更多的家族中寻找突变。 拟议的研究应有助于更好地了解血管瘤和畸形的发病机制，从而为开发有效的治疗方法奠定基础。此外，更好地了解血管异常的原因和机制将为血管的形成和生长提供新的见解。这将大大增加为癌症、糖尿病视网膜病变和类风湿性关节炎开发新的抗血管生成疗法的努力。

DESCRIPTION (provided by applicant): This Program Project, entitled '"Molecular and Cellular Mechanisms of Vascular Anomalies," represents the concerted and collaborative efforts of three research groups, two in Boston and one in Brussels, Belgium, to elucidate the causes and abnormal mechanisms that are responsible for vascular anomalies in the skin. Commonly called birthmarks, these anomalies include infantile hemangioma, a vascular tumor found in 5-10% of Caucasian children at 1 year of age, and vascular malformations. 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. In most cases, no treatment is needed, but sometimes vital, structures can be obstructed or distorted causing serious problems. In contrast to hemangiomas, malformations do not regress, but grow with the child, and can become life-threatening. The investigators have recently found that hemangiomas contain clonal expansions of abnormal endothelial cells, and they have discovered two types of mutations that cause localized abnormalities in the skin of patients with venous malformations and glomuvenous malformations. In three research Projects, supported by three Cores, the Program investigators propose to examine and test the hypotheses that hemangiomas result from somatic mutations in genes that control endothelial cell proliferation and/or maturation from precursor cells, causing rapid growth of abnormal capillaries. In addition to identifying such genes and mutations, it is also proposed to identify genes responsible for rare cases of inherited hemangiomas and to establish mouse models allowing further studies of detailed pathological mechanisms. Finally, they now propose to generate mouse models for venous and glomuvenous malformations, characterize the cellular and molecular consequences of the causative mutations, and search for mutations in additional families. The proposed studies should lead to a better understanding of the pathogenesis of hemangiomas and malformations and therefore a basis for development of effective therapies. In addition, a better understanding of the causes and mechanisms of vascular anomalies will provide novel insights into blood vessel formation and growth. This will add significantly to the efforts to develop novel antiangiogenic therapies for cancer, diabetic retinopathy, and rheumatoid arthritis.