Pathogenic mechanisms of venous anomalies

血管畸形是一种局限性的血管形态发生缺陷。它们会因疼痛而导致严重的疾病， 周围组织出血和破坏。目前的治疗方法仅限于手术切除和硬化治疗， 这两种方法都有局限性。需要更好地了解病因。尽管大多数人 的血管异常是零星的，可观察到遗传形式。因此，我们的长期目标是：1)确定 遗传形式的血管异常的分子原因；2)测试克努森双重打击模型作为一种 对这些病变的多灶性的解释；3)从通常罕见的遗传性形式推断结果 对常见的零星形式；4)在体外表征突变蛋白的功能变化和 相关的病理生理级联；以及5)创建基因操纵的小鼠品系以获得活体模型 这概括了畸形，并允许测试新的治疗方法。这样的数据不仅有助于 不计其数的血管异常患者，也要处理其他血管新生疾病，如类风湿 关节炎、糖尿病视网膜病变和癌症。我们对遗传性血管异常的早期研究揭开了SOX18和 淋巴水肿中的VEGFR3突变，皮肤毛细血管-静脉畸形中的KRIT1突变，TIE2突变 遗传性皮肤粘膜静脉畸形、肾小球静脉畸形的球蛋白突变和鼻腔静脉畸形 一种我们称之为毛细血管畸形-动静脉畸形的疾病的突变。最近，我们发现49%的人 散发性静脉畸形的原因是体细胞TIE2突变。最后，对于项目1和2，我们描述了 基因改变参与了血管瘤的发病机制。在这笔赠款中，我们的目标是1)在体外和体内表征 TIE2基因突变对内皮细胞功能的影响；2)体内外实验研究 球蛋白功能丧失对VSMC分化的影响；3)进一步筛查静脉畸形患者 新基因座的(体细胞)突变。这些数据将揭开导致静脉异常的致病机制， 建立它们的体内模型，并确定对它们的病因起重要作用的新因素。这个项目 取决于核心B和C提供的样本，以及与项目1和2的密切合作，我们 目的探讨血管瘤的致病途径。 相关性(请参阅说明)： 这个项目的目的是描述导致糖尿病发生的遗传原因和机制。 静脉畸形(“海绵状血管瘤”)，并为它们制作小鼠模型。这将有助于诊断 以及对这些患者的管理，并允许开发新的治疗方法。

Vascular anomalies are localized defects of vascular morphogenesis. They cause important morbidity due to pain, bleeding and distruction of adjacent tissues. Current treatments are limited to surgical resection and sclerotherapy, both of which have limitations. Better understanding of the etiopathogenic causes is needed. Although the majority of vascular anomalies are sporadic, inherited forms are observed. Thus, our long term goals are: 1) to identify the molecular causes of the inherited forms of vascular anomalies; 2) to test the Knudson double-hit model as an explanation for the multifocal nataare of these lesions; 3) to extrapolate the results from the often rare inherited forms to the common sporadic forms; 4) to characterize in vitro the altered function of the mutated proteins and the associated pathophysiological cascades; and 5) to create genetically manipulated mouse lines to obtain in vivo models that recapitulate the malformations and allow testing of novel therapeutic approaches. Such data would not only serve the numerous vascular anomaly patients, but also the management of other angiogenic disorders, such as rheumatoid arthritis, diabetic retinopathy and cancer. Our earher studies on hereditary vascular anomalies unraveled SOX18 and VEGFR3 mutations in lymphedema, KRITl mutations in cutaneous capillary-venous malformations, TIE2 mutations in hereditary mucocutaneous venous malformations, glomulin mutations in glomuvenous malformations, and RASAl mutations in a disorder we named capillary malformation-arteriovenous malformation. Recently, we showed that 49% of sporadic venous malformations are due to somatic TIE2 mutations. Finally, with Project 1 and 2 we described genetic changes involved in hemangioma pathogenesis. In this grant, we aim 1) to characterize in vitro and in vivo the effects of the TIE2 mutations on endothelial cell function; 2) to characterize in vitro and in vivo the effects of glomulin loss-of-function on VSMC differentiation, and 3) to further screen patients with venous anomalies for (somatic) mutations in novel loci. This data would unravel the pathogenic mechanisms that lead to venous anomalies, generate in vivo models of them, and identify novel factors important for their etiopathogenesis. This project depends on samples provided by Cores B and C, and the tight collaborations with Projects 1 and 2, with which we aim to characterize the pathogenic pathways involved in hemangiomas. RELEVANCE (See instructions): This project aims to characterize the genetic causes and mechanisms that lead to the development of venous anomalies ("cavernous angiomas"), and to make mouse models for them. This would help diagnosis and management of these patients, and allow development of novel therapeutic approaches.