Pathogenic mechanisms of venous anomalies

血管畸形是血管形态发生的局限性缺陷。它们由于疼痛而引起严重的发病率， 出血和邻近组织破坏。目前的治疗仅限于手术切除和硬化疗法， 两者都有局限性。需要更好地了解发病原因。虽然现在绝大多 血管异常的发生是散发性的，可观察到遗传形式。因此，我们的长期目标是：1）确定 遗传性血管畸形的分子原因; 2）检验Knudson双重打击模型， 解释这些病变的多灶性nataare; 3）从通常罕见的遗传形式推断结果 4）在体外表征突变蛋白质的改变的功能，以及突变蛋白质的突变。 相关的病理生理学级联反应;和5）创建遗传操作的小鼠品系以获得体内模型 概括畸形并允许测试新的治疗方法。这样的数据不仅可以 许多血管异常患者，而且还管理其他血管生成疾病，如类风湿性关节炎， 关节炎、糖尿病视网膜病变和癌症。我们早期对遗传性血管异常的研究揭示了SOX 18， 水肿中的VEGFR 3突变，皮肤毛细血管-静脉畸形中的KRIT 1突变，TIE 2突变 在遗传性粘膜皮肤静脉畸形、球静脉畸形中的球蛋白突变和RASAl中， 我们称之为毛细血管畸形-动静脉畸形。最近，我们发现， 的散发性静脉畸形是由于体细胞TIE 2突变。最后，在项目1和2中，我们描述了 血管瘤发病机制中涉及的遗传变化。在这项研究中，我们的目标是：1）在体外和体内表征 TIE 2突变对内皮细胞功能的影响; 2）在体外和体内表征TIE 2突变对内皮细胞功能的影响。 血管球蛋白功能丧失对VSMC分化的影响，以及3）进一步筛查静脉异常患者， （体细胞）突变的新基因座。这些数据将揭示导致静脉异常的致病机制， 产生它们的体内模型，并鉴定对其发病机制重要的新因子。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的紧密合作，我们与项目1和2合作， 目的是表征血管瘤中涉及的致病途径。 相关性（参见说明）： 该项目旨在描述导致发展的遗传原因和机制， 静脉异常（“海绵状血管瘤”），并为它们制作小鼠模型。这将有助于诊断 和管理这些患者，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.