Microphysiological systems to model vascular malformations

项目总结 血管畸形，包括毛细血管畸形、静脉畸形和动静脉畸形 畸形通常在出生时出现，随着时间的推移往往会发展成危及生命的。大多数人， 即使不是全部，也是由合子后(体细胞)突变引起的，因此是零星的，因此很难 模特。遗传性出血性毛细血管扩张症(HHT)是一种遗传性疾病，其特征是 多脏器血管畸形破裂导致急性出血和 慢性出血，以及中风、心力衰竭和肝功能衰竭。它的患病率是五万分之一，所以是罕见的， 但这仍相当于美国的3万名患者。HHT中的VMS范围从小粘膜到皮肤 毛细血管畸形(导致鼻部和胃肠道急性和慢性出血)，大到 肝、脑和肺动静脉畸形(AVM)，破裂可导致死亡。这个 绝大多数HHT患者有两个基因突变-ACVRL1(Alk1，HHT2)和ENG(endoglin， HHT1)。葡萄酒色斑(PWS)是由皮肤毛细血管畸形引起的胎记，发生于 大约每200个新生儿中就有一个。它们可以发生在身体的任何地方，但在面部很常见，而且 并驾齐驱，终生坚持。它们可能很小(米哈伊尔·戈尔巴乔夫的额头上有波尔多葡萄酒的污渍)， 然而，许多都更大，可能会严重毁容。斯特奇-韦伯综合征是一种相关疾病。 畸形在大脑中发生的地方。最近，G蛋白GNAQ的激活突变(p.R183Q) 已注意到与孤立的PWS和SWS有很强的相关性。目前治疗这两种疾病的方法 疾病是非常有限的。这项提案的重点是利用我们的专业知识创建血管化和 将培养的组织灌流，建立血管畸形HHT、PWS和SWS的体外模型。 在UG3阶段，我们将追求三个目标：G1：建立遗传性出血的MPS疾病模型 毛细血管扩张症(HHT)；G2：为鲜红斑点(PWS)建立微生理学疾病模型；G3： 建立HHT和PWS的组织特异性微生理模型。在UH3阶段，我们将在此基础上 三个进一步目标：h1：展示疾病生物学研究平台的效用；h2：展示 进行药物筛查的平台的效用；以及，H3：演示平台的效用 对候选疗法的评估。该项目的完成将产生具有改造潜力的平台 目前药物支持很少的两种罕见疾病的药物发现和测试 工业。我们希望为HHT和PWS患者取得重大进展。

PROJECT SUMMARY Vascular malformations (VM), including capillary malformations, venous malformations and arteriovenous malformations are generally present at birth and can often develop over time to become life-threatening. Most, if not all, arise from post-zygotic (somatic) mutations and are consequently sporadic, and thereby hard to model. Hereditary hemorrhagic telangiectasia (HHT) is a dominant genetic disorder characterized by the pres- ence of vascular malformations (VMs) in multiple organs, the rupture of which leads to acute hemorrhage and chronic bleeding, as well as stroke, heart failure and liver failure. Its prevalence is 1 in 5-10,000, so it is rare, but that still equates to >30,000 patients in the US. VMs in HHT range from small mucosal and cutaneous capillary malformations (causing acute and chronic bleeding from the nose and gastrointestinal tract), to large arteriovenous malformations (AVM) of the liver, brain and lung, the rupture of which can lead to death. The vast majority of HHT patients have mutations in two genes – ACVRL1 (Alk1, HHT2) and ENG (Endoglin, HHT1). Port-wine stains (PWS) are birthmarks caused by capillary malformations in the skin and occur in approximately 1 in 200 newborns. They can occur anywhere on the body but are common on the face, and neck and persist throughout life. They can be small (Mikhail Gorbachev has a port-wine stain on his forehead), however many are larger and can be grossly disfiguring. Sturge-Weber syndrome (SWS) is a related disease where the malformations occur in the brain. Recently, activating mutations (p.R183Q) in the G-protein GNAQ have been noted to have a strong correlation with both isolated PWS and SWS. Current therapies for either disease are very limited. The focus of this proposal is to leverage our expertise in creating vascularized and perfused tissues in culture to create in vitro models of the vascular malformations HHT, PWS and SWS. In the UG3 phase we will pursue three aims: G1: Develop an MPS disease model for Hereditary Hemorrhagic Telangiectasia (HHT); G2: Develop a microphysiological disease model for Port Wine Stain (PWS); and, G3: Develop tissue-specific micro-physiological models of HHT and PWS. In the UH3 phase we will build on this in three further aims: H1: Demonstrate utility of the platforms for investigating disease biology; H2: Demonstrate utility of the platforms for performing drug screens; and, H3: Demonstrate utility of the platforms for assessment of candidate therapies. Completion of this project will yield platforms with the potential to transform drug discovery and testing for two rare diseases that currently have very little support from the pharmaceutical industry. We hope to make significant advances on behalf of HHT and PWS patients.