Microphysiological systems to model vascular malformations

模拟血管畸形的微生理系统

• 批准号: 9401128
• 负责人: CHRISTOPHER C. W. HUGHES
• 金额: $ 99.34万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9401128
• 关键词: ACVRL1 gene; Acute; Affect; Arteriovenous malformation; Biology; Birth; Blood Vessels; Blood capillaries; Brain; Cessation of life; Chronic; Cutaneous; Disease; Disease model; Dominant Genetic Conditions; Drug Industry; ENG gene; Endoglin; Face; Forehead; G alpha q Protein; G-substrate; GNAQ gene; GTP-Binding Proteins; Gastrointestinal tract structure; Gene Frequency; Heart failure; Hemorrhage; Hereditary Disease; Hereditary hemorrhagic telangiectasia; Lasers; Lead; Learning; Life; Liver; Liver Failure; Lung; Microfluidics; Modeling; Mutation; Neck; Newborn Infant; Nose; Operative Surgical Procedures; Organ; Patients; Pharmacologic Substance; Phase; Port-Wine Stain; Pre-Clinical Model; Preclinical Drug Evaluation; Prevalence; Rare Diseases; Research Personnel; Rupture; Severity of illness; Skin; Somatic Mutation; Stroke; Sturge-Weber Syndrome; System; Testing; Time; Tissues; Venous Malformation; capillary; drug discovery; drug testing; in vitro Model; malformation; novel; novel therapeutics; physiologic model; prevent; tool

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.

项目摘要 血管畸形（VM），包括毛细血管畸形、静脉畸形和动静脉畸形 畸形通常在出生时就存在，并且常常随着时间的推移而发展成危及生命的。大多数， 如果不是全部，则由合子后（体细胞）突变引起，因此是散发性，因此难以 模型遗传性出血性毛细血管扩张症（HHT）是一种显性遗传性疾病，其特征是前- 多个器官中存在血管畸形（VM），其破裂导致急性出血， 慢性出血以及中风、心力衰竭和肝衰竭。其患病率为1/5- 10，000，因此很罕见， 但这仍然相当于美国的30，000多名患者。HHT中的VM范围从小的粘膜和皮肤 毛细血管畸形（导致鼻子和胃肠道的急性和慢性出血），大 肝、脑和肺的动静脉畸形（AVM），其破裂可导致死亡。的 绝大多数HHT患者在两个基因ACVRL 1（Alk 1，HHT 2）和ENG（内皮糖蛋白， HHT 1）。葡萄酒色斑（PWS）是由皮肤中的毛细血管畸形引起的胎记， 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，但常见于面部， 颈部，并坚持一生。它们可以很小（米哈伊尔·戈尔巴乔夫的额头上有一个葡萄酒渍）， 然而，许多都是较大的，可以严重毁容。Sturge-Weber综合征（SWS）是一种相关疾病， 大脑中畸形发生的位置最近，G蛋白GNAQ中的激活突变（p.R183Q） 已经注意到与孤立的PWS和SWS都有很强的相关性。目前的治疗方法 疾病非常有限。该提案的重点是利用我们的专业知识， 在培养物中灌注组织以产生血管畸形HHT、PWS和SWS的体外模型。 在UG 3阶段，我们将追求三个目标：G1：开发遗传性出血性疾病的MPS疾病模型 毛细血管扩张症（HHT）; G2：开发鲜红斑痣（PWS）的微生理学疾病模型;以及G3： 建立HHT和PWS的组织特异性微生理模型。在UH 3阶段，我们将以此为基础， 三个进一步的目标：H1：展示研究疾病生物学的平台的效用; H2：展示 H3：展示平台在药物筛选方面的实用性， 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 药物发现和两种罕见疾病的测试，目前很少得到制药公司的支持 行业我们希望代表HHT和PWS患者取得重大进展。