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 畸形通常在出生时出现，并且经常会随着时间的流逝而发展以使其威胁生命。最多， 如果不是全部 模型。遗传性出血性毛细血管扩张（HHT）是一种主要的遗传疾病，其特征是 多个器官中的血管畸形（VM）的影响，其破裂导致急性出血和 慢性出血以及中风，心力衰竭和肝衰竭。它的患病率是5-10,000中的1个，因此很少见 但这仍然等于美国> 30,000名患者。 HHT的VM范围从小粘膜和皮肤 毛细血管畸形（从鼻子和胃肠道引起急性和慢性出血）， 肝，脑和肺的动静脉畸形（AVM），其破裂可能导致死亡。 绝大多数HHT患者在两个基因中都有突变-ACVRL1（ALK1，HHT2）和ENG（Endoglin，Endoglin， HHT1）。港口染色（PWS）是由皮肤毛细血管畸形引起的胎记，发生在 大约200名新生儿中有1个。它们可以发生在体内的任何地方，但在脸上很常见，并且 脖子和持续一生。它们可能很小（Mikhail Gorbachev的额头上有港口葡萄酒的污渍）， 但是，许多人更大，可能会严重毁容。 Sturge-Weber综合征（SWS）是一种相关疾病 畸形发生在大脑中。最近，在G蛋白GNAQ中激活突变（P.R183Q） 已经注意到与孤立的PW和SWS都有很强的相关性。当前的疗法 疾病非常有限。该建议的重点是利用我们在创建血管化和的专业知识 培养中的灌注组织以创建血管畸形的体外模型HHT，PWS和SWS。 在UG3阶段，我们将追求三个目标：G1：为遗传性出血开发MPS病模型 Telangiectia（HHT）; G2：开发一种用于港口葡萄酒染色（PWS）的微生物生理疾病模型；而且，G3： 开发HHT和PWS的组织特异性微生物学模型。在UH3阶段，我们将以这一点为基础 另外三个目的：H1：证明了调查疾病生物学平台的实用性； H2：演示 执行药物屏幕平台的实用性；和，H3：展示平台的实用性 评估候选疗法。该项目的完成将产生平台，并有可能转换 药物发现和测试两种稀有疾病目前几乎没有药物支持 行业。我们希望代表HHT和PWS患者取得重大进步。