Capillary malformation: From somatic GNAQ mutations and disrupted endothelial biology

毛细血管畸形：来自体细胞 GNAQ 突变和内皮生物学破坏

• 批准号: 9244833
• 负责人: Joyce E. Bischoff
• 金额: $ 44.25万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9244833
• 关键词: 3-Dimensional; Adolescent; Adult; Affect; Animal Model; Architecture; Arteries; Basement membrane; Behavior; Biochemical; Biological Assay; Biology; Birth; Blood Vessels; Blood capillaries; Brain; Capillary Endothelial Cell; Cell Communication; Cell physiology; Cells; Cheek structure; Child; Coculture Techniques; Communication; Critical Pathways; Data; Defect; Deformity; Dermis; Disease; Endothelial Cells; Eyelid structure; Face; Forehead; G alpha q Protein; G-Protein-Coupled Receptors; GNAQ gene; GTP Binding; Genotype; Goals; Growth; Guanosine Triphosphate Phosphohydrolases; Histologic; Human; Immune; Implant; Infant; Infection; Lesion; Link; Lymphatic vessel; Medical; Mesenchymal Differentiation; Mesenchymal Stem Cells; Migration Assay; Modeling; Molecular; Morbidity - disease rate; Morphogenesis; Mus; Mutation; Neurologic Deficit; Ocular orbit; Pain; Pathologic; Pathway interactions; Patients; Pericytes; Phospholipase; Play; Population; Port-Wine Stain; Prevention; Property; Publishing; Reporting; Research; Retinal Diseases; Rheumatoid Arthritis; Role; Side; Signal Pathway; Signal Transduction; Skin; Smooth Muscle Myocytes; Specimen; Strawberry nevus; Sturge-Weber Syndrome; Supporting Cell; Surface; TEK gene; Testing; Time; Tissues; Veins; Venous Malformation; blood vessel development; capillary; cell behavior; cell type; cellular engineering; drug testing; in vitro Model; in vivo; link protein; malformation; mutant; nervous system disorder; novel strategies; platelet-derived growth factor BB; prevent; programs; public health relevance; tissue regeneration; tissue repair; tumor; venule

 DESCRIPTION (provided by applicant): Vascular malformations are defects in the architecture and function of blood vessels that can occur in arteries, veins, capillaries and lymphatic vessels. The malformations can be familial or sporadic, and are often associated with tissue overgrowth, deformity and infections in children, adolescents and adults. In this proposal, we will focus on capillary malformations (CM), which consist of excessive and abnormal capillary/venule-like vessels just below the surface of the skin. CMs are also referred to as port-wine stain or port-wine birthmarks. CM is a sporadic, non-familial congenital vascular malformation that is present at birth and progresses over a lifetime, causing significant morbidity for children. Sturge-Weber syndrome (SWS) is a rare neurological disorder that is strongly associated with CM. In SWS patients, CMs of variable size are located on one or both sides of the face, typically on the upper eyelid and forehead. In addition, excessive abnormal vessels are found on the surface of the brain and are thought to contribute to the neurologic deficits in children with SWS. A somatic, activating mutation in GNAQ (p.R183Q) has been reported in patients with SWS and CM, linking the vascular defect in these two disorders. GNAQ encodes Gαq, the alpha subunit of the heterotrimeric Gq protein that links G-protein coupled receptors to phospholipase Cβ. We confirmed the GNAQ (p.R183Q) mutation in CM specimens and then fractionated CM lesions into specific cell populations that were then genotyped for the GNAQ (p.R183Q) mutation. Our results, recently published, show that the GNAQ (p.R183Q) mutation is enriched in the endothelial cells of CM. With the identification of the molecular defect (Gαq) and the cellular context in which the defect resides (endothelial cells), we can now build a research program to investigate how CMs form, how to prevent CM and how to regress CM. These studies will be relevant for children with progressive, tissue-destroying CM and for children with SWS, as the abnormal vessels in the brain are likely disrupted by the same mechanisms. This research will have two tiers of impact. The first will be to decipher the underlying cellular and biochemical causes of CM, a relatively rare vascular malformation. The second will be much broader. The pathways and mechanisms discovered by our studies of CM may reveal unique and critical steps needed to assemble networks of human blood vessels. This will point to essential steps needed to build capillary networks for tissue regeneration and repair. Conversely, the lessons learned could be turned around and applied to prevention of pathological vessels in settings such as tumors, retinal diseases and rheumatoid arthritis. In summary, the study of CM could provide a well-spring of clues to advance our understanding of normal and pathologic vasculature.

 描述(申请人提供)：血管畸形是血管结构和功能的缺陷，可发生在动脉、静脉、毛细血管和淋巴管中。这些畸形可以是家族性的，也可以是散发性的，通常与儿童、青少年和成人的组织过度生长、畸形和感染有关。在这项提案中，我们将重点关注毛细血管畸形(CM)，它由皮肤表面下过度和异常的毛细血管/小静脉样血管组成。CMS也被称为波尔图酒渍或波尔图葡萄酒胎记。先天性肌萎缩侧索硬化症是一种零星的、非家族性的先天性血管畸形，在出生时就存在，并在一生中发展，导致显著的发病率。 为儿童准备的。斯特奇-韦伯综合征(SWS)是一种罕见的神经系统疾病，与CM密切相关。在SWS患者中，不同大小的CMS位于面部的一侧或两侧，通常位于上眼睑和前额。此外，在大脑表面发现过多的异常血管，被认为是导致SWS儿童神经功能缺陷的原因之一。已有报道在SWS和CM患者中发现了GNAQ(p.R183Q)的体细胞激活突变，将这两种疾病中的血管缺陷联系在一起。GNAQ编码GαQ，它是异源三聚体GQ蛋白的阿尔法亚单位，连接G蛋白偶联受体和磷脂酶Cβ。我们确认了CM标本中的GNAQ(p.R183Q)突变，然后将CM病变分成特定的细胞群体，然后对GNAQ(p.R183Q)突变进行基因分型。我们最近发表的结果表明，GNAQ(p.R183Q)突变在CM的内皮细胞中丰富。随着分子缺陷(GαQ)和缺陷所在的细胞环境(内皮细胞)的确定，我们现在可以建立一个研究计划来研究CMS是如何形成的，如何预防CM以及如何使CM退化。这些研究将适用于患有进行性、破坏组织的CM的儿童和患有SWS的儿童，因为大脑中的异常血管可能会被相同的机制破坏。这项研究将产生两方面的影响。第一个将是破译CM的潜在细胞和生化原因，CM是一种相对罕见的血管畸形。第二个将是更广泛的。我们对CM的研究发现的途径和机制可能揭示组装人类血管网络所需的独特和关键步骤。这将指向为组织再生和修复建立毛细血管网络所需的基本步骤。相反，所学到的经验教训可以逆转，并应用于预防肿瘤、视网膜疾病和类风湿性关节炎等环境中的病理性血管。综上所述，CM的研究可以提供丰富的线索，促进我们对正常和病理血管系统的理解。