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（由申请人提供）：血管畸形是动脉、静脉、毛细血管和淋巴管中血管结构和功能的缺陷，畸形可以是家族性的或散发性的，并且通常与组织过度生长、畸形和淋巴管相关。在本提案中，我们将重点关注儿童、青少年和成人的毛细血管畸形 (CM)，其中包括过度和异常的毛细血管/小静脉样血管感染。皮肤表面的 CM 也称为鲜红斑痣或鲜红胎记 CM 是一种散发性、非家族性先天性血管畸形，在出生时就存在，并在一生中不断发展，导致严重的发病率。 Sturge-Weber 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 CM 位于面部的一侧或两侧，通常位于上眼睑和前额。据报道，大脑表面存在过多的异常血管，这被认为是导致 SWS 儿童神经功能缺陷的原因之一。 SWS 和 CM，将这两种疾病中的血管缺陷联系起来，编码 Gαq，异源三聚体 Gq 蛋白的 α 亚基，将 G 蛋白偶联受体与磷脂酶 Cβ 连接起来。然后将 CM 病变分成特定的细胞群，然后对这些细胞群进行 GNAQ (p.R183Q) 突变的基因分型。我们最近发表的结果表明， GNAQ (p.R183Q) 突变在 CM 的内皮细胞中富集。通过识别分子缺陷 (Gαq) 和缺陷所在的细胞环境（内皮细胞），我们现在可以建立一个研究计划来研究如何进行治疗。 CM 的形成、如何预防 CM 以及如何消退 CM，这些研究对于患有进行性、组织破坏性 CM 的儿童和患有 SWS 的儿童具有重要意义，因为大脑中可能存在异常血管。这项研究将产生两层影响，第一层是破译 CM（一种相对罕见的血管畸形）的潜在细胞和生化原因，第二层将是我们发现的更广泛的途径和机制。对 CM 的研究可能会揭示组装人体血管网络所需的独特且关键的步骤，这将指出建立用于离线组织再生和修复的毛细血管网络所需的基本步骤，所学到的经验教训可以扭转并应用于预防病理。船只在总之，CM 的研究可以为增进我们对正常和病理性脉管系统的理解提供丰富的线索。