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Capillary malformation: From somatic GNAQ mutations to disrupted endothelial biology

毛细血管畸形：从体细胞 GNAQ 突变到内皮生物学破坏

基本信息

批准号：
10206231
负责人：
Joyce E. Bischoff
金额：
$ 84.07万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10206231
关键词：
ANGPT2 gene Address Affect Alleles Angiopoietin-2 Animal Model Automobile Driving Bar Codes Biology Blood Vessels Blood capillaries Brain Cell model Cell physiology Cells Choroid Cognitive Collaborations Coupled Cutaneous Data Defect Dermis Development Endothelial Cells Endothelium Event Experimental Models Eye Face Functional disorder G alpha q Protein G-substrate GNAQ gene Gene Expression Profile Genomics Genotype Glaucoma Goals Growth Hematopoietic Hemorrhage Heterogeneity Heterotrimeric G Protein Subunit Histologic Human Image Impairment Implant In Situ Hybridization In Vitro Infant Inflammatory Knock-in Lead Leptomeninges Lesion Malignant Neoplasms Massachusetts Mediator of activation protein Medical Medical center Modeling Molecular Morphogenesis Mus Mutation NF-kappa B Neurocutaneous Syndromes Neurologic Nodule Nude Mice Pathogenesis Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Phospholipase Play Port-Wine Stain Protein Kinase C Reporting Resistance Retinal Detachment Role Seizures Signal Transduction Skin Small Interfering RNA Somatic Mutation Specimen Stains Sturge-Weber Syndrome Surface TNFSF5 gene Tamoxifen Technology Testing Time Tissue Engineering Transcript Universities Work Zebrafish causal variant cell type cerebral capillary drug candidate drug testing high risk improved in vivo insight knock-down malformation mouse model mutant nervous system disorder novel prevent response shear stress single-cell RNA sequencing skeletal small hairpin RNA small molecule inhibitor soft tissue stroke-like episode tissue repair transcriptome sequencing venule

项目摘要

Project Abstract Our studies are focused on capillary malformation (CM) (previously referred to as “port-wine stain”), the most common type of vascular malformation. CM, excessive, enlarged capillary-like vessels just below the surface of the skin, are sporadic congenital lesions that darken, form nodules, and cause soft-tissue and skeletal overgrowth beneath the stain. Sturge-Weber syndrome (SWS) is a neurocutaneous disorder associated with CMs of the face, leptomeninges, and the choroid of the eye; patients suffer from neurological defects and glaucoma. Importantly, drug treatment for CMs does not exist and there is no cure. The 2013 discovery of a somatic activating mutation in GNAQ (p.R183Q) in non-syndromic cutaneous CMs and SWS CMs set the stage for molecular studies of this understudied vascular malformation. GNAQ encodes Gαq, the α-subunit of the heterotrimeric Gq protein that activates phospholipase Cβ. We showed that the GNAQ R183Q allele is enriched in the endothelial cell (EC) sorted from cutaneous CM and SWS brain specimens. We have worked on creating cellular and mouse models to elucidate how the GNAQ mutation affects EC function, how these alterations lead to CM, and how we can prevent the formation or growth of CM. We show that human ECs with the R183Q mutation do not respond properly to laminar shear stress, fail to form an endothelial barrier, and form enlarged CM-like vessels when implanted into mice. We implicate protein kinase C (PKC) and angiopoietin-2 (ANGPT2) as potential targets to reverse the GNAQ R183Q-driven CM. We are making strong progress towards an inducible, endothelial-specific knock-in of Gnaq R183Q in mice in which we have found CM-like lesions upon tamoxifen-induced expression of the knocked-in mutant allele. In this proposal we will identify the breadth of cell types that carry the somatic GNAQ R183Q allele and how the mutation alters the transcriptional profile versus non-mutant cells of the same phenotype (Aim 1). We will develop novel animal models in mice and zebrafish to elucidate the cellular steps leading to CM and will use them as platforms for testing candidate drugs (Aim 2). We will deeply interrogate the role of (ANGPT2) as a downstream functional mediator of constitutively active, mutant Gαq (Aim 3). These studies will deepen our understanding of how Gαq activity participates in capillary morphogenesis, result in the first animal models for CM/SWS, and provide a platform to test drugs that can prevent or regress CM. Discoveries about the pathophysiology of CM will also help us understand the mechanisms that underlie additional vascular lesions and improve our ability to identify new pathways for preventing vascular overgrowth (e.g., cancer) and promoting vascular growth during tissue repair or engineering.

项目摘要