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Determining the pathophysiology of pediatric arteriovenous malformation

确定小儿动静脉畸形的病理生理学

基本信息

批准号：
10410504
负责人：
Arin K. Greene
金额：
$ 67.42万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-10 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10410504
关键词：
Affect Alleles Animal Model Arteries Arteriovenous malformation Birth Blood Vessels Blood capillaries Boston Candidate Disease Gene Cell physiology Cells Child Childhood Clinical Coculture Techniques Code Congenital arteriovenous malformation Congestive Heart Failure Cre driver Defect Deformity Disease Endothelial Cells Engineering Etiology Excision Exhibits Exploratory/Developmental Grant for Diagnostic Cancer Imaging FDA approved Functional disorder Funding GNAQ gene Genes Genome Genotype Goals Growth Heart failure Hemorrhage Heterogeneity Histologic Human Immunodeficient Mouse Implant Individual Infection Intervention Knowledge Lesion Libraries MAP2K1 gene MAPK Signaling Pathway Pathway Malignant Neoplasms Mental Depression Methods Mitogen-Activated Protein Kinases Modeling Molecular Morbidity - disease rate Morphogenesis Mus Mutation Operative Surgical Procedures Pain Pathway interactions Patients Pediatric Hospitals Pericytes Pharmaceutical Preparations Pharmacology Pharmacotherapy Phenotype Population Pre-Clinical Model Process Production Proteins RAS genes RNA Recurrence Sampling Series Signal Pathway Smooth Muscle Myocytes Somatic Mutation Specificity Specimen Structure Technology Testing Therapeutic Embolization Time Tissue Engineering Tissues Ulcer Vascular Diseases Veins Virus Xenograft procedure capillary bed causal variant cell behavior cell type cellular transduction deep sequencing design drug efficacy exome experimental study gain of function gain of function mutation genome sequencing improved in vitro testing in vivo inhibitor malformation mutant prevent prospective psychologic radiological imaging self esteem targeted treatment tissue repair transcriptome sequencing treatment strategy vasculogenesis whole genome

项目摘要

The goal of this project is to understand the mechanisms by which arteriovenous malformation (AVM) forms and progresses. This will inform us about the fundamental process of vascular morphogenesis and, importantly, identify specific genes/pathways for which targeted therapies can be developed to improve the lives of patients affected by AVM and other vascular diseases. AVM is present at birth and undergoes significant progression over time. The lesion enlarges, bleeds, ulcerates, and causes pain and deformity. Vital structures can be threatened and congestive heart failure may occur. Currently, there is no cure for AVM and drug treatment does not exist. We recently found that most human AVMs contain somatic mutations in MAP2K1, and that this mutation is exclusive to the endothelial cell. We now aim to: (1) identify other somatic mutations in human AVMs, (2) determine how MAP2K1 mutations affect endothelial cell function, and (3) develop animal models of AVM to further study its pathophysiology as well as to test pharmacotherapy. We will perform molecular inversion probe, RNA, whole-exome, and whole genome sequencing on AVM tissues and isolated endothelial cells to find additional mutations in human AVMs. Mutant endothelial cells containing the MAP2K1 mutation will be studied to determine how the mutation affects signaling pathways, protein production, and the ability of the cells to interact with pericytes to form blood vessels. An animal model of AVM will be developed by inserting mutant MAP2K1 endothelial cells into immunodeficient mice, as we have successfully done with other types of vascular anomalies. FDA-approved inhibitors of MAP2K1 will be tested in vitro and in vivo to understand the pathophysiology of how the mutation affects cell behavior and to determine the efficacy of the drugs. These experiments will be high impact when we succeed in identifying the pathophysiology responsible for AVM formation and enlargement. For the first time we would be able to pursue a targeted approach for treating this lesion. For example, pathway specific topical, intralesional, and/or systemic pharmacologic agents could be developed to prevent AVM progression or recurrence. Discoveries into the pathophysiology of AVM also will help us to understand the mechanisms that underlie other pediatric vascular lesions, and will improve our ability to manipulate vascular growth in a broad range of diseases.

这个项目的目的是了解动静脉畸形（AVM）的机制。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Vascular Malformations: Current Progress Toward Drug Therapy.

DOI：
10.1097/scs.0000000000007310
发表时间：
2021-05-01
期刊：
The Journal of craniofacial surgery
影响因子：
0
作者：
Greene AK;Sudduth CL
通讯作者：
Sudduth CL

Arteriovenous malformation Map2k1 mutation affects vasculogenesis.

DOI：
10.1038/s41598-023-35301-6
发表时间：
2023-07-08
期刊：
Scientific reports
影响因子：
4.6
作者：
通讯作者：

Arteriovenous malformation phenotype resembling congenital hemangioma contains KRAS mutations.

DOI：
10.1111/cge.13833
发表时间：
2020-12
期刊：
Clinical genetics
影响因子：
3.5
作者：
Sudduth CL;McGuire AM;Smits PJ;Konczyk DJ;Al-Ibraheemi A;Fishman SJ;Greene AK
通讯作者：
Greene AK

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Arin K. Greene其他文献

Somatic Arteriovenous Malformation <em>MAP2K1</em> Mutation Causes Cartilage Overgrowth by a Cell Non-Autonomous Mechanism

DOI：
10.1016/j.jamcollsurg.2019.08.505
发表时间：
2019-10-01
期刊：
Conference abstract
影响因子：
作者：
Jeremy A. Goss;Patrick J. Smits;Arin K. Greene
通讯作者：
Arin K. Greene

Effect of calvarial burring on resorption of onlay cranial bone graft: An experimental study

DOI：
10.1016/j.jamcollsurg.2010.06.216
发表时间：
2010-09-01
期刊：
Conference abstract
影响因子：
作者：
Aladdin H. Hassanein;James E. Clune;John B. Mulliken;Praveen R. Arany;Gary F. Rogers;Ann M. Kulungowski;Arin K. Greene
通讯作者：
Arin K. Greene

Surgical Treatment of Gynecomastia Improves Quality of Life in Adolescents: A Longitudinal Cohort Study

DOI：
10.1016/j.jamcollsurg.2017.07.375
发表时间：
2017-10-01
期刊：
Conference abstract
影响因子：
作者：
Joseph M. Firriolo;Carolyn M. Pike;Laura C. Nuzzi;Arin K. Greene;Brian I. Labow
通讯作者：
Brian I. Labow