Determining the pathophysiology of pediatric arteriovenous malformation

确定小儿动静脉畸形的病理生理学

• 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
• 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

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.

该项目的目标是了解动静脉畸形 (AVM) 的机制 形式和进展。这将告诉我们血管形态发生的基本过程 并且重要的是，确定可以开发靶向治疗的特定基因/途径 改善受 AVM 和其他血管疾病影响的患者的生活。 AVM 在出生时就存在 并随着时间的推移经历显着的进展。病变扩大、出血、溃疡并引起 疼痛和畸形。重要结构可能受到威胁，并可能发生充血性心力衰竭。 目前，AVM 无法治愈，也不存在药物治疗。 我们最近发现大多数人类 AVM 都含有 MAP2K1 体细胞突变，并且这 突变是内皮细胞独有的。我们现在的目标是：（1）鉴定其他体细胞突变 人类 AVM，(2) 确定 MAP2K1 突变如何影响内皮细胞功能，以及 (3) 开发 AVM 动物模型进一步研究其病理生理学以及测试药物治疗。我们 将在 AVM 上进行分子倒置探针、RNA、全外显子组和全基因组测序 组织和分离的内皮细胞，以发现人类 AVM 中的其他突变。突变内皮细胞 将研究含有 MAP2K1 突变的细胞以确定突变如何影响信号传导 途径、蛋白质产生以及细胞与周细胞相互作用形成血液的能力 船只。将通过插入突变的 MAP2K1 内皮细胞来开发 AVM 动物模型 正如我们已经成功地治疗其他类型的血管异常一样。 FDA 批准的 MAP2K1 抑制剂将在体外和体内进行测试，以了解 突变如何影响细胞行为的病理生理学并确定药物的功效。 当我们成功确定病理生理学时，这些实验将产生巨大影响 负责AVM的形成和扩大。我们第一次能够追求 治疗这种病变的有针对性的方法。例如，路径特定的局部、病灶内和/或 可以开发全身药物来预防 AVM 进展或复发。 AVM 病理生理学的发现也将帮助我们了解 AVM 的机制 是其他儿科血管病变的基础，并将提高我们操纵血管生长的能力 广泛的疾病。

项目成果

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
• 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

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