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Pathogenic mechanisms of venous anomalies

静脉异常的发病机制

基本信息

批准号：
8379597
负责人：
MIIKKA S. VIKKULA
金额：
$ 31.09万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-15 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8379597
关键词：
Affect Alcohols Anatomy Arteries Arteriovenous malformation Biological Assay Blood Vessels Blood capillaries Cavernous Hemangioma Cell physiology Classification Collaborations Copy Number Polymorphism Cutaneous Data Defect Development Diabetic Retinopathy Diagnosis Diffuse Disease Endothelial Cells Endothelium Excision Finland Functional disorder Genetic Genotype Goals Grant Hemangioma Hemorrhage Implant In Vitro Inherited Instruction Knock-in Mouse Lead Lesion Location Lymphedema Malignant Neoplasms Missense Mutation Modeling Molecular Morbidity - disease rate Morphogenesis Mus Mutate Mutation Names Neoplasms in Vascular Tissue Nerve Obstruction Operative Surgical Procedures Ophthalmologic Surgical Procedures Pain Pathogenesis Pathway interactions Patients Predisposing Factor Principal Investigator Program Research Project Grants Proteins Research Rheumatoid Arthritis Role Sampling Sclerosing Agents Sclerotherapy Signal Transduction Smooth Muscle Myocytes Somatic Mutation Specialized Center Structure TEK gene Testing Tissues United States National Institutes of Health Vascular Endothelial Growth Factor Receptor-3 Venous Venous Malformation angiogenesis base capillary cell behavior experience genome-wide human GLMN protein in vivo in vivo Model interest loss of function loss of function mutation malformation mouse model mutant novel novel therapeutic intervention

项目摘要

Vascular anomalies are localized defects of vascular morphogenesis. They cause important morbidity due to pain, bleeding and distruction of adjacent tissues. Current treatments are limited to surgical resection and sclerotherapy, both of which have limitations. Better understanding of the etiopathogenic causes is needed. Although the majority of vascular anomalies are sporadic, inherited forms are observed. Thus, our long term goals are: 1) to identify the molecular causes of the inherited forms of vascular anomalies; 2) to test the Knudson double-hit model as an explanation for the multifocal nataare of these lesions; 3) to extrapolate the results from the often rare inherited forms to the common sporadic forms; 4) to characterize in vitro the altered function of the mutated proteins and the associated pathophysiological cascades; and 5) to create genetically manipulated mouse lines to obtain in vivo models that recapitulate the malformations and allow testing of novel therapeutic approaches. Such data would not only serve the numerous vascular anomaly patients, but also the management of other angiogenic disorders, such as rheumatoid arthritis, diabetic retinopathy and cancer. Our earher studies on hereditary vascular anomalies unraveled SOX18 and VEGFR3 mutations in lymphedema, KRITl mutations in cutaneous capillary-venous malformations, TIE2 mutations in hereditary mucocutaneous venous malformations, glomulin mutations in glomuvenous malformations, and RASAl mutations in a disorder we named capillary malformation-arteriovenous malformation. Recently, we showed that 49% of sporadic venous malformations are due to somatic TIE2 mutations. Finally, with Project 1 and 2 we described genetic changes involved in hemangioma pathogenesis. In this grant, we aim 1) to characterize in vitro and in vivo the effects of the TIE2 mutations on endothelial cell function; 2) to characterize in vitro and in vivo the effects of glomulin loss-of-function on VSMC differentiation, and 3) to further screen patients with venous anomalies for (somatic) mutations in novel loci. This data would unravel the pathogenic mechanisms that lead to venous anomalies, generate in vivo models of them, and identify novel factors important for their etiopathogenesis. This project depends on samples provided by Cores B and C, and the tight collaborations with Projects 1 and 2, with which we aim to characterize the pathogenic pathways involved in hemangiomas. RELEVANCE (See instructions): This project aims to characterize the genetic causes and mechanisms that lead to the development of venous anomalies ("cavernous angiomas"), and to make mouse models for them. This would help diagnosis and management of these patients, and allow development of novel therapeutic approaches.

血管畸形是血管形态发生的局部性缺陷。由于疼痛，它们会引起严重的疾病，