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Developmental Basis of Aneurysm in Marfan Syndrome and Therapeutic Implication

马凡氏综合征动脉瘤的发生基础及治疗意义

基本信息

批准号：
8317953
负责人：
Harry C., III Dietz
金额：
$ 50.79万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8317953
关键词：
AGTR2 gene Abnormal Cell Adult Agonist Alleles Aneurysm Angiotensin II Angiotensins Animals Aorta Aortic Aneurysm Attenuated Automobile Driving BMP7 gene Behavior Biological Availability Blood Vessels Cardiac Cells Cessation of life Clinical Clinical Trials Collaborations Complement Complex Data Developed Countries Development Disease Disease Progression Endothelial Cells Environment Enzymes Event Exhibits FBN1 Family Fibrosis Future Genes Genetic Genotype Growth Factor Heart Homeostasis Individual Integrins Knowledge Lead Life Ligands Light Losartan Lung MAP2K1 gene MAPK14 gene MAPK3 gene Marfan Syndrome Matrix Metalloproteinases Medial Mediating Mediator of activation protein Mesenchymal Modeling Mus Muscle Mutation Myofibroblast Myopathy Neonatal Neural Crest Normal Cell PECAM1 gene Pathogenesis Pathologic Pathway interactions Performance Phenotype Process Production Property Proteins Pulmonary Emphysema Recombinants Reporter Sampling Series Severities Signal Transduction Skeletal Muscle Skeleton Smooth Muscle Sorting - Cell Movement Stratification Surveys System TGFB1 gene Testing Therapeutic Therapeutic Agents Therapeutic Effect Thinking Thrombospondin 1 Time Tissues Transforming Growth Factor beta Translational Research Type 2 Angiotensin II Receptor U-0126 Vascular Diseases Work ascending aorta autocrine base extracellular fasudil human disease inhibitor/antagonist insight meetings mouse model mutant neutralizing antibody novel paracrine postnatal prevent receptor response rho GTP-Binding Proteins therapeutic target

项目摘要

Marfan syndrome (MFS) is a common disorder caused by mutations in the gene encoding the matrix protein fibrillin-1. Our prior work has shown that many manifestations of MFS, including aortic aneurysm, valve disease, emphysema and skeletal muscle myopathy, are caused by excessive activation of and signaling by the TGFbeta family of growth factors and can be attenuated by TGFbeta blockade in mouse models. The prevailing view has been that MFS manifests abnormal behaviors of "normal" cells due to alterafions in their extracellular environment. We now present evidence for "abnormal" cells within the aortic wall of adult MFS mice that have undergone a TGFbeta-dependent permanent transifion in identity and character during early development due to a process termed endothelial-to-mesenchymal transifion (EnMT). After transifion, resulfing myofibroblasts exhibit many deleterious behaviors including high TGFbeta signaling, angiotensin II (Angll)-dependent fibrosis, and high expression of matrix-degrading enzymes. The major hypotheses to be tested in this work are that EnMT-derived cells drive progression of disease and that EnMT continues to populate the ascending aorta during postnatal life in disease states. Using mouse models, we will determine the pathways that drive EnMT in the aorta of fibrillin-1 deficient mice and will purify EnMT-derived cells, allowing identification of their deleterious behaviors and explorafion of strategies to tame them. Currently, we can envision at least 9 different therapeutic agents that will theoretically prevent ongoing EnMT and/or modulate the nonproducfive performance of myofibroblasts resident within the aortic wall at the time of initiation of treatment. These will be tested in genetically defined and validated mouse models of MFS. Remarkably, a number of these agents are already in clinical use for other indications, suggesting the potential for rapid translafion to people with MFS. Our current data suggest a developmentally-imposed fixed alterafion in cellular idenfity in the prediposition for apparently acquired late-onset phenotypes in MFS, This paradigm represents a novel way of thinking about genefic predisposifion, aids in the elucidation of therapeufic limitafions and opportunities, and will likely prove relevant to other condifions.

马凡氏综合征（MFS）是一种由编码基质蛋白的基因突变引起的常见疾病