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.

Marfan综合征（MFS）是由编码基质蛋白的基因突变引起的常见疾病纤维蛋白-1。我们先前的工作表明，许多MF的表现，包括主动脉瘤，瓣膜疾病，肺气肿和骨骼肌肌病是由过度激活和信号引起的 TGFBETA系列生长因子家族，可以通过小鼠模型中的TGFBETA阻断来减弱。这盛行的观点是，由于其替代品的变化，MF表现出“正常”细胞的异常行为细胞外环境。现在，我们提供了成人MF主动脉壁内“异常”细胞的证据早期经历了身份和特征的TGFBETA依赖性永久性变化的小鼠由于所谓的内皮到间质转移（ENMT）的过程而导致的开发。移位后，重建肌纤维细胞表现出许多有害行为，包括高TGFBETA信号传导，血管紧张素II （Angll）依赖性纤维化和基质降解酶的高表达。主要假设是在这项工作中测试的是，ENMT衍生的细胞驱动疾病的进展，并且ENMT继续在疾病状态下产后生活期间填充升主动脉。使用鼠标模型，我们将确定驱动ENMT在原纤维素-1缺陷小鼠主动脉中的途径，并将净化ENMT衍生的细胞，允许识别其有害行为和驯服它们的策略的探索。目前，我们可以设想至少9种不同的治疗剂，从理论上讲将防止正在进行的ENMT和/或调节肌纤维细胞在开始治疗时居住在主动脉壁内的非产生性能。这些将在基因定义和验证的MF的小鼠模型中进行测试。值得注意的是，这些药物中的许多药物已经用于其他适应症的临床用途，这表明有可能向MFS快速翻译。我们当前的数据表明，在MFS中明显获得的后期发作表型的预性中，细胞染色性的固定替代方案是一种细胞染色性的，这种范式代表了一种思考基因性倾向的新方法，有助于阐明疗法限制的限制和机会，并且可能对其他相关的孔子相关。