Nodal Points in Marfan Syndrome Progression

马凡氏综合症进展的节点

基本信息

批准号：
7779682
负责人：
DANIEL B RIFKIN
金额：
$ 36.54万
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/7779682
关键词：
AGTR2 gene Abnormal Cell Address Angiotensin II Type 1 Receptor Blockers Angiotensins Aortic Aneurysm Autoimmune Process Binding Binding Proteins Biological Assay Blood Vessels Cardiac Cells Child Cleaved cell Clinical Clinical Trials Complement Factor B Complex Defect Deposition Development Endothelial Cells Endothelium Event Extracellular Matrix FBN1 Fibrosis Gelatinase A Gelatinase B Gene Expression Grant Heart In Vitro Individual Losartan Malignant Neoplasms Marfan Syndrome Matrix Metalloproteinases Measures Medial Mediating Mesoderm Modeling Molecular Monitor Mus Mutant Strains Mice Mutation Myofibroblast Nature Neural Crest Nodal Normal Cell Pathology Phenotype Plant Roots Process Production Program Research Project Grants Property Reagent Receptor Signaling Receptor, Angiotensin, Type 1 Role Signal Transduction Smooth Muscle Myocytes Syndrome Testing Thrombospondin 1 Tissues Transforming Growth Factors Translational Research Up-Regulation Vascular Diseases Work base cell type cytokine dimer in vivo insight interest member neutralizing antibody novel therapeutic intervention programs receptor receptor expression research study skills therapeutic target

项目摘要

This PPG has shown that certain clinical manifestafions of Marfan Syndrome (MFS), caused by mutations in fibrillin-1, are mediated by high levels of active TGF-B and that progression of selected phenotypes is blocked by the angiotensin type 1 (ATI) receptor antagonist losartan. Work from Project 2 (Rifkin) has shown that latent TGF-S is activated in cultures of MFS vascular smooth muscle cells (VSMCs), that the activator of latent TGF-B is an MMP, most likely MMP-9, and that TGF-B stimulates AT1 receptor expression. We propose a model in which defective matrix yields abnormal latent TGF-B sequestration followed by acfivafion, the active TGF-B sfimulates enhanced ATI receptor and MMP-9 expression, MMP-9 activates latent TGF-S, and ATI receptor signaling promotes confinued TGF-B expression. Thus, a cycle of activafion, enhanced expression, and activafion is established. However, the initiating event in this cycle is unknown, as are some ofthe interrelationships. This grant addresses three quesfions concerning TGF-B, ATI receptor, and MMPs in MFS. In Aim 1, we will test whether perturbing the matrix results in the cycle of TGF-B formafion, ATI receptor expression up-regulation, and MMP-mediated latent TGF-B activation and if these changes are interrelated. In Aim 2, we will use FACS to isolate and characterize cells of different lineages that contribute to aortic root VSMC populafions. Cells include cardiac nural crest, secondary heart field, mesoderm, and endothelium. Thus, we will determine whether or not abnormal cells in MFS arise from specific lineages, in which cells normally acfivate latent TGF-B, and have high levels of ATI receptor and MMPs. These results will be compared to those of Aim 1 in which cells generate these molecules because of failed matrix. In Aim 3, we will generate MFS mice that are missing MMP-9 to establish if the in vitro activator MMP-9 is an in vivo acfivator. The completion of these aims will inform us as to the initiator of latent TGF-B activation, the cell that activates, and the nature ofthe in vivo activator.

该PPG表明，由Marfan综合征（MFS）的某些临床表现原纤维素-1中的突变是由高水平的活性TGF-B介导的，所选的进展表型被1型血管紧张素（ATI）受体拮抗剂氯沙坦阻塞。项目2（Rifkin）的工作表明，潜在的TGF-S在MFS血管平滑肌细胞（VSMC）的培养物中被激活，潜在TGF-B的激活因素是MMP，最有可能是MMP-9，并且TGF-B-B刺激AT1受体表达。我们提出了一个模型，其中有缺陷的矩阵产生异常潜在的TGF-B固隔次，然后进行ACFIVAFION，活动的TGF-B SFIMULS可增强的ATI受体和MMP-9表达，MMP-9激活潜在的TGF-S，ATI受体信号促进了TGF-B-B表达约束。因此，建立了一个激活，增强的表达和活化的循环。但是，在此周期中的启动事件和某些相互关系也是未知的。该赠款介绍了MFS中有关TGF-B，ATI受体和MMP的三个问题。在AIM 1中，我们将测试扰动矩阵是否会导致TGF-B Formafion，ATI受体表达上调和MMP介导的潜在TGF-B激活以及这些变化是否相互关联。在AIM 2中，我们将使用FACS隔离和表征有助于主动脉根VSMC人群的不同谱系的细胞。细胞包括心脏nur骨，次生心脏场，中胚层和内皮。因此，我们将确定MF中的异常细胞是否来自特定的谱系，其中细胞通常会吸收潜在的TGF-B，并且具有高水平的ATI受体和MMP。这些结果将与AIM 1的结果进行比较，在该目标的结果下，细胞由于基质失败而产生这些分子。在AIM 3中，我们将生成缺少MMP-9的MFS小鼠，以确定体外激活剂MMP-9是否是体内散热器。这些目标的完成将告知我们潜在的TGF-B激活，激活的细胞和体内激活剂的性质。