Novel therapeutic targets and/or prognostic markers in Marfan syndrome

马凡综合征的新治疗靶点和/或预后标志物

基本信息

批准号：
8379274
负责人：
Francesco B Ramirez
金额：
$ 29.22万
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
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8379274
关键词：
Achievement Adaptor Signaling Protein Address Aneurysm Aorta Aortic Aneurysm Aortic Diseases Binding Biological Biological Availability Biological Markers Bone Growth Caring Cell Differentiation process Cell Proliferation Cells Chemicals Clinical Collaborations Complement Complex Congenital Disorders Connective Tissue Connective Tissue Diseases Consultations Data Deformity Diagnostic Disease Disease Outcome Disease Progression Effector Cell Equilibrium Event Experimental Designs Extracellular Matrix FBN1 Funding Growth Heterogeneity Human Image In Vitro Individual Injury Investigation Knowledge Ligands Light Losartan MAP Kinase Gene MAP3K7 gene MAPK14 gene MAPK3 gene MAPK8 gene Marfan Syndrome Mediating Microfibrils Morbidity - disease rate Morphogenesis Mus Mutant Strains Mice Mutation Natural History Neonatal Organ Osteogenesis Outcome Pathogenesis Pathway interactions Patients Performance Pharmaceutical Preparations Phenotype Phosphorylation Phosphotransferases Physiological Play Process Prognostic Marker Program Research Project Grants Reading Reagent Receptor, Angiotensin, Type 1 Role Seminal Series Services Signal Pathway Signal Transduction Skeletal system Skeleton Specificity Stimulus Stress Stress Response Signaling TGF-beta type I receptor TRAF6 gene Testing Therapeutic Therapeutic Intervention Tissues Translational Research Vascular System Work body system bone bone morphogenetic protein receptor type II clinically significant evidence base extracellular fibrillin improved in vivo inhibitor/antagonist innovation malformation member mortality mouse model mutant new therapeutic target postnatal receptor repaired research study response skeletal stem ubiquitin ligase

项目摘要

Marfan syndrome (MFS) is a congenital disorder of the connective tissue that is caused by mutations in fibrillin-1, the major structural component of extracellular microfibrils. We have originally hypothesized and subsequently demonstrated that flbrillin-1 mutations impair the sequestration of latent TGFp complexes in the extracellular matrix with deleterious consequence to cell performance. This seminal discovery has led to the realization that TGFp blockade is a productive new strategy to mitigate systemic manifestations in mouse models of MFS and perhaps in human pafients. We now present data that implicate MAPKs and BMPs as addifional contributors to organ-specific abnormalifies in mouse models of MFS. These exciting new findings are consistent with the emerging role of microfibrils in the extracellular storage of several TGFp superfamily members. They are also in line with the notion that TGFp and BMPs can signal through MAPK-mediated pathways and that MAPKs can influence Smad activity in response to environmental stress and tissue injury. We therefore hypothesize that flbrillin-1 mutations trigger a series of matrix-dependent events that disrupt the physiological balance of TGFp and BMP signaling in individual tissues, and that improper stimulafion of p38 MAPK activity (through TGFp and/or stress-response signals) exacerbates this disease-causing process Accordingly, the main focus of the present project is to evaluate the potential role of p38 and BMPs in the pathogenesis of aortic aneurysm and skeletal deformities in mouse models of progressively severe MFS Specifically, we propose to: Aim 1: Interrogate the contribufion of p38 activity to aortic aneurysm in Fbn1 mutant mice that are also defective in non-canonical TGFp signaling or are systemically treated with inhibitors of p38 or Smad2/3 signaling. Aim 2: Evaluate the role of unbalanced TGFp and BMP signaling in bone overgrowth using mice in which Fbnl deficiency is paired with loss of TGFp or BMP type II receptors, or with over-expression of a BMP antagonist. The proposed studies will complement and be informed by parallel investigations on the contribution to aortic aneurysm of ERK1/2 signaling (Project 1), latent TGFp activators (Project 2) and a structurally abnormal extracellular matrix (Project 3). Additionally, the unique reagents and imaging services of Core B will provide critical support to the work. Collectively, our efforts will shed new light on the complexity of the physiological roles that fibrillin-rich microfibrils play in organ formafion and function, in addition to providing evidence-based opportunities for therapeutic intervention in MFS and related disorders of the connective tissue.

Marfan综合征（MFS）是结缔组织的先天性疾病，是由Fibrillin-1突变引起的，Fibrillin-1是细胞外微纤维的主要结构成分。我们最初假设并随后证明了Flbrillin-1突变会损害细胞外基质中潜在的TGFP复合物的静止，对细胞性能有害。这种开创性的发现导致了这样一种意识到，TGFP阻滞是一种有效的新策略，可以减轻MFS鼠标模型甚至人类Pafients中的系统性表现。现在，我们提出的数据将MAPK和BMP视为MFS小鼠模型中器官特异性异常的附加因素。这些令人兴奋的新发现与微纤维在几个TGFP超家族成员的细胞外存储中的新兴作用一致。它们还与TGFP和BMP可以通过MAPK介导的途径发出信号的观念一致，并且MAPK可以影响SMAD活动，以应对环境压力和组织损伤。 We therefore hypothesize that flbrillin-1 mutations trigger a series of matrix-dependent events that disrupt the physiological balance of TGFp and BMP signaling in individual tissues, and that improper stimulafion of p38 MAPK activity (through TGFp and/or stress-response signals) exacerbates this disease-causing process Accordingly, the main focus of the present project is to evaluate the potential role of p38 and BMP在主动脉瘤的发病机理中和骨骼畸形在逐渐严重的MFS的小鼠模型中，我们建议：目标1：询问p38活性对FBN1突变小鼠中主动脉瘤的贡献在非典型的TGFP信号传导中有缺陷，或在系统地用p38或SMAD2/3信号传导的抑制剂处理。 AIM 2：使用FBNL缺乏症与TGFP或TGFP或BMP II型受体的损失或BMP拮抗剂的过表达，评估不平衡TGFP和BMP信号传导在骨过度生长中的作用。拟议的研究将补充并通过对ERK1/2信号（项目1），潜在TGFP激活剂（项目2）和结构异常异常细胞外基质（项目3）（项目3）的贡献的平行研究进行补充和告知。此外，核心B的独特试剂和成像服务将为工作提供关键的支持。总的来说，我们的努力将对富含纤维蛋白的微纤维在器官形式和功能中发挥作用的生理作用的复杂性进行新的启示，此外还提供了基于证据的机会来对MFS的治疗干预和结缔组织的相关疾病进行治疗。