Transmembrane Proteolytic Induction and Thoracic Aneurysms

跨膜蛋白水解诱导和胸动脉瘤

• 批准号: 8586540
• 负责人: John S. Ikonomidis
• 金额: $ 36.14万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8586540
• 关键词: Address; Affect; Aneurysm; Animal Model; Aorta; Aortic Aneurysm; Architecture; Attenuated; Binding Proteins; Biological Assay; Biological Models; Biological Process; Blood Vessels; Cardiovascular system; Chest; Cleaved cell; Clinical; Clinical Research; Collagen; Critical Pathways; Development; Diagnostic; Disease; Etiology; Extracellular Matrix; Family; Fibroblasts; Fibrosis; Growth; Intervention; Laboratories; Matrix Metalloproteinases; Microbubbles; Modeling; Mus; Myofibroblast; Natural History; Operative Surgical Procedures; Pathway interactions; Patients; Pattern; Peptide Hydrolases; Phenotype; Process; Proteolysis; Pump; RNA Interference; Recording of previous events; Role; Rupture; Signal Pathway; Signal Transduction; Signaling Molecule; Small Interfering RNA; Structure; Therapeutic; Thoracic Aortic Aneurysm; Thoracic aorta; Transforming Growth Factor beta; Transgenic Model; Transgenic Organisms; Ultrasonography; abstracting; antibody conjugate; high risk; human MMP14 protein; in vivo; indexing; insight; interstitial; novel; promoter; reconstruction; response; signal processing

Abstract A dramatic clinical example of where disruption of the extracellular matrix within the cardiovascular system leads to a devastating disease process is thoracic aortic aneurysms (TAAs). Surgical reconstruction/endovascular interventions are possible for TAAs, but are in and of themselves high risk and do not affect the underlying pathways which drive this devastating disease. This laboratory and others have demonstrated that a specific cassette of proteolytic enzymes, the matrix metalloproteinases (MMPs), are increased in patients with TAAs.Using a murine TAA model developed by this laboratory, a cause-effect relationship was demonstrated between TAA progression and MMP induction/activational states. However, it remains unclear how and which MMP types are causative to these ECM changes and contribute to TAA progression. We have recently identified that a unique MMP, membrane type-1 (MT1-MMP) was upregulated with TAA progression and was accompanied by a loss in ECM architecture, interstitial vascular fibrosis, and a switch of thoracic aortic fibroblasts to a myofibroblast phenotype. Our new results have established that MT1-MMP cleaves the latent transforming growth factor-beta (TGF) binding protein-1 (LTBP-1), which would in turn enhance signaling of this potent profibrotic signaling pathway. Thus, the central hypothesis of this study is that the induction of MT1-MMP contributes to the natural history of TAAs in a bi-phasic manner- initiation due to enhanced ECM proteolysis, - and progression through an altered fibroblast phenotype and abnormal collagen accumulation which is an MT1-MMP/TGF driven process. This hypothesis will be addressed through the following specific aims: (1) Through transgenic reduction and amplification of MT1-MMP, establish that early induction of MT1-MMP primarily causes a localized and amplified MMP proteolytic response and initiates the TAA, whereas prolonged MT1- MMP induction causes heightened profibrotic signaling through an LTBP-TGF mechanism thereby sustaining ECM remodeling and TAA progression. (2) Using RNA interference (siRNA), demonstrate the early induction of MT1-MMP promoter activity in TAA progression results in a net amplification of MMP proteolytic activity and a loss of ECM structural integrity. (3) Establish that prolonged MT1-MMP induction causes a phenotypic switch in aortic fibroblasts, whereby selective targeting of fibroblast specific MT1-MMP will directly attenuate TAA progression. These studies will establish how a transmembrane proteolytic pathway contributes to TAA propagation and thereby provide new insights for the development of diagnostic and therapeutic strategies for this insidious and clinically devastating disease.

摘要 一个引人注目的临床例子，在心血管系统中细胞外基质的破坏， 胸主动脉瘤（TAAs）是胸主动脉系统导致的一种破坏性疾病过程。手术 胸主动脉瘤的重建/血管内介入是可能的，但本身就很高， 风险和不影响驱动这种毁灭性疾病的潜在途径。这个实验室 和其他人已经证明，蛋白水解酶的特定盒，基质 在TAA患者中，金属蛋白酶（MMPs）增加。 由该实验室开发，证明了TAA进展之间的因果关系 和MMP诱导/活化状态。然而，仍不清楚MMP类型如何以及哪些MMP类型是 导致这些ECM变化并有助于TAA进展。我们最近发现， 一种独特的MMP，膜型-1（MT1-MMP）随着TAA进展而上调， 伴随着ECM结构的丧失、间质性血管纤维化和胸主动脉的转换， 主动脉成纤维细胞转化为肌成纤维细胞表型。我们的新结果已经确定MT1-MMP 切割潜在的转化生长因子-β（TGF）结合蛋白-1（LTBP-1）， 反过来增强这种有效的促纤维化信号传导途径的信号传导。因此，这个问题的核心假设 研究表明，MT1-MMP的诱导有助于TAAs的自然病程， 方式-由于ECM蛋白水解增强而引发，-并通过改变的成纤维细胞进展 表型和异常胶原积累，这是MT1-MMP/TGF驱动的过程。这 将通过以下具体目标来解决这一假设：（1）通过减少转基因 和MT1-MMP的扩增，确立了MT1-MMP的早期诱导主要导致了 定位和放大MMP蛋白水解反应，并启动TAA，而延长MT1- MMP诱导通过LTBP-TGF机制引起促纤维化信号传导增强， 维持ECM重塑和TAA进展。(2)使用RNA干扰（siRNA），证明 在TAA进展中MT1-MMP启动子活性的早期诱导导致 MMP蛋白水解活性和ECM结构完整性的丧失。(3)确定延长的MT1-MMP 诱导导致主动脉成纤维细胞的表型转换，从而选择性靶向成纤维细胞 特异性MT1-MMP将直接减弱TAA进展。这些研究将确定 跨膜蛋白水解途径有助于TAA增殖，从而提供新的见解 为发展诊断和治疗策略， 毁灭性的疾病