Transmembrane Proteolytic Induction and Thoracic Aneurysms

跨膜蛋白水解诱导和胸动脉瘤

基本信息

项目摘要

DESCRIPTION (provided by applicant): 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 up regulated 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. PUBLIC HEALTH RELEVANCE: A common disease of the thoracic aorta, causing a loss of its uniform structure by expansion, dilation, and possible rupture, is termed thoracic aortic aneurysm disease. This study will identify how molecules within the wall of the aorta can cause destruction of the aortic wall and induce an aneurysm formation. Because there is no cure for this disease, this study will be the first to identify how we might be able to predict and stop thoracic aortic aneurysms before the aorta ruptures, thereby saving lives of patients with this disease.
描述(由申请人提供):胸主动脉瘤(TAA)是心血管系统内细胞外基质破坏导致毁灭性疾病过程的一个引人注目的临床实例。外科重建/血管内介入治疗TAA是可能的,但其本身风险较高,不会影响驱动这种毁灭性疾病的潜在途径。这个实验室和其他实验室已经证明,一种特定的蛋白水解酶,基质金属蛋白酶(MMPs),在TAA患者中增加。使用本实验室开发的小鼠TAA模型,证明了TAA进展与MMP诱导/激活状态之间的因果关系。然而,目前尚不清楚MMP类型是如何引起这些ECM变化并促进TAA进展的。我们最近发现,一种独特的MMP,膜型-1(MT 1-MMP)随着TAA进展而上调,并伴有ECM结构的丧失、间质性血管纤维化和胸主动脉成纤维细胞向肌成纤维细胞表型的转变。我们的新结果已经确定,MT 1-MMP切割潜在的转化生长因子-β(TGF)结合蛋白-1(LTBP-1),这反过来又会增强这种有效的促纤维化信号通路的信号传导。因此,本研究的中心假设是,MT 1-MMP的诱导以双相方式促进TAA的自然史-由于ECM蛋白水解增强而引发-以及通过改变的成纤维细胞表型和异常胶原积累而进展,这是MT 1-MMP/TGF驱动的过程。这一假设将通过以下具体目标来解决:(1)通过转基因减少和扩增MT 1-MMP,确定MT 1-MMP的早期诱导主要引起局部和扩增的MMP蛋白水解反应并启动TAA,而延长的MT 1- MMP诱导通过LTBP-TGF机制引起促纤维化信号传导增强,从而维持ECM重塑和TAA进展。(2)使用RNA干扰(siRNA),证明在TAA进展中MT 1-MMP启动子活性的早期诱导导致MMP蛋白水解活性的净扩增和ECM结构完整性的丧失。(3)确定延长MT 1-MMP诱导导致主动脉成纤维细胞中的表型转换,由此选择性靶向成纤维细胞特异性MT 1-MMP将直接减弱TAA进展。这些研究将确定跨膜蛋白水解途径如何促进TAA的传播,从而为这种阴险和临床破坏性疾病的诊断和治疗策略的发展提供新的见解。 公共卫生相关性:胸主动脉瘤病是胸主动脉的一种常见疾病,由于扩张、扩张和可能的破裂而导致其均匀结构的丧失。这项研究将确定主动脉壁内的分子如何破坏主动脉壁并诱导动脉瘤形成。由于这种疾病无法治愈,这项研究将是第一个确定我们如何能够在主动脉破裂之前预测和阻止胸主动脉瘤,从而挽救这种疾病患者的生命。

项目成果

期刊论文数量(0)
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John S. Ikonomidis其他文献

Optimal flow rates for retrograde warm cardioplegia.
逆行温停跳液的最佳流速。
  • DOI:
  • 发表时间:
    1994
  • 期刊:
  • 影响因子:
    6
  • 作者:
    John S. Ikonomidis;Terrance M Yau;R. Weisel;Nobuhiko Hayashida;Xinping Fu;Masashi Komeda;Joan Ivanov;S. Carson;M. K. Mohabeer;L. Tumiati;Donald A. G. Mickle
  • 通讯作者:
    Donald A. G. Mickle
Choosing Wisely: Cardiothoracic Surgeons Partnering With Patients to Make Good Health Care Decisions
  • DOI:
    10.1016/j.athoracsur.2013.01.008
  • 发表时间:
    2013-03-01
  • 期刊:
  • 影响因子:
  • 作者:
    Douglas E. Wood;John D. Mitchell;DeLaine S. Schmitz;Sean C. Grondin;John S. Ikonomidis;Faisal G. Bakaeen;Robert E. Merritt;Dan M. Meyer;Susan D. Moffatt-Bruce;T. Brett Reece;Michael A. Smith
  • 通讯作者:
    Michael A. Smith
Functioning Cooley-Cutter aortic valve prosthesis 40 years after implantation
  • DOI:
    10.1016/j.jtcvs.2013.10.068
  • 发表时间:
    2014-03-01
  • 期刊:
  • 影响因子:
  • 作者:
    Sahar A. Saddoughi;Daniel H. Steinberg;John S. Ikonomidis
  • 通讯作者:
    John S. Ikonomidis
Pulmonary Artery Aneurysm and Coronary Artery Disease in the Clinical Presentation of Watson Syndrome
  • DOI:
    10.1016/j.athoracsur.2005.10.016
  • 发表时间:
    2006-08-01
  • 期刊:
  • 影响因子:
  • 作者:
    James L. Foster;Scott M. Bradley;John S. Ikonomidis
  • 通讯作者:
    John S. Ikonomidis
Composite risk factors predict survival after transplantation for congenital heart disease
  • DOI:
    10.1016/j.jtcvs.2013.06.016
  • 发表时间:
    2013-10-01
  • 期刊:
  • 影响因子:
  • 作者:
    Minoo N. Kavarana;Andrew Savage;Robert O'Connell;Catherine S. Rubinstein;Jennifer Flynn-Reeves;Kishor Joshi;Martha R. Stroud;John S. Ikonomidis;Scott M. Bradley
  • 通讯作者:
    Scott M. Bradley

John S. Ikonomidis的其他文献

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{{ truncateString('John S. Ikonomidis', 18)}}的其他基金

Device-Based Pathway Intervention: Mechanistic Study of Cellular Localization of Proteolytic Enzymes in Thoracic Aortic Aneurysm Disease
基于装置的通路干预:胸主动脉瘤疾病中蛋白水解酶细胞定位的机制研究
  • 批准号:
    10705335
  • 财政年份:
    2022
  • 资助金额:
    $ 36.88万
  • 项目类别:
Exploration of key proteases and validation of biomarkers in genetically triggered thoracic aortic aneurysms
基因触发的胸主动脉瘤中关键蛋白酶的探索和生物标志物的验证
  • 批准号:
    9808798
  • 财政年份:
    2019
  • 资助金额:
    $ 36.88万
  • 项目类别:
Age-Dependent Mechanisms in Thoracic Aortic Aneurysms
胸主动脉瘤的年龄依赖性机制
  • 批准号:
    8040379
  • 财政年份:
    2011
  • 资助金额:
    $ 36.88万
  • 项目类别:
Age-Dependent Mechanisms in Thoracic Aortic Aneurysms
胸主动脉瘤的年龄依赖性机制
  • 批准号:
    8526324
  • 财政年份:
    2011
  • 资助金额:
    $ 36.88万
  • 项目类别:
Age-Dependent Mechanisms in Thoracic Aortic Aneurysms
胸主动脉瘤的年龄依赖性机制
  • 批准号:
    8877381
  • 财政年份:
    2011
  • 资助金额:
    $ 36.88万
  • 项目类别:
Age-Dependent Mechanisms in Thoracic Aortic Aneurysms
胸主动脉瘤的年龄依赖性机制
  • 批准号:
    8324210
  • 财政年份:
    2011
  • 资助金额:
    $ 36.88万
  • 项目类别:
Transmembrane Proteolytic Induction and Thoracic Aneurysms
跨膜蛋白水解诱导和胸动脉瘤
  • 批准号:
    9070876
  • 财政年份:
    2010
  • 资助金额:
    $ 36.88万
  • 项目类别:
Transmembrane Proteolytic Induction and Thoracic Aneurysms
跨膜蛋白水解诱导和胸动脉瘤
  • 批准号:
    8399033
  • 财政年份:
    2010
  • 资助金额:
    $ 36.88万
  • 项目类别:
Transmembrane Proteolytic Induction and Thoracic Aneurysms
跨膜蛋白水解诱导和胸动脉瘤
  • 批准号:
    9478272
  • 财政年份:
    2010
  • 资助金额:
    $ 36.88万
  • 项目类别:
Transmembrane Proteolytic Induction and Thoracic Aneurysms
跨膜蛋白水解诱导和胸动脉瘤
  • 批准号:
    8586540
  • 财政年份:
    2010
  • 资助金额:
    $ 36.88万
  • 项目类别:

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