Regulation of Cellular Phenotype Change in Thoracic Aortic Aneurysms

胸主动脉瘤细胞表型变化的调节

• 批准号: 9275333
• 负责人: Jeffrey A. Jones
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275333
• 关键词: Address; Adrenergic Receptor; Aneurysm; Angiotensin II; Antibodies; Antihypertensive Agents; Apoptotic; Attenuated; Binding Proteins; Cause of Death; Clinical; Complex; Cytomegalovirus; DDR2 gene; Deposition; Development; Dilatation - action; Disease; Enterobacteria phage P1 Cre recombinase; Etiology; Exons; Extracellular Matrix; Extracellular Matrix Proteins; Family suidae; Fibroblasts; Growth Factor; Homeostasis; Inhibition of Matrix Metalloproteinases Pathway; Intervention; Intraperitoneal Injections; Knock-out; Laboratories; Left; LoxP-flanked allele; Marfan Syndrome; Matrix Metalloproteinases; Mediating; Mediator of activation protein; Modality; Mutate; Myofibroblast; Myosin ATPase; Operative Surgical Procedures; Oral; Outcome; Pathway interactions; Peptides; Pharmacology; Phenotype; Plant Roots; Play; Process; Production; Proteolysis; Risk; Role; Rupture; Secondary to; Series; Signal Transduction; Signaling Protein; Smooth Muscle Myocytes; Staining method; Stains; Structure; Symptoms; TGFB1 gene; Tamoxifen; Testing; Therapeutic; Thoracic Aortic Aneurysm; Tissues; Transforming Growth Factor beta; Transgenic Mice; attenuation; cell growth regulation; cell type; clinically relevant; matrix metalloproteinase 26; migration; mouse model; neutralizing antibody; overexpression; public health relevance; receptor; therapeutic target; transdifferentiation

DESCRIPTION (provided by applicant): Thoracic aortic aneurysms (TAAs) develop as a consequence to abnormal remodeling of the aortic extracellular matrix (ECM). TAA development is influenced by a series of interrelated mechanisms that disrupt ECM homeostasis through the stimulation of proteolytic pathways, such as the matrix metalloproteinases (MMPs) and dysregulation of the production and deposition of ECM proteins. Importantly, these mechanisms are mediated in part through changes in the resident cellular constituents within the aortic wall. Numerous studies have demonstrated that aortic dilatation is accompanied by the apoptotic loss of smooth muscle cells, suggesting that the aortic fibroblast may be the key cellular mediator of ECM remodeling during aneurysm formation. Moreover, recent evidence from this laboratory suggests that aortic fibroblasts undergo a stable transformation to a myofibroblast phenotype, that is characterized by increased myosin staining (DDR2/Myh11) and enhanced production of both MMPs and ECM proteins. It is hypothesized that the transdifferentiation of fibroblasts is essential for TAA progression. However, the mediator(s) regulating this fibroblast-to-myofibroblast transition during TAA development remain undefined. One upstream signaling protein capable of regulating the structure and composition of the aortic ECM, and known to play an important role in mediating the fibroblast-to- myofibroblast transformation, is transforming growth factor-beta (TGF-?). TGF-? is a soluble peptide growth factor, produced by multiple cell types within the aortic wall, and is known to play a significant role in aortic root dilatation secondary to Marfan syndrome, but its involvement remains undefined in non-MFS etiologies of TAA. TGF-? is sequestered within the ECM, bound by latent TGF-? binding proteins. These latent complexes are proteolytic targets for key MMPs (MT1-MMP) that are induced during TAA development. Accordingly, using an established mouse model of TAA, and isolated primary aortic fibroblast cultures (normal and TAA), the role of fibroblast transdifferentiation in TAA development will be examined with the central hypothesis that MT1-MMP- dependent TGF-? signaling is essential for TAA development through the modulation of aortic fibroblast phenotype change. This hypothesis will be tested by demonstrating that selective targeting of fibroblast transdifferentiation can modulate TAA formation and progression, that increased TGF-? signaling during TAA development is a direct result of altered MT1-MMP-dependent release of TGF-? from latent ECM bound stores, and that indirect pharmacological inhibition of TGF-? signaling results in the attenuation of TAA development. The outcomes from this unified set of aims will establish a cause-effect relationship between MT1-MMP activation, TGF-? dependent myofibroblast differentiation, and TAA development.

描述（由申请人提供）： 胸主动脉瘤（TAAs）是主动脉细胞外基质（ECM）异常重塑的结果。 TAA 的发育受到一系列相互关联的机制的影响，这些机制通过刺激蛋白水解途径破坏 ECM 稳态，例如基质金属蛋白酶 (MMP) 以及 ECM 蛋白的产生和沉积失调。重要的是，这些机制部分是通过主动脉壁内驻留细胞成分的变化来介导的。大量研究表明主动脉扩张伴随着平滑肌细胞的凋亡丧失，提示主动脉成纤维细胞可能是动脉瘤形成过程中ECM重塑的关键细胞介质。此外，该实验室的最新证据表明，主动脉成纤维细胞经历了向肌成纤维细胞表型的稳定转变，其特征是肌球蛋白染色（DDR2/Myh11）增加以及MMP和ECM蛋白的产生增强。据推测，成纤维细胞的转分化对于 TAA 进展至关重要。然而，在 TAA 发育过程中调节成纤维细胞向肌成纤维细胞转变的介质仍不清楚。转化生长因子-β (TGF-β) 是一种上游信号蛋白，能够调节主动脉 ECM 的结构和组成，并且在介导成纤维细胞向肌成纤维细胞的转化中发挥重要作用。转化生长因子-？是一种可溶性肽生长因子，由主动脉壁内多种细胞类型产生，已知在继发于马凡综合征的主动脉根部扩张中发挥重要作用，但其在 TAA 的非 MFS 病因学中的参与尚不清楚。转化生长因子-？被隔离在 ECM 内，被潜在的 TGF-？结合蛋白。这些潜在复合物是 TAA 发育过程中诱导的关键 MMP (MT1-MMP) 的蛋白水解靶标。因此，使用已建立的 TAA 小鼠模型和分离的原代主动脉成纤维细胞培养物（正常和 TAA），将通过 MT1-MMP 依赖性 TGF-β 的中心假设来检查成纤维细胞转分化在 TAA 发育中的作用。信号传导通过调节主动脉成纤维细胞表型变化对于 TAA 发育至关重要。这一假设将通过证明成纤维细胞转分化的选择性靶向可以调节 TAA 的形成和进展（即增加 TGF-β）来进行检验。 TAA 发育过程中的信号传导是 MT1-MMP 依赖性 TGF-β 释放改变的直接结果。来自潜在的 ECM 结合储存，以及 TGF-β 的间接药理学抑制信号传导导致 TAA 发育减弱。这组统一目标的结果将在 MT1-MMP 激活、TGF-β 之间建立因果关系。依赖性肌成纤维细胞分化和 TAA 发育。