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）： 胸腔主动脉瘤（TAAS）是由于主动脉外基质（ECM）的异常重塑而发展的。 TAA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（例如基质金属蛋白酶（MMP））和ECM蛋白的产生和沉积失调而破坏ECM稳态。重要的是，这些机制是通过主动脉壁内驻留细胞成分的变化部分介导的。大量研究表明，主动脉扩张伴随着平滑肌细胞的凋亡丧失，表明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稳定的肌纤维细胞表型，其特征是肌球蛋白染色增加（DDR2/MYH11），并增强了MMPS和ECM蛋白的产生。假设成纤维细胞的转分化对于TAA进展至关重要。然而，调节这种成纤维细胞到果纤维细胞在TAA发育过程中的介体仍然不确定。一种能够调节主动脉ECM结构和组成的上游信号蛋白，并且已知在介导成纤维细胞对成肌纤维细胞转化方面起着重要作用，它是转化生长因子β（TGF-？）。 tgf-？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，并且已知在继发于Marfan综合征的主动脉根扩张中起重要作用，但其参与在TAA的非MFS病因中仍然不确定。 tgf-？是否在ECM内隔离，受潜在TGF-束缚？结合蛋白。这些潜在的复合物是在TAA发育过程中诱导的关键MMP（MT1-MMP）的蛋白水解靶标。因此，使用既定的TAA小鼠模型和孤立的原发主动脉成纤维细胞培养物（正常和TAA），将通过中心假设检查成纤维细胞转差异化在TAA发育中的作用，即MT1-MMP-依赖性TGF-？通过调节主动脉成纤维细胞表型变化，信号传导对于TAA发育至关重要。该假设将通过证明成纤维细胞转分解的选择性靶向可以调节TAA形成和进展，从而增加TGF-？ TAA发育过程中的信号传导是TGF-释放MT1-MMP释放改变的直接结果？来自潜在的ECM界商店，以及对TGF-的间接药理抑制作用？信号导致TAA发育的衰减。这组统一的目标的结果将在MT1-MMP激活（TGF-）之间建立原因效应关系。依赖性肌纤维细胞分化和TAA发育。