Transforming Growth Factor-beta Signaling Pathways in Thoracic Aortic Aneurysms

胸主动脉瘤中生长因子-β信号通路的转化

• 批准号: 8398916
• 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 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8398916
• 关键词: ACVRL1 gene; Aging; Aneurysm; Animal Model; Aorta; Aortic Rupture; Attention; Cardiovascular Diseases; Cause of Death; Clinical Treatment; Collagen; Complementary DNA; Data; Deposition; Development; Diagnostic; Dilatation - action; Disease; Elastin; Etiology; Event; Extracellular Matrix; Extracellular Matrix Degradation; Fibroblasts; Genes; Growth; Growth Factor; High Prevalence; Human; Incidence; Laboratories; Ligands; Matrix Metalloproteinases; Mediating; Modeling; Modification; Molecular Profiling; Morbidity - disease rate; Mus; Mutant Strains Mice; Mutation; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Peptide Hydrolases; Peptides; Play; Population; Process; Production; Proteolysis; RNA Interference; Regulation; Risk; Role; Rupture; Signal Pathway; Signal Transduction; Signaling Protein; Stimulus; Structure; Surveillance Program; Symptoms; Testing; Therapeutic; Thoracic Aortic Aneurysm; Tissues; Transforming Growth Factor beta; Treatment Protocols; Vascular remodeling; Veterans; cell type; extracellular; gain of function; in vivo; inhibitor/antagonist; insight; loss of function; member; mortality; overexpression; prognostic; public health relevance; receptor; receptor expression; repaired; response; spatiotemporal

DESCRIPTION (provided by applicant): Thoracic aortic aneurysm (TAA) disease is a potentially devastating disease process which often causes death by rupture in the absence of symptoms. TAA formation proceeds by a multifactorial process, influenced by both cellular and extracellular mechanisms that result in alterations of the structure and composition of the extracellular matrix (ECM). There are currently no effective non-surgical clinical treatment protocols available which will halt or reverse the aortic remodeling process during aneurysm formation. While current data demonstrate that this pathological remodeling is a result of a significant spatiotemporal change in the expression/abundance of the matrix metalloproteinases and their endogenous tissue inhibitors, little attention has been focused on the upstream signaling events that regulate the remodeling process. One upstream signaling protein known to alter the structure and composition of the ECM, and known to play an important role in vascular remodeling is transforming growth factor-beta (TGF-b). Examination of the TGF-b signaling pathway during TAA development revealed a shift in signaling from a TGF-bRI-mediated pathway to an ALK-1- mediated pathway. Accordingly, the present proposal will test the central hypothesis that signaling through the ALK-1 pathway drives aberrant vascular remodeling and TAA development. Using a small animal model of TAA, cellular studies of isolated aortic fibroblasts, and in vivo delivery of specific genes/inhibitors, this hypothesis will be tested by: (1) establishing the relationship between alterations in TGF-b signaling and changes in the determinants of ECM degradation/deposition during TAA development; (2) demonstrating that alterations in MMP/TIMP expression and abundance are mediated by the effects of TGF-b on aortic fibroblasts; and (3) demonstrating that MMP/TIMP abundance and aortic dilatation can be altered by modifying TGF-b signaling in vivo. This unique set of proposed studies will establish the relationship between altered TGF-b signaling and the production of the degradative determinants of ECM remodeling. The outcomes of this proposal will provide exceptional insight into the development of TAA and may identify significant targets through which TAA formation and progression can be disrupted.

描述（由申请人提供）： 胸主动脉瘤（TAA）疾病是一种潜在的破坏性疾病过程，常常在没有症状的情况下导致破裂死亡。 TAA 的形成是一个多因素过程，受到细胞和细胞外机制的影响，导致细胞外基质 (ECM) 的结构和组成发生变化。目前尚无有效的非手术临床治疗方案可以阻止或逆转动脉瘤形成过程中的主动脉重塑过程。虽然目前的数据表明这种病理重塑是基质金属蛋白酶及其内源性组织抑制剂的表达/丰度显着时空变化的结果，但很少有人关注调节重塑过程的上游信号事件。已知一种上游信号蛋白可以改变 ECM 的结构和组成，并且在血管重塑中发挥重要作用，那就是转化生长因子-β (TGF-b)。对 TAA 发育过程中 TGF-b 信号传导途径的检查揭示了信号传导从 TGF-bRI 介导的途径转变为 ALK-1 介导的途径。因此，本提案将测试中心假设，即通过 ALK-1 途径的信号传导驱动异常血管重塑和 TAA 发展。使用TAA小动物模型、分离的主动脉成纤维细胞的细胞研究以及特定基因/抑制剂的体内递送，将通过以下方式检验该假设：(1)建立TGF-b信号传导的改变与决定因素的改变之间的关系TAA 开发过程中 ECM 降解/沉积的影响； (2)证明MMP/TIMP表达和丰度的改变是由TGF-b对主动脉成纤维细胞的作用介导的； (3)证明MMP/TIMP丰度和主动脉扩张可以通过改变体内TGF-b信号传导来改变。这组独特的拟议研究将建立改变的 TGF-b 信号传导与 ECM 重塑的降解决定因素的产生之间的关系。该提案的结果将为 TAA 的发展提供独特的见解，并可能确定扰乱 TAA 形成和进展的重要目标。