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: 8242629
• 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/8242629
• 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. PUBLIC HEALTH RELEVANCE: Thoracic aortic aneurysm (TAA) disease is a potentially devastating disease process which often lacks specific symptomology, rendering them unnoticed until the aorta ruptures, resulting in significant morbidity and mortality. Currently, there are no noninvasive interventional treatments available for TAA patients. A "watch and wait" surveillance program is initiated until the risk of aortic rupture outweighs the risk of the surgical repair. With a growing concern of increased aneurysm incidence due to a rapidly aging Veterans population and a high prevalence for cardiovascular disease, further diagnostic and therapeutic advancement is critical. The present proposal will assess key components of the TGF-b signaling pathway, in an effort to understand the role of TGF-b signaling in the etiology of TAA disease. Elucidating the underlying mechanisms may assist in developing strategies to arrest TAA formation or even reverse TAA progression, and will carry significant diagnostic, prognostic, and therapeutic implications for Veteran's and the public at large.

描述（由申请人提供）： 胸动脉瘤（TAA）疾病是一种潜在的毁灭性疾病过程，在没有症状的情况下通常会因破裂而导致死亡。 TAA形成是通过多因素过程进行的，受细胞和细胞外机制的影响，导致细胞外基质（ECM）的结构和组成改变。目前尚无有效的非手术临床治疗方案，可以在动脉瘤形成过程中停止或逆转主动脉重塑过程。尽管目前的数据表明，这种病理重塑是由于基质金属蛋白酶及其内源性组织抑制剂的表达/丰度的显着时空变化的结果，但很少关注的关注集中在调节重塑过程的上游信号事件上。一种已知可以改变ECM的结构和组成并在血管重塑中起重要作用的上游信号传导蛋白是转化生长因子-Beta（TGF-B）。 TAA发育过程中TGF-B信号通路的检查表明，信号从TGF-BRI介导的途径转移到ALK-1介导的途径。因此，本提案将检验中心假设，即通过ALK-1途径发出信号传导驱动异常的血管重塑和TAA发育。使用TAA的小动物模型，对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，该假设将通过：（1）确定TGF-B信号传导的变化与ECM在TAA发育过程中ECM脱位/dep的决定因素的变化之间的关系； （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影响介导的； （3）证明MMP/TIMP丰度和主动脉扩张可以通过在体内修改TGF-B信号传导来改变。这项独特的提议研究将确定TGF-B信号改变与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的发展提供非凡的见解，并可能确定可以破坏TAA形成和进展的重要目标。 公共卫生相关性： 胸动脉瘤（TAA）疾病是一种潜在的毁灭性疾病过程，通常缺乏特定的症状，使它们浮动直到主动脉破裂，导致显着的发病率和死亡率。目前，TAA患者尚无无创介入治疗。启动“观察和等待”监视计划，直到主动脉破裂的风险超过手术修复的风险。由于迅速老化的退伍军人人口以及心血管疾病的高患病率，人们对动脉瘤发生率的增加越来越关注，进一步的诊断和治疗性进步至关重要。本提案将评估TGF-B信号通路的关键组成部分，以了解TGF-B信号传导在TAA病病因中的作用。阐明潜在的机制可能有助于制定阻止TAA形成甚至反向TAA进展的战略，并将对退伍军人和整个公众产生重大诊断，预后和治疗意义。