Age-Dependent Mechanisms in Thoracic Aortic Aneurysms

胸主动脉瘤的年龄依赖性机制

• 批准号: 8526324
• 负责人: John S. Ikonomidis
• 金额: $ 28.57万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8526324
• 关键词: A Mouse; Acceleration; Address; Affect; Age-Years; Aging; Aneurysm; Aorta; Aortic Rupture; Binding; Cause of Death; Cessation of life; Chest; Collagen; Coupled; Data; Defect; Deposition; Development; Diagnostic; Dimensions; Disease; Drug Design; Extracellular Matrix; Family; Fibroblasts; Frequencies; Functional disorder; Gene Expression; Genetic Transcription; Histology; Individual; Laboratories; Lead; Left; Matrix Metalloproteinases; Mediating; Mediator of activation protein; Microbubbles; Modeling; Mus; Operative Surgical Procedures; Outcome; Pathologic; Pathway interactions; Patients; Peptide Hydrolases; Persons; Phenotype; Play; Process; Resolution; Risk; Risk Factors; Role; Rupture; Severities; Signal Pathway; Signal Transduction; Stimulus; Structure; Symptoms; Testing; Therapeutic; Thoracic Aortic Aneurysm; Thoracic aorta; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Ultrasonography; Vascular remodeling; age related; aged; antibody conjugate; base; disease diagnosis; extracellular; human old age (65+); in vivo; indexing; inhibitor/antagonist; insight; lentiviral-mediated; novel; older patient; outcome forecast; overexpression; promoter; response; restoration

DESCRIPTION (provided by applicant): Current projections indicate that the number of individuals 65 years and older is expected to double by the year 2030. Because thoracic aortic aneurysm (TAAs) occur most frequently in persons 60-70 years of age, it follows that over the next two decades the frequency of aneurysm disease diagnosis is going to increase dramatically. TAA disease is an insidious process which often causes death by rupture in the absence of antecedent symptomology. There are presently no available indices to determine which patients may be at greater risk for acceleration of TAA development, warranting more immediate treatment. Therefore, further diagnostic and therapeutic advancement is critical, especially for those patients who have not yet reached surgical criteria. TAA development proceeds by a multifactorial process that is regulated by both intracellular and extracellular mechanisms which drive the pathological remodeling of the aortic extracellular matrix (ECM). The matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that play an obligate role in TAA-induced ECM remodeling. In addition to structural remodeling, changes in the cellular constituents have also been demonstrated, and recent data has identified the aortic fibroblast as a critical mediator. When age-dependent changes in aortic structure and composition are overlaid with other risk factors for aneurysm development, the threshold, severity, and prognosis of aneurysm disease is likely accelerated. Therefore, the present application proposes to test the central hypothesis that age-related changes in thoracic aortic aneurysm development are driven by alterations in signaling through the transforming growth factor-beta pathway and result in altered aortic extracellular matrix mediated by phenotypically unique fibroblasts. This hypothesis will be addressed through three specific aims: 1) Demonstrate that differential acceleration of TAA development in young and old mice is a direct result of structural and compositional differences in aortic substrate; 2) Establish that age- dependent changes in TAA progression are a direct result of alterations in aortic fibroblast number, phenotype, and function; and 3) Establish that defects in TGF-b signaling are responsible for age-dependent changes in TAA progression in the "old" aorta. The outcomes from this project will establish that the structural and compositional changes in the aortic ECM of old mice are mediated by age-dependent defects in collagen and MMP/TIMP gene expression. These age-dependent changes are affected by reduced signaling through the TGF-b pathway and result in a weakened aortic substrate that is hyper-responsive to TAA stimuli. Collectively, these studies will provide significant insight toward understanding the pathophysiology of TAA development, and will form the basis for novel, rational drug design for therapeutic modulation of TAA progression in patients with this devastating disease.

描述（由申请人提供）：目前的预测表明，到2030年，65岁及以上的人数预计将翻一番。由于胸主动脉瘤（TAA）最常发生在60-70岁的人群中，因此在未来20年内，动脉瘤疾病诊断的频率将急剧增加。TAA疾病是一种隐匿性过程，通常在没有先前病理学检查的情况下因破裂而导致死亡。目前没有可用的指标来确定哪些患者可能处于加速TAA发展的更大风险中，从而避免更直接的治疗。因此，进一步的诊断和治疗进展至关重要，特别是对于那些尚未达到手术标准的患者。TAA的发育是一个多因素过程，该过程受到细胞内和细胞外机制的调节，这些机制驱动主动脉细胞外基质（ECM）的病理性重塑。基质金属蛋白酶（matrix metalloproteinases，MMPs）是一类在TAA诱导的ECM重塑中发挥特异性作用的蛋白水解酶家族。除了结构重塑，细胞成分的变化也已被证明，最近的数据已确定主动脉成纤维细胞作为一个关键的调解人。当主动脉结构和组成的年龄依赖性变化与动脉瘤发展的其他风险因素叠加时，动脉瘤疾病的阈值，严重程度和预后可能会加速。因此，本申请提出测试中心假设，即胸主动脉瘤发展中的年龄相关变化是由通过转化生长因子-β途径的信号传导的改变驱动的，并导致由表型独特的成纤维细胞介导的主动脉细胞外基质改变。该假设将通过三个具体目标来解决：1）证明年轻和老年小鼠中TAA发育的差异加速是主动脉基质的结构和组成差异的直接结果; 2）确定TAA进展中的年龄依赖性变化是主动脉成纤维细胞数量、表型和功能改变的直接结果;和3）确定TGF-β信号传导的缺陷是“老”主动脉中TAA进展的年龄依赖性变化的原因。该项目的结果将确定老年小鼠主动脉ECM的结构和组成变化是由胶原蛋白和MMP/TIMP基因表达的年龄依赖性缺陷介导的。这些年龄依赖性变化受到通过TGF-β途径的信号传导减少的影响，并导致对TAA刺激过度反应的主动脉基质减弱。总的来说，这些研究将为了解TAA发展的病理生理学提供重要的见解，并将为新型，合理的药物设计奠定基础，用于治疗这种毁灭性疾病患者的TAA进展。