Age-Dependent Mechanisms in Thoracic Aortic Aneurysms

描述(由申请人提供)：目前的预测表明，到2030年，65岁及以上的个人数量预计将翻一番。由于胸主动脉瘤(TAA)最常发生在60-70岁的人群中，因此在接下来的20年里，诊断为主动脉瘤疾病的频率将显著增加。TAA病是一种潜伏的过程，在没有先兆症状的情况下，通常会因破裂而死亡。目前还没有可用的指标来确定哪些患者可能有更大的风险加速TAA的发展，从而保证更立即的治疗。因此，进一步的诊断和治疗进步是至关重要的，特别是对于那些尚未达到手术标准的患者。TAA的发生是一个多因素的过程，受细胞内和细胞外机制的调节，这些机制驱动了主动脉细胞外基质(ECM)的病理性重构。基质金属蛋白酶(MMPs)是一类蛋白水解酶，在TAA诱导的ECM重塑中起着决定性的作用。除了结构重建，细胞成分的变化也被证明，最近的数据已经确定主动脉成纤维细胞是一个关键的介质。当年龄相关的主动脉结构和成分的改变与动脉瘤发展的其他危险因素叠加时，动脉瘤疾病的阈值、严重程度和预后可能会加快。因此，本申请建议验证这一中心假设，即胸主动脉瘤发展中年龄相关的变化是由转化生长因子-β途径中的信号变化驱动的，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。这一假说将通过三个具体目标来解决：1)证明年轻和老年小鼠TAA发育的差异是主动脉基质结构和成分差异的直接结果；2)证实TAA进展中的年龄相关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；3)证实转化生长因子-b信号的缺陷与“老年”主动脉中TAA进展的年龄相关性变化有关。该项目的结果将证实，老年小鼠主动脉ECM的结构和成分变化是由年龄相关的胶原和基质金属蛋白酶/TIMP基因表达缺陷所介导的。这些与年龄相关的改变受到通过转化生长因子-b途径的信号减少的影响，并导致对TAA刺激高度反应的减弱的主动脉基质。总之，这些研究将为理解TAA发生的病理生理学提供重要的见解，并将形成新的、合理的药物设计的基础，用于治疗调节这种毁灭性疾病患者的TAA进展。 公共卫生相关性：TAA病是一种潜伏的过程，通常在没有任何症状的情况下通过破裂而导致死亡。目前还没有可用的指数来确定哪些患者可能面临加速发生TAA的最大风险。该项目将确定主动脉内与年龄相关的缺陷，这些缺陷导致对TAA刺激高度反应的主动脉基质减弱，从而为开发治疗潜伏性和临床破坏性疾病的诊断和治疗策略提供新的见解。

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. PUBLIC HEALTH RELEVANCE: TAA disease is an insidious process which often causes death by rupture in the absence of any symptoms. There are no available indices to determine which patients may be at greatest risk for accelerated TAA development. This project will identify age-dependent defects within the aorta that result in a weakened aortic substrate that is hyper-responsive to TAA stimuli and thereby provide new insights for the development of diagnostic and therapeutic strategies for treating insidious and clinically devastating disease.