Smooth Muscle Cell Proliferation and Degradative Phenotype in Thoracic Aorta Aneurysm and Dissection

项目总结 胸主动脉瘤和夹层(Taad)是一组知之甚少的疾病。 无论男女和所有年龄段都有显著的发病率和死亡率，但没有特定的药物治疗。 疾病机制的阐明主要集中在中膜平滑肌细胞(SMC)丢失的明显区域， 而SMC增殖灶则被忽视。我们发现在临床上SMC的数量增加。 塔阿德的标本，就像其他几个调查人员一样。我们认为，SMC过度增殖可能会 当分裂细胞从收缩表型转变为进入细胞周期和子代时，加剧TAAD 细胞可能会中断与相邻弹性膜的相互作用或驱动管壁的生长。测试我们的 假设SMC增殖和增殖信号参与了大动脉病变，我们开发了一种新的 实验模型。TSC1，结节性硬化症复合体的一种成分，在出生后有条件地缺失 小鼠SMC导致调节细胞的关键激酶雷帕霉素的机械性靶点(MTOR)的激活 在其他过程中，核扩散。我们的初步研究表明，mTOR信号和SMC的诱导 增殖导致进行性TAAD与SMC的一种新的“退化表型”相关。我们的目标是 了解疾病过程的细胞和分子机制，并确定是否与其他 TAAD实验模型和临床标本。我们不认为收购部分 降解性主动脉中膜细胞的巨噬细胞标志物和功能代表转分化为 最近描述的动脉粥样硬化斑块中的巨噬细胞。相反，退化的SMC获得了某些 模仿巨噬细胞成熟的特性，包括增加蛋白酶分泌，吞噬， 内吞作用、自噬和溶酶体活性。更大的蛋白质分解，以及丢失的后遗症 收缩和合成活动，导致弹性纤维断裂和TAAD，通过清除细胞外 碎片和大分子的循环利用可能会延缓疾病的发展。我们的假设是挑衅性的，我们的 初步数据令人信服。我们提议的实验的完成将使我们对 TAAD和其他依赖mTOR的动脉病变的发病机制，如动脉粥样硬化和主动脉硬化， 为这一致命疾病找到新的治疗靶点。

PROJECT SUMMARY Thoracic aortic aneurysm and dissection (TAAD) are a poorly understood group of disorders responsible for significant morbidity and mortality in both sexes and all age groups, but without specific pharmacotherapy. Elucidation of disease mechanisms focus on conspicuous areas of medial smooth muscle cell (SMC) loss, whereas foci of SMC proliferation are overlooked. We found that the number of SMCs is increased in clinical specimens of TAAD, as have several other investigators. We considered that excessive SMC proliferation may exacerbate TAAD as dividing cells transition from a contractile phenotype to enter the cell cycle and daughter cells may interrupt interactions with contiguous elastic laminae or drive growth of the vessel wall. To test our hypothesis that SMC proliferation and proliferative signaling contributes to aortopathy, we developed a novel experimental model. Conditional deletion of Tsc1, a component of the tuberous sclerosis complex, in postnatal murine SMCs leads to activation of a key kinase, mechanistic target of rapamycin (mTOR), that regulates cell proliferation among other processes. Our preliminary studies reveal that induction of mTOR signaling and SMC proliferation cause progressive TAAD associated with a novel "degradative phenotype" of SMCs. Our goals are to understand cellular and molecular mechanisms of the disease process and to determine if relevant in other experimental models and clinical specimens of TAAD. We do not believe that the acquisition of a subset of macrophage markers and functions by degradative SMCs in the aortic media represents transdifferentiation to macrophages as recently described in atherosclerotic plaques. Rather, degradative SMCs acquire certain properties that mimic macrophage maturation, including increased protease secretion, phagocytosis, endocytosis, autophagy, and lysosome activity. Greater proteolysis, together with sequelae from loss of contractile and synthetic activity, lead to elastic fiber fragmentation and TAAD, though clearance of extracellular debris and recycling of macromolecules may retard disease progression. Our hypothesis is provocative and our preliminary data compelling. Completion of our proposed experiments will yield considerable insight into the pathogenesis of TAAD and other mTOR-dependent arteriopathies, such as atherosclerosis and aortic stiffening, and discover new therapeutic targets for this lethal disease.