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

项目摘要 胸主动脉瘤和夹层（TAAD）是一组知之甚少的疾病， 男女和所有年龄组的发病率和死亡率都很高，但没有具体的药物治疗。 疾病机制的阐明集中在中膜平滑肌细胞（SMC）损失的明显区域， 而SMC增殖灶被忽略。我们发现，在临床上， TAAD的标本，还有其他几个研究人员。我们认为SMC过度增殖可能 当分裂细胞从收缩表型转变为进入细胞周期和子代细胞时， 细胞可以中断与相邻弹性层的相互作用或驱动血管壁的生长。来测试我们 假设SMC增殖和增殖信号有助于动脉粥样硬化病，我们开发了一种新的 实验模型出生后结节性硬化综合征的一个组成部分Tsc1的条件性缺失 鼠SMC导致一种关键激酶的激活，雷帕霉素的机制靶点（mTOR）， 扩散等过程。我们的初步研究表明，诱导mTOR信号和SMC 增殖导致与SMC的新“降解表型”相关的进行性TAAD。我们的目标是 了解疾病过程的细胞和分子机制，并确定是否与其他疾病相关。 TAAD的实验模型和临床标本。我们不认为收购一个子集 巨噬细胞标志物和主动脉中降解SMC的功能代表了向 巨噬细胞，如最近描述的动脉粥样硬化斑块。相反，降解的SMC获得某些 模拟巨噬细胞成熟的性质，包括增加的蛋白酶分泌，吞噬作用， 内吞作用、自噬和溶酶体活性。更大的蛋白质水解，以及丧失蛋白质的后遗症。 收缩和合成活性，导致弹性纤维断裂和TAAD，虽然细胞外的清除 大分子的碎片和再循环可以延缓疾病的进展。我们的假设是挑衅性的， 初步数据令人信服。完成我们提出的实验将产生相当深入的了解 TAAD和其他mTOR依赖性动脉病的发病机制，如动脉粥样硬化和主动脉硬化， 并为这种致命疾病发现新的治疗靶点。

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.