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

胸主动脉瘤和夹层中的平滑肌细胞增殖和降解表型

• 批准号: 10184861
• 负责人: Jay D. Humphrey
• 金额: $ 7.33万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-18 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10184861
• 关键词: Aortic Aneurysm; Area; Arterial Disorder; Arterial Fatty Streak; Atherosclerosis; Autophagocytosis; Cell Cycle; Cell Proliferation; Cells; Clinical; Data; Disease; Disease Progression; Dissection; Elastic Fiber; Endocytosis; Experimental Models; FRAP1 gene; Goals; Growth; Interruption; Lead; Lysosomes; Medial; Medical; Medical Genetics; Medical Imaging; Molecular; Morbidity - disease rate; Mus; Pathogenesis; Peptide Hydrolases; Phagocytosis; Pharmacotherapy; Phenotype; Phosphotransferases; Process; Property; Proteolysis; Recycling; Research Personnel; Rupture; Signal Transduction; Smooth Muscle Myocytes; Specimen; TSC1 gene; Testing; Thoracic Aortic Aneurysm; Thoracic aorta; Tuberous sclerosis protein complex; age group; daughter cell; experimental study; extracellular; improved; insight; macromolecule; macrophage; mortality; new therapeutic target; novel; postnatal; public health relevance; sex; targeted treatment; transdifferentiation

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.

项目概要 胸主动脉瘤和夹层 (TAAD) 是一组人们知之甚少的疾病，其原因是 在两性和所有年龄组中都有显着的发病率和死亡率，但没有特定的药物治疗。 疾病机制的阐明侧重于内侧平滑肌细胞 (SMC) 损失的显着区域， 而 SMC 增殖灶则被忽视。我们发现临床上SMC的数量有所增加 TAAD 的样本，其他几位研究人员也是如此。我们认为过度的 SMC 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细胞时，TAAD 会加剧 细胞可能会中断与邻近弹性层的相互作用或驱动血管壁的生长。来测试我们的 假设 SMC 增殖和增殖信号传导导致主动脉病，我们开发了一种新的 实验模型。产后条件性删除 Tsc1（结节性硬化症复合体的一个组成部分） 鼠 SMC 会激活关键激酶，即雷帕霉素 (mTOR) 的机制靶标，调节细胞 其他进程之间的扩散。我们的初步研究表明，mTOR 信号传导和 SMC 的诱导 增殖导致进行性 TAAD，与 SMC 的新型“降解表型”相关。我们的目标是 了解疾病过程的细胞和分子机制，并确定是否与其他相关 TAAD的实验模型和临床标本。我们不认为收购的子集 主动脉中膜中降解 SMC 的巨噬细胞标记和功能代表转分化 最近在动脉粥样硬化斑块中描述了巨噬细胞。相反，降解的 SMC 会获得某些 模拟巨噬细胞成熟的特性，包括增加蛋白酶分泌、吞噬作用、 内吞作用、自噬和溶酶体活性。更大的蛋白水解作用，以及丧失蛋白水解作用的后遗症 收缩和合成活性，通过细胞外清除导致弹性纤维断裂和 TAAD 碎片和大分子的回收可能会延缓疾病的进展。我们的假设是具有挑衅性的，我们的 初步数据令人信服。完成我们提出的实验将对 TAAD 和其他 mTOR 依赖性动脉病（例如动脉粥样硬化和主动脉硬化）的发病机制， 并发现这种致命疾病的新治疗靶点。