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: 10376852
• 负责人: Jay D. Humphrey
• 金额: $ 65.28万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376852
• 关键词: Aorta; Aortic Aneurysm; Area; Arterial Disorder; Arterial Fatty Streak; Atherosclerosis; Autophagocytosis; Biogenesis; Biomechanics; Cell Culture Techniques; Cell Cycle; Cell Death; Cell Proliferation; Cell Survival; Cell physiology; Cells; Chronic; Clinical; Collection; Complex; Data; Disease; Disease Progression; Dissection; Elastic Fiber; Endocytosis; Enzymes; Etiology; Event; Exocytosis; Experimental Models; Extracellular Matrix; FRAP1 gene; Functional disorder; Genes; Genetic Transcription; Goals; Growth; Hand; Histologic; Human; Interruption; Lead; Lysosomes; Maps; Medial; Medical; Medical Genetics; Medical Imaging; Molecular; Morbidity - disease rate; Morphology; Mus; Names; Organelles; Pathogenesis; Pathologic; Pathology; Peptide Hydrolases; Phagocytosis; Pharmacotherapy; Phenotype; Phosphotransferases; Process; Production; Property; Protein Biosynthesis; Proteins; Proteolysis; RNA marker; Recycling; Research Personnel; Role; Rupture; Sampling; Severity of illness; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Specimen; Stress; Structure; TSC1 gene; TSC2 gene; Testing; Thoracic Aortic Aneurysm; Thoracic aorta; Tissues; Tuberous Sclerosis; age group; cell growth; daughter cell; experimental study; extracellular; hemodynamics; improved; inhibitor; insight; macromolecule; macrophage; mortality; mouse model; new therapeutic target; novel; postnatal; protein biomarkers; public health relevance; response; sex; targeted treatment; transcription factor; transdifferentiation; tumor growth; uptake

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.

项目摘要 胸动脉瘤和解剖（TAAD）是一群造成的疾病，负责 性别和所有年龄组的发病率和死亡率很高，但没有特定的药物治疗。 阐明疾病机制的重点是内侧平滑肌细胞（SMC）损失的显着区域， 而SMC增殖的焦点被忽略了。我们发现临床中的SMC数量增加 TAAD的标本，还有其他几个研究人员。我们认为过度SMC增殖可能 加剧TAAD作为将细胞从收缩表型转变为进入细胞周期的细胞和女儿 细胞可能会中断与连续的弹性层或驱动血管壁的生长相互作用。测试我们的 SMC增殖和增殖信号传导有助于主动脉肿大的假设，我们开发了一种新颖的 实验模型。 TSC1的有条件缺失，TSC1是结节性硬化症复合物的一个组成部分 鼠SMC会导致激活雷帕霉素（MTOR）的密钥激酶，可调节细胞 其他过程之间的扩散。我们的初步研究表明，MTOR信号传导和SMC的诱导 增殖导致与SMC的新型“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 TAAD的实验模型和临床标本。我们不认为获得一部分 主动脉介质中降解SMC的巨噬细胞标记和功能代表转变为 巨噬细胞在动脉粥样硬化斑块中最近描述。相反，降解的SMC可以确定 模仿巨噬细胞成熟的特性，包括蛋白酶分泌增加，吞噬作用， 内吞作用，自噬和溶酶体活性。更大的蛋白水解以及后遗症因丧失的损失 收缩和合成活性，导致弹性纤维碎片和TAAD，尽管细胞外的清除率 大分子的碎屑和回收可能会阻碍疾病进展。我们的假设是挑衅的，我们的 初步数据引人注目。我们提出的实验的完成将有大量见解 TAAD和其他MTOR依赖性动脉病的发病机理，例如动脉粥样硬化和主动脉僵硬， 并发现这种致命疾病的新治疗靶标。