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
基本信息
- 批准号:10184861
- 负责人:
- 金额:$ 7.33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Aortic AneurysmAreaArterial DisorderArterial Fatty StreakAtherosclerosisAutophagocytosisCell CycleCell ProliferationCellsClinicalDataDiseaseDisease ProgressionDissectionElastic FiberEndocytosisExperimental ModelsFRAP1 geneGoalsGrowthInterruptionLeadLysosomesMedialMedicalMedical GeneticsMedical ImagingMolecularMorbidity - disease rateMusPathogenesisPeptide HydrolasesPhagocytosisPharmacotherapyPhenotypePhosphotransferasesProcessPropertyProteolysisRecyclingResearch PersonnelRuptureSignal TransductionSmooth Muscle MyocytesSpecimenTSC1 geneTestingThoracic Aortic AneurysmThoracic aortaTuberous sclerosis protein complexage groupdaughter cellexperimental studyextracellularimprovedinsightmacromoleculemacrophagemortalitynew therapeutic targetnovelpostnatalpublic health relevancesextargeted treatmenttransdifferentiation
项目摘要
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jay D. Humphrey其他文献
A Computational Framework to Predict and Understand in situ Heart Valve Tissue Engineering
- DOI:
10.1080/24748706.2021.1900703 - 发表时间:
2021-06-01 - 期刊:
- 影响因子:
- 作者:
Elmer Middendorp;Marcos Latorre;Jason M. Szafron;Frank P.T. Baaijens;Jay D. Humphrey;Sandra Loerakker - 通讯作者:
Sandra Loerakker
ブレインサイエンス・レビュー2004
脑科学评论 2004
- DOI:
- 发表时间:
2004 - 期刊:
- 影响因子:0
- 作者:
Daisuke Mori;Guido David;Jay D. Humphrey;James E. Moore Jr.;Miho Terunuma;平田 雅人 - 通讯作者:
平田 雅人
Altered mechanical behavior and properties of the human anterior lens capsule after cataract surgery.
白内障手术后人类晶状体前囊的机械行为和特性发生改变。
- DOI:
10.1016/j.exer.2009.06.001 - 发表时间:
2009 - 期刊:
- 影响因子:3.4
- 作者:
R. Pedrigi;J. Dziezyc;Jay D. Humphrey - 通讯作者:
Jay D. Humphrey
Journal of Mechanics of Materials and Structures SPONTANEOUS UNWINDING OF A LABILE DOMAIN IN A COLLAGEN TRIPLE HELIX
材料与结构力学杂志 胶原三螺旋中不稳定域的自发展开
- DOI:
- 发表时间:
2007 - 期刊:
- 影响因子:0
- 作者:
Krishnakumar M. Ravikumar;Jay D. Humphrey;Wonmuk Hwang - 通讯作者:
Wonmuk Hwang
FSGe: A fast and strongly-coupled 3D fluid-solid-growth interaction method
FSGe:一种快速、强耦合的 3D 流固生长相互作用方法
- DOI:
10.48550/arxiv.2404.13523 - 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
Martin R. Pfaller;Marcos Latorre;Erica L. Schwarz;F. Gerosa;Jason M. Szafron;Jay D. Humphrey;Alison L. Marsden - 通讯作者:
Alison L. Marsden
Jay D. Humphrey的其他文献
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{{ truncateString('Jay D. Humphrey', 18)}}的其他基金
Computational model-driven design to mitigate vein graft failure after coronary artery bypass
计算模型驱动的设计可减轻冠状动脉搭桥术后静脉移植失败的风险
- 批准号:
10683327 - 财政年份:2022
- 资助金额:
$ 7.33万 - 项目类别:
Computational model-driven design to mitigate vein graft failure after coronary artery bypass
计算模型驱动设计减轻冠状动脉搭桥术后静脉移植失败
- 批准号:
10539814 - 财政年份:2022
- 资助金额:
$ 7.33万 - 项目类别:
Modeling Multiscale Immuno-Mechanics in Aortic Disease
主动脉疾病的多尺度免疫力学建模
- 批准号:
10532786 - 财政年份:2022
- 资助金额:
$ 7.33万 - 项目类别:
Modeling Multiscale Immuno-Mechanics in Aortic Disease
主动脉疾病的多尺度免疫力学建模
- 批准号:
10352581 - 财政年份:2022
- 资助金额:
$ 7.33万 - 项目类别:
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 - 财政年份:2019
- 资助金额:
$ 7.33万 - 项目类别:
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:
10573756 - 财政年份:2019
- 资助金额:
$ 7.33万 - 项目类别:
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:
10132382 - 财政年份:2019
- 资助金额:
$ 7.33万 - 项目类别:
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:
9904189 - 财政年份:2019
- 资助金额:
$ 7.33万 - 项目类别:
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Smooth Muscle Cell Proliferation and Degradative Phenotype in Thoracic Aorta Aneurysm and Dissection
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