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:10376852
- 负责人:
- 金额:$ 65.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AortaAortic AneurysmAreaArterial DisorderArterial Fatty StreakAtherosclerosisAutophagocytosisBiogenesisBiomechanicsCell Culture TechniquesCell CycleCell DeathCell ProliferationCell SurvivalCell physiologyCellsChronicClinicalCollectionComplexDataDiseaseDisease ProgressionDissectionElastic FiberEndocytosisEnzymesEtiologyEventExocytosisExperimental ModelsExtracellular MatrixFRAP1 geneFunctional disorderGenesGenetic TranscriptionGoalsGrowthHandHistologicHumanInterruptionLeadLysosomesMapsMedialMedicalMedical GeneticsMedical ImagingMolecularMorbidity - disease rateMorphologyMusNamesOrganellesPathogenesisPathologicPathologyPeptide HydrolasesPhagocytosisPharmacotherapyPhenotypePhosphotransferasesProcessProductionPropertyProtein BiosynthesisProteinsProteolysisRNA markerRecyclingResearch PersonnelRoleRuptureSamplingSeverity of illnessSignal PathwaySignal TransductionSmooth Muscle MyocytesSpecimenStressStructureTSC1 geneTSC2 geneTestingThoracic Aortic AneurysmThoracic aortaTissuesTuberous Sclerosisage groupcell growthdaughter cellexperimental studyextracellularhemodynamicsimprovedinhibitorinsightmacromoleculemacrophagemortalitymouse modelnew therapeutic targetnovelpostnatalprotein biomarkerspublic health relevanceresponsesextargeted treatmenttranscription factortransdifferentiationtumor growthuptake
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。
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
Multi-Scale Multi-Cell Computational Model of Inflammation-Mediated Aortic Remodeling in Hypertension
- DOI:
10.1007/s10439-025-03685-3 - 发表时间:
2025-02-04 - 期刊:
- 影响因子:5.400
- 作者:
Ana C. Estrada;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
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
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:
$ 65.28万 - 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:
$ 65.28万 - 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:
$ 65.28万 - 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:
$ 65.28万 - 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:
10184861 - 财政年份:2020
- 资助金额:
$ 65.28万 - 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:
$ 65.28万 - 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:
$ 65.28万 - 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:
$ 65.28万 - 项目类别:
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