Novel Role of Thrombospondin-1 in Protection against Rupture of Abdominal Aortic Aneurysm
Novel Role of Thrombospondin-1 in Protection against Rupture of Abdominal Aortic Aneurysm
批准号:
10609876
负责人:
Bo Liu
金额:
$45.99万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-05-01 至 2025-04-30
关键词:
Abdominal Aortic AneurysmActinsAddressAdoptive TransferAffectAneurysmAngiotensin IIAnimalsAortaAortic AneurysmAortic RuptureApoptoticAreaAtherosclerosisBlood VesselsBone MarrowBreedingCD47 geneCellsClinicalComplicationCoupledDataDeoxyribonuclease IDetectionDevelopmentDilatation - actionElastasesFemaleGene DeletionGrowthHumanImipramineImmunohistochemistryImpairmentIn Situ HybridizationIncidenceInfiltrationInflammationInfusion proceduresKnock-outKnockout MiceKnowledgeLife StyleLow-Density LipoproteinsLoxP-flanked alleleMacrophageMediatingModelingMolecularMolecular ProfilingMonitorMouse StrainsMusOperative Surgical ProceduresPatientsPhagocytosisPhenotypePlayPolymersPreventiveProteinsPublicationsReportingResearchRoleRuptureRuptured Abdominal Aortic AneurysmRuptured AneurysmSmall Interfering RNASourceSystemTHBS1 geneTelemetryTestingThrombospondin 1TissuesUnited StatesVascular Diseasesatherosclerotic plaque rupturebeta Aminopropionitrileconditional knockoutextracellularhuman diseasehypercholesterolemiainduced pluripotent stem cellinhibitorknock-downmalemigrationmortalitymouse modelneutrophilnovelpolymerizationreceptorresponsesingle-cell RNA sequencingspatial relationshiptherapeutic developmentultrasounduptake
中文摘要
腹主动脉瘤(AAA)是指主动脉的进行性变弱和扩张。一大笔钱
在了解导致动脉瘤破裂的分子机制方面存在知识差距,
AAA患者死亡的主要原因。在我们先前报告血栓反应蛋白-1(TSP1)升高之后
在人和小鼠动脉瘤组织中,我们进行了单细胞RNA测序(scRNA-seq)分析和
巨噬细胞(Mɸ,S)是小鼠主动脉瘤TSP 1升高的主要来源。我们
随后将ɸ-Cre与我们的新基因杂交,获得了M只Thbs1特异性Thbs1基因敲除小鼠(Thbs1∆Mɸ
构建Thbs1 FLOX/FLOX小鼠。血管紧张素II(Ang II)联合血管紧张素II(Ang II)诱导动脉瘤时
高胆固醇血症,超过60%的Thbs1∆Mɸ死于腹主动脉破裂,发病率是前者的2.6倍
比Thbs1wt.有趣的是,存活到28天血管紧张素II输注结束的Thbs1∆Mɸ小鼠显示出较少的动脉瘤
膨胀比Thbs1wt。当Thbs1∆Mɸ小鼠接受
血管周围应用CaCl2,这是一种不会产生破裂的AAA模型。我们提出了两个具体目标
M-ɸ特异性Thbs1基因缺失对主动脉影响的机制探讨
扩张和破裂,重点是AAA破裂。具体目标1致力于确定破裂-
MɸTSP1的预防功能。具体地说,我们将确定发生致命性破裂的主动脉反应。
在血管紧张素Ⅱ模型中雄性和雌性Ths1∆Mɸ小鼠随后识别破裂相关分子
通过scRNA-seq、原位杂交和免疫染色进行标记。此外,我们还将研究
M-ɸ特异性Thbs1基因敲除对晚期破裂小鼠模型的影响
与Ang II模型造成的早期破裂相比,这与人类AAA的相关性更大。特定的
目的2重点研究动脉瘤破裂的分子机制。初步研究表明,
与野生型相比,Thbs1-/-MɸS的迁移或吞噬凋亡细胞的能力也显著降低
中性粒细胞胞外陷阱(NETs)。我们将测试MɸTSP1是否通过CD47促进净清算-
介导的肌动蛋白聚合。接下来,我们将确定M-ɸ迁移受损和
巨噬细胞对Thbs1∆Mɸ小鼠动脉瘤破裂的影响我们将首先确定净负担是否增加
在Thbs1中,∆Mɸ死于破裂,以及篮网和MɸS之间的空间关系。第二,我们将测试
在Thbs1ɸM∆中恢复Mɸ迁移可通过采用迁移策略减少净积累。此外,我们
将检查增强或减弱净清除是否影响Thbs1∆Mɸ中的动脉瘤破裂。最后,我们
将分析破裂型和非破裂型TSP1的表达及其与M-ɸ和净蓄积的关系
人体AAA组织。本项目通过对MɸS的TSP1操作,对其多方面的功能进行剖析
将对动脉瘤破裂的认识产生重大影响。
英文摘要
Abdominal aortic aneurysm (AAA) is the progressive weakening and dilation of the aorta. A substantial
knowledge gap exists in the understanding of molecular mechanisms responsible for aneurysm rupture, the
major cause of mortality among AAA patients. Following our prior report of elevated thrombospondin-1 (TSP1)
in human and mouse aneurysmal tissues, we conducted single-cell RNA sequencing (scRNA-seq) analysis and
identified macrophages (Mɸs) being the primary source of elevated TSP1 in mouse aneurysmal aorta. We
subsequently generated Mɸ-specific Thbs1 knockout mice (Thbs1∆Mɸ) by crossing Lyz2-Cre with our newly
constructed Thbs1flox/flox mice. When subjected to aneurysm induction by angiotensin II (Ang II) coupled with
hypercholesterolemia, over 60% of Thbs1∆Mɸ died due to AAA rupture, an incidence that was 2.6 times higher
than Thbs1wt. Intriguingly, Thbs1∆Mɸ mice that survived to the end of 28-day Ang II infusion showed less aneurysm
dilation than Thbs1wt. Smaller aneurysmal expansion was also found when Thbs1∆Mɸ mice were challenged with
perivascular application of CaCl2, an AAA model that does not produce rupture. We propose two specific aims
to delineate the mechanisms through which Mɸ-specific Thbs1 gene deletion differentially affects aortic
dilation and rupture with an emphasis on AAA rupture. Specific Aim 1 devotes to establishing the rupture-
preventive function of Mɸ TSP1. Specifically, we will determine the aortic responses proceeding lethal rupture in
male and female Thbs1∆Mɸ mice in the Ang II model followed by identifying rupture-associated molecular
signatures through scRNA-seq, in situ hybridization and immunostaining. Furthermore, we will examine the
effects of Mɸ-specific Thbs1 knockout using a different murine model that produces rupture in advanced stages
of aneurysm, which is more relevant to human AAA than the early rupture produced by the Ang II model. Specific
Aim 2 focuses on investigating molecular mechanisms of aneurysm rupture. Preliminary studies showed that
compared to wildtype, Thbs1-/- Mɸs had significantly reduced ability to migrate or to engulf apoptotic cells as well
as neutrophil extracellular traps (NETs). We will test whether Mɸ TSP1 promotes NET clearance through CD47-
mediated actin polymerization. Next, we will establish the causal effect of impaired Mɸ migration and
phagocytosis on aneurysm rupture of Thbs1∆Mɸ mice. We will first determine whether NET burden is increased
in Thbs1∆Mɸ died from rupture, and the spatial relationship between NETs and Mɸs. Second, we will test whether
restoring Mɸ migration in Thbs1∆Mɸ reduces NET accumulation via adoptive transfer strategies. Furthermore, we
will examine whether enhancing or attenuating NET clearance affect aneurysm rupture in Thbs1∆Mɸ. Lastly, we
will analyze TSP1 expression and its association with Mɸ and NET accumulation in ruptured and non-ruptured
human AAA tissues. By dissecting the multifaceted functions of Mɸs through TSP1 manipulations, this project
will produce significant impact on the understanding of aneurysm rupture.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
DOI:
10.3390/biom12091295
发表时间:
2022-09-14
期刊:
BIOMOLECULES
影响因子:
5.5
作者:
[Sorenson, Christine M., Song, Yong-Seok, Wang, Shoujian, Darjatmoko, Soesiawati R., Saghiri, Mohammad Ali, Ranji, Mahsa, Sheibani, Nader]
通讯作者:
Sheibani, Nader
Novel Role of Thrombospondin-1 in Protection against Rupture of Abdominal Aortic Aneurysm
-
批准号:10383732
-
项目类别:
-
资助金额:$45.99万
-
财政年份:2021
-
负责人:Bo Liu
-
依托单位:
Role of RIP3-laden extracellular vesicles in thrombosis and aortic aneurysm
-
批准号:10630195
-
项目类别:
-
资助金额:$47.28万
-
财政年份:2020
-
负责人:Bo Liu
-
依托单位:
Role of RIP3-laden extracellular vesicles in thrombosis and aortic aneurysm
-
批准号:10414974
-
项目类别:
-
资助金额:$47.23万
-
财政年份:2020
-
负责人:Bo Liu
-
依托单位:
Role of RIP3-laden extracellular vesicles in thrombosis and aortic aneurysm
-
批准号:10214685
-
项目类别:
-
资助金额:$51.26万
-
财政年份:2020
-
负责人:Bo Liu
-
依托单位:
Engineered Models of Diseased Heart Valves to Study Sex Bias in Disease Progression
-
批准号:10317066
-
项目类别:
-
资助金额:$38.21万
-
财政年份:2019
-
负责人:Bo Liu
-
依托单位:
Institutional Career Development Core
-
批准号:10627344
-
项目类别:
-
资助金额:$103.8万
-
财政年份:2017
-
负责人:Bo Liu
-
依托单位:
Institutional Career Development Core
-
批准号:10673208
-
项目类别:
-
资助金额:$103.8万
-
财政年份:2017
-
负责人:Bo Liu
-
依托单位:
Vascular smooth muscle cell apoptosis in intimal hyperplasia
-
批准号:9266463
-
项目类别:
-
资助金额:$44.07万
-
财政年份:2015
-
负责人:Bo Liu
-
依托单位:
Vascular smooth muscle cell apoptosis in intimal hyperplasia
-
批准号:9110305
-
项目类别:
-
资助金额:$37.83万
-
财政年份:2015
-
负责人:Bo Liu
-
依托单位:
Molecular mechanisms in Abdominal Aortic Aneuysm
-
批准号:8399030
-
项目类别:
-
资助金额:$41.27万
-
财政年份:2010
-
负责人:Bo Liu
-
依托单位:
Molecular mechanisms in Abdominal Aortic Aneuysm
-
批准号:8576467
-
项目类别:
-
资助金额:$43.36万
-
财政年份:2010
-
负责人:Bo Liu
-
依托单位:
Molecular Mechanisms in Abdominal Aortic Aneuysm
-
批准号:9899284
-
项目类别:
-
资助金额:$45.74万
-
财政年份:2010
-
负责人:Bo Liu
-
依托单位:
Molecular mechanisms in Abdominal Aortic Aneuysm
-
批准号:8040544
-
项目类别:
-
资助金额:$47.62万
-
财政年份:2010
-
负责人:Bo Liu
-
依托单位:
Molecular mechanisms in Abdominal Aortic Aneuysm
-
批准号:8206613
-
项目类别:
-
资助金额:$42.47万
-
财政年份:2010
-
负责人:Bo Liu
-
依托单位:
PKC-Delta in Intimal Hyperplasia after Vascular Bypass
-
批准号:7468499
-
项目类别:
-
资助金额:$11.64万
-
财政年份:2005
-
负责人:Bo Liu
-
依托单位:
海外基金