Define the mechanisms of aortopathy in bicuspid aortic valve patients
Define the mechanisms of aortopathy in bicuspid aortic valve patients
批准号:
10379956
负责人:
Bo Yang
金额:
$69.68万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-04-13 至 2024-03-31
关键词:
AffectAneurysmAortaAortic AneurysmArteriesBiomechanicsBlood VesselsCardiovascular systemCell Differentiation processCell LineageCellsCongenital AbnormalityDataDefectDevelopmentDiseaseDissectionEngineeringExcisionExtracellular MatrixFRAP1 geneFoundationsFutureGeneral PopulationGenesGenetic TranscriptionGoalsHumanImpairmentIn VitroInferiorInterventionLeadLifeMYH11 geneMedicalMesoderm CellModelingMolecularMusMutationMyosin Heavy ChainsNeural CrestNeural Crest CellOperative Surgical ProceduresOryctolagus cuniculusParaxial MesodermPathway interactionsPatientsPilot ProjectsPlant RootsPopulationProcessPropertyResearchRisk FactorsSignal PathwaySignal TransductionSirolimusSmooth Muscle MyocytesStructural defectTherapeuticTherapeutic AgentsThoracic Aortic AneurysmThoracic aortaTissue EngineeringTissuesTransforming Growth Factor betaTransforming Growth Factor beta ReceptorsTransplantationVascular Smooth Muscleabdominal aortaaortic archaortic valveaortic valve disorderascending aortabicuspid aortic valvecase controldisorder controldrug testinggenetic varianthemodynamicshigh riskimprovedin vivoin vivo Modelinduced pluripotent stem cellinnovationinsightmalformationmortalitymyocardinnerve stem cellnovelpreventresponsescaffoldscreeningstem cellstranscriptome sequencing
中文摘要
胸主动脉瘤发生在大约50%-70%的二叶主动脉瓣(BAV)患者中,
影响1-2%的总人口。迫切需要制定证据来确定
手术干预,并开发可预防或逆转BAV患者动脉瘤的治疗方法。胸腔
BAV中的主动脉瘤通常累及近端的主动脉,其来源为平滑肌细胞。
来自神经干细胞(NCSCs)。然而,它省去了胸主动脉降支,后者的SMC
起源于轴旁中胚层。我们研究的长期目标是确定分子
BAV相关大动脉病变的发病机制及发展治疗策略
脑动静脉内的动脉瘤。本研究的目的是利用来源的SMC在体外建立BAV大动脉病变模型。
BAV诱导的多能干细胞(IPSCs)及其在体内的组织工程血管
SMCS。模型将被用于探索BAV中主动脉瘤的治疗方法。我们的中心假设是BAV
在转化生长因子-依赖的SMC向NCSCs分化的过程中,主动脉SMC存在缺陷,但不存在轴旁中胚层分化缺陷
这种缺陷导致这些细胞的收缩功能和细胞外基质分泌减少,
导致BAV的大动脉病变和随后的大动脉近端动脉瘤。目标1:我们将描述
BAV/动脉瘤患者体外血管SMC分化缺陷。我们将区分BAV和CONTROL
IPSCs分化为NCSCs和旁轴向中胚层,然后是SMC。我们将确定分化、伸缩性和
BAV-和对照-SMC的细胞外基质。我们将定义导致缺陷的关键信号通路
BAVNCSC-SMC分化的研究--以转化生长因子-β信号和肌钙蛋白转录为中心
在我们的初步研究中确定了。我们还将进行rna-seq以无偏见地识别其他潜在的引起
SMC和NCSCs的分化缺陷。我们将拯救分化有缺陷的BAV SMC
神经干细胞的谱系通过不依赖转化生长因子-通路的途径,如雷帕霉素,它促进
通过抑制雷帕霉素的哺乳动物靶点和激活Akt2向SMC分化。目标2:我们将确定
BAV构建的工程化主动脉在裸兔体内形成动脉瘤的机制
病人的IPSCs。我们将创建植入BAV NCSC-SMC的组织工程血管来取代
兔子的腹主动脉。我们将确定工程血管的生物力学和动脉瘤的形成。
在兔体内,我们将定义SMC的分化和成熟以及转化生长因子信号转导
工程船。最后,我们将在支架中加入雷帕霉素,以预防工程中的动脉瘤
船只。我们的人IPSC体外和体内模型在研究胸主动脉机制方面具有创新性。
用于BAV中的动脉瘤和治疗药物的筛选。这些研究将产生关于大动脉疾病的新数据,
阐明BAV患者主动脉瘤形成的机制,指导外科干预,并提供
为未来BAV主动脉瘤的医疗治疗奠定基础。
英文摘要
Thoracic aortic aneurysm occurs in approximately 50–70% of patients with bicuspid aortic valve (BAV), which
affects 1–2% of the general population. There is a critical need to develop evidence to determine criteria for
surgical intervention and to develop treatment that will prevent or reverse aneurysms for BAV patients. Thoracic
aortic aneurysm in BAV frequently involves the proximal aorta, with smooth muscle cells (SMCs) that originate
from neural crest stem cells (NCSCs). However, it spares the descending thoracic aorta, which has SMCs that
originate from the paraxial mesoderm. The long-term goal of our research is to determine the molecular
mechanisms responsible for the aortopathy associated with BAV and develop therapeutic strategies for aortic
aneurysm in BAV. The objective of this research is to model BAV aortopathy in vitro using SMCs derived from
BAV induced pluripotent stem cells (iPSCs) and in vivo using tissue-engineered vessels generated from these
SMCs. Models will be used to explore treatments for aortic aneurysm in BAV. Our central hypothesis is that BAV
aortic SMCs are defective in TGF--dependent differentiation of SMCs from NCSCs but not paraxial mesoderm
and this defect causes decreased contractile function and secretion of extracellular matrix from these cells,
resulting in aortopathy and subsequent aneurysm at the proximal aorta in BAV. Aim 1: We will characterize
defects in vascular SMC differentiation in BAV/aneurysm cases in vitro. We will differentiate BAV and control
iPSCs into NCSCs and paraxial mesoderm, then SMCs. We will determine the differentiation, contractility, and
extracellular matrix of the BAV- and control-SMCs. We will define the key signaling pathway leading to defective
differentiation in BAV NCSC-SMCs with a focus on canonical TGF-β signaling and myocardin transcription as
identified in our pilot study. We will also perform RNA-seq to unbiasedly identify other potential pathways causing
the defective differentiation of SMCs from NCSCs. We will rescue the defective differentiation of BAV SMCs from
the NCSC lineage through pathways independent of the TGF- pathway, such as rapamycin, which promotes
SMC differentiation by inhibiting mammalian target of rapamycin and activating Akt2. Aim 2: We will determine
the mechanism of aneurysm formation in vivo using nude rabbits that host engineered aorta generated from BAV
patients’ iPSCs. We will create tissue-engineered vessels populated with BAV NCSC-SMCs to replace the
rabbits’ abdominal aorta. We will determine the biomechanics and aneurysm formation of the engineered vessels
in rabbits, and we will define differentiation and maturation of the SMCs and the TGF- signaling of the
engineered vessel. Finally, we will incorporate rapamycin into the scaffold to prevent the aneurysm in engineered
vessels. Our human iPSC in vitro and in vivo model is innovative for studying the mechanisms of thoracic aortic
aneurysm in BAV and for screening therapeutic agents. These studies will produce novel data on aortopathy,
clarify mechanisms of aortic aneurysm formation in BAV patients, guide surgical intervention, and provide a
foundation for future medical treatment of aortic aneurysm in BAV.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
Distal Aortic Progression After Hemiarch, Zones 1-3 Arch Replacement in Acute Type A Aortic Dissection.
急性 A 型主动脉夹层半弓、1-3 区弓形置换后的远端主动脉进展。
DOI:
10.1016/j.athoracsur.2022.10.035
发表时间:
2023
期刊:
The Annals of thoracic surgery
影响因子:
--
作者:
[Graham,NathanJ, Titsworth,Marc, Ahmad,Rana-Armaghan, Wu,Xiaoting, Naeem,Aroma, Kim,KarenM, Fukuhara,Shinichi, Patel,Himanshu, Deeb,GMichael, Yang,Bo]
通讯作者:
Yang,Bo
Defining mechanisms of aortic root aneurysm in Loeys-Dietz syndrome using patients’ induced pluripotent stem cells and genome editing
-
批准号:10153875
-
项目类别:
-
资助金额:$69.36万
-
财政年份:2020
-
负责人:Bo Yang
-
依托单位:
Defining mechanisms of aortic root aneurysm in Loeys-Dietz syndrome using patients’ induced pluripotent stem cells and genome editing
-
批准号:10398015
-
项目类别:
-
资助金额:$69.36万
-
财政年份:2020
-
负责人:Bo Yang
-
依托单位:
Defining mechanisms of aortic root aneurysm in Loeys-Dietz syndrome using patients’ induced pluripotent stem cells and genome editing
-
批准号:10609896
-
项目类别:
-
资助金额:$69.36万
-
财政年份:2020
-
负责人:Bo Yang
-
依托单位:
Define the mechanisms of aortopathy in bicuspid aortic valve patients
-
批准号:10132379
-
项目类别:
-
资助金额:$69.68万
-
财政年份:2018
-
负责人:Bo Yang
-
依托单位:
Define the mechanisms of aortopathy in bicuspid aortic valve patients
-
批准号:9908158
-
项目类别:
-
资助金额:$69.68万
-
财政年份:2018
-
负责人:Bo Yang
-
依托单位:
海外基金