Browning of perivascular adipose tissue protects against thoracic aortic aneurysm
血管周围脂肪组织褐变可预防胸主动脉瘤
基本信息
- 批准号:10580855
- 负责人:
- 金额:$ 58.62万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAddressAdipocytesAdipose tissueAffectAneurysmAortaAortic AneurysmApoptosisAtherosclerosisBlood VesselsBrown FatCardiacCardiovascular DiseasesCharacteristicsChestClinicalClinical TreatmentClinical TrialsCoculture TechniquesConditioned Culture MediaDataDevelopmentDiseaseDissectionFatty AcidsFatty acid glycerol estersFunctional disorderGenerationsGenesGenetic Predisposition to DiseaseHealthHeritabilityHomeostasisHumanHypertensionIn VitroInduction of ApoptosisInflammationInflammatoryInfusion proceduresKnockout MiceKnowledgeLesionLifeMediatingMetabolic DiseasesModelingMorbidity - disease rateMusNitrogen DioxideOperative Surgical ProceduresOther GeneticsOutcomeOxidative StressPathologyPatientsPharmaceutical PreparationsPharmacotherapyPhase II Clinical TrialsProcessPropertyProteinsRepressionResearchRisk AdjustmentRoleRuptureSignal TransductionSmooth Muscle MyocytesTestingThoracic Aortic AneurysmTransgenic MiceVascular DiseasesVascular Smooth MuscleWorkadipokinesclinical translationepidemiology studygain of functiongenetic approachin vivoinflammatory markerknock-downloss of functionmortalitynitrated conjugated linoleic acidnovelnovel drug classnovel therapeutic interventionoverexpressionparacrineperioperative mortalitypharmacologicpreventprogramsrepairedresistin
项目摘要
PROJECT SUMMARY/ABSTRACT
Thoracic aortic aneurysm (TAA) is a life-threatening disease and has a high mortality rate if rupture occurs.
Currently, apart from endovascular or open surgery repair, no drug has been demonstrated to be effective for
TAA treatment. Even though some patients with TAA have evidence of a heritable aortopathy, about 75% of
TAA patients have severe aortic damage without a clear genetic etiology. The scant mechanistic knowledge is
limiting the development of medications for the treatment of TAA, thus highlighting a pressing need for better
understanding TAA formation and progression. Aorta is naturally surrounded by perivascular adipose tissue
(PVAT). Recent large-scale epidemiological studies demonstrated that PVAT was highly associated with a
significantly higher adjusted risk of all-cause cardiac mortality. We and others documented that brown-like
PVAT contributes to vascular homeostasis in health, while whitening of PVAT is dysfunctional and contributes
to development of the vascular diseases. A causal relationship between PVAT and TAA and the underlying
mechanisms remain unknown. Our preliminary studies indicate that the PVAT near the TAA lesion in patients
lost brown characteristics, and that TAA formation was dramatically increased in mice that lack normal PVAT,
suggesting that dysfunctional PVAT is associated with TAA. The conditioned medium from PVAT of TAA
patients induced apoptosis and inflammation in human aortic smooth muscle cells, suggesting that signaling
from PVAT can cause loss of vascular smooth muscle cells (VSMC) in the aorta, which may promote TAA
lesion. It is unknown whether browning of PVAT could protect against TAA. PR-domain containing 16
(PRDM16) is a determinant of browning gene programs. We show that PRDM16 expression in PVAT of TAA
patients is significantly reduced when compared to that in normal PVAT. PRDM16 inhibited resistin expression
in PVAT. We found that nitrated conjugated linoleic acid (NO2-CLA) induced the browning of human PVAT
adipocytes by mediating PRDM16 signaling. Based on these data, we hypothesize that PRDM16-mediated
PVAT browning prevents TAA formation. We will determine that 1) PRDM16 in PVAT prevents and reverses
TAA in mice; 2) PRDM16 inhibits TAA by regulating PVAT crosstalk with VSMC; 3) NO2-CLA prevents TAA by
targeting PRDM16. Outcomes will demonstrate that a previously unrecognized process involving loss of
browning features in PVAT promotes TAA formation through crosstalk to VSMC. This work will accelerate
clinical translation of a nitro-fatty acid-based treatment for TAA targeting PVAT homeostasis with this new
class of drugs, currently on clinical trials for other diseases.
项目总结/摘要
胸主动脉瘤(TAA)是一种危及生命的疾病,如果发生破裂,死亡率很高。
目前,除了血管内或开放手术修复,没有药物被证明是有效的,
TAA治疗。尽管一些TAA患者有遗传性脊椎病的证据,但约75%的TAA患者
TAA患者有严重的主动脉损伤,没有明确的遗传病因。缺乏机械知识是
限制了治疗TAA的药物的开发,从而突出了对更好的治疗的迫切需要。
了解TAA的形成和进展。主动脉自然地被血管周围脂肪组织包围
(PVAT)。最近的大规模流行病学研究表明,PVAT与
全因心源性死亡的校正风险显著更高。我们和其他人记录了棕色的
PVAT有助于健康中的血管稳态,而PVAT的增白功能失调,
血管疾病的发展。PVAT和TAA之间的因果关系以及潜在的
机制仍然未知。我们的初步研究表明,患者TAA病变附近的PVAT
失去棕色特征,并且在缺乏正常PVAT的小鼠中TAA形成显著增加,
提示功能失调的PVAT与TAA相关。TAA PVAT的条件培养基
患者诱导人主动脉平滑肌细胞凋亡和炎症,表明信号转导
PVAT可导致主动脉血管平滑肌细胞(VSMC)损失,这可能会促进TAA
损伤。PVAT的布朗宁是否能保护TAA还不清楚。PR结构域包含16
(PRDM 16)是布朗宁基因程序的决定因子。我们发现PRDM 16在TAA的PVAT中表达,
与正常PVAT相比,患者的PVAT显著降低。PRDM 16抑制了cDNAn的表达
在PVAT。结果表明,硝酸共轭亚油酸(NO2-CLA)可诱导PVAT的布朗宁
脂肪细胞通过介导PRDM 16信号传导。基于这些数据,我们假设PRDM 16介导的
PVAT布朗宁防止TAA形成。我们将确定1)PVAT中的PRDM 16阻止并逆转
2)PRDM 16通过调节PVAT与VSMC的串扰抑制TAA; 3)NO2-CLA通过调节PVAT与VSMC的串扰抑制TAA。
针对PRDM 16结果将表明,一个以前未被认识到的过程,涉及损失的
PVAT中的布朗宁特征通过对VSMC的串扰促进TAA形成。这项工作将加快
临床翻译的硝基脂肪酸为基础的治疗TAA靶向PVAT稳态与这种新的
这类药物目前正在对其他疾病进行临床试验。
项目成果
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YUQING Eugene CHEN其他文献
YUQING Eugene CHEN的其他文献
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{{ truncateString('YUQING Eugene CHEN', 18)}}的其他基金
Browning of perivascular adipose tissue protects against thoracic aortic aneurysm
血管周围脂肪组织褐变可预防胸主动脉瘤
- 批准号:
10462357 - 财政年份:2022
- 资助金额:
$ 58.62万 - 项目类别:
Development of gene editing based therapy for cardiovascular diseases
开发基于基因编辑的心血管疾病疗法
- 批准号:
10652321 - 财政年份:2021
- 资助金额:
$ 58.62万 - 项目类别:
Development of gene editing based therapy for cardiovascular diseases
开发基于基因编辑的心血管疾病疗法
- 批准号:
10313701 - 财政年份:2021
- 资助金额:
$ 58.62万 - 项目类别:
Development of gene editing based therapy for cardiovascular diseases
开发基于基因编辑的心血管疾病疗法
- 批准号:
10441548 - 财政年份:2021
- 资助金额:
$ 58.62万 - 项目类别:
IDOL and dyslipidemia in cardiovascular diseases
IDOL 与心血管疾病中的血脂异常
- 批准号:
10221773 - 财政年份:2019
- 资助金额:
$ 58.62万 - 项目类别:
IDOL and dyslipidemia in cardiovascular diseases
IDOL 与心血管疾病中的血脂异常
- 批准号:
10451711 - 财政年份:2019
- 资助金额:
$ 58.62万 - 项目类别:
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