The role of TFEB in aortic aneurysms
TFEB 在主动脉瘤中的作用
基本信息
- 批准号:10406283
- 负责人:
- 金额:$ 53.84万
- 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:2020-06-20 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:Abdominal Aortic AneurysmAmino AcidsAneurysmAnimal ModelAnimalsAnti-Inflammatory AgentsAortic AneurysmApoE knockout mouseApolipoprotein EApoptosisAtherosclerosisAutophagocytosisBiogenesisBlood VesselsCardiovascular DiseasesCell physiologyClinicalConjugated Linoleic AcidsDependenceDetectionDiabetes MellitusExperimental ModelsFatty AcidsFoundationsFunctional disorderHistidineHomeostasisHumanImpairmentIn VitroInflammationInterventionKnock-outLeadLifeLinoleic AcidsLipidsMMP2 geneMetabolic DiseasesMethodologyModelingMusNitritesNitrogen DioxideNuclear TranslocationOperative Surgical ProceduresOralPathologicPatientsPharmacologyPhase II Clinical TrialsPhysiologicalPlasmaPreventionProductionProteinsResearchRoleRuptureSignal TransductionSmooth Muscle MyocytesSolidStimulusSupplementationTestingTherapeuticTranscriptional ActivationTranslationsVascular DiseasesVascular Smooth Musclebaseclinically relevanthuman modelin vivoinhibitorlipidomicsmetabolomicsmortalitymouse modelnanomolarnew therapeutic targetnitrated conjugated linoleic acidnitrationnitroalkenenovelnovel strategiesnovel therapeutic interventionpreventprotective effecttranscription factor
项目摘要
ABSTRACT
Abdominal Aortic aneurysm (AAA) results in very high mortality upon rupture. To date, besides surgical
intervention –with only 10% of patients eligible-, no alternative therapeutic approaches are available.
Therefore, it would be of high significance to identify novel strategies to effectively treat or prevent AAA in vivo.
Vascular smooth muscle cells (VSMCs) are crucial in maintaining vascular wall integrity and function and
VSMC homeostasis is disrupted in AAA. Transcription factor-EB (TFEB) is a “master” regulator of lysosomal
biogenesis and autophagy. However, the role of TFEB in VSMC functions and AAA formation remain to be
explored. We demonstrated that TFEB inhibits apoptosis, MMP2/9 activity and inflammation in VSMCs. VSMC
specific TFEB knockout (KO) significantly aggravates vascular wall matrix degradation in a mouse AAA model.
Nitroalkene derivatives of fatty acids such as oleic (OA-NO2) and linoleic acid (LNO2) have profound protective
effects against cardiovascular and metabolic diseases. Conjugated linoleic acid (CLA) was identified as the
preferential and major nitrated endogenous fatty acid and is readily bioavailable in humans and experimental
models upon oral delivery of CLA and inorganic nitrite (NO2), making it an attractive intervention for CVD. We
found that nitro-CLA protects against AAA formation in the Ang II-induced AAA mouse model and inhibits
VSMC inflammation and apoptosis in a TFEB-dependent manner. It also promotes TFEB nuclear translocation
in vitro in an H148-dependent fashion suggesting that TFEB is a direct target of nitro-CLA. Based on these
evidences, we will test the central hypothesis that activation of TFEB by enhancing the endogenous production
of nitro-CLA protects against AAA formation through inhibition of VSMC dysfunction. By taking advantage of
our unique animal models generated specifically for these studies and the combined expertise of the
assembled team, we propose 3 aims. Aim 1: Characterize the protective role of VSMC TFEB in AAA formation.
We will test our working sub-hypothesis that VSMC TFEB protects against AAA formation through inhibition of
VSMC dysfunction. Aim 2: Determine that activation of TFEB by nitro-CLA inhibits VSMC dysfunction in vitro.
The working sub-hypothesis is that nitro-CLA prevents VSMC dysfunction in a TFEB-dependent manner. Aim
3: Define TFEB as a novel therapeutic target for nitro-CLA inhibition of AAA formation in vivo. The working sub-
hypothesis is that endogenous production of nitro-CLA protects against AAA formation through activation of
VSMC TFEB. In summary, we will characterize the protective role of TFEB in AAA formation and establish
nitro-CLA as a novel therapeutic strategy against AAA by targeting VSMC TFEB. This mechanistic research
will set a solid foundation for rapid translation into clinical utilization of nitro-CLA and may lead to a
breakthrough for treatment or/and prevention of AAA.
摘要
腹主动脉瘤(AAA)破裂后的死亡率非常高。到目前为止,除了外科手术外,
然而,由于只有10%的患者有资格接受干预,因此没有其他治疗方法可用。
因此,这将是非常重要的,以确定新的策略,以有效地治疗或预防腹主动脉瘤在体内。
血管平滑肌细胞(VSMC)在维持血管壁完整性和功能方面至关重要,
腹主动脉瘤中VSMC的稳态被破坏。转录因子-EB(TFEB)是溶酶体的“主”调节剂,
生物发生和自噬。然而,TFEB在VSMC功能和AAA形成中的作用仍有待进一步研究。
探讨了我们证明TFEB抑制VSMCs的凋亡、MMP 2/9活性和炎症。VSMC
特异性TFEB敲除(KO)显著地抑制了小鼠AAA模型中的血管壁基质降解。
脂肪酸的硝基烯烃衍生物如油酸(OA-NO2)和亚油酸(LNO 2)具有深刻的保护作用,
对心血管和代谢疾病的影响。共轭亚油酸(CLA)被鉴定为
优先和主要硝化的内源性脂肪酸,并且在人体和实验中易于生物利用
在口服CLA和无机亚硝酸盐(NO2)的模型,使其成为一个有吸引力的干预CVD。我们
发现硝基-CLA在血管紧张素II诱导的AAA小鼠模型中保护AAA的形成,并抑制
VSMC炎症和凋亡以TFEB依赖的方式。它还促进TFEB核转位
在体外以H148依赖的方式表明TFEB是硝基-CLA的直接靶标。基于这些
证据,我们将测试的中心假设,激活TFEB通过增强内源性生产
硝基-CLA通过抑制VSMC功能障碍来防止AAA的形成。通过利用
我们专门为这些研究生成的独特动物模型以及
团队合作,我们提出三个目标。目的1:研究VSMC TFEB对AAA形成的保护作用。
我们将测试我们的工作子假设,即VSMC TFEB通过抑制AAA形成来保护AAA。
VSMC功能障碍。目的2:确定硝基-CLA激活TFEB抑制体外VSMC功能障碍。
工作子假设是硝基-CLA以TFEB依赖性方式预防VSMC功能障碍。目的
3:将TFEB定义为用于体内AAA形成的硝基-CLA抑制的新型治疗靶标。工作分-
假设是内源性硝基-CLA的产生通过激活
VSMC TFEB。总之,我们将描述TFEB在AAA形成中的保护作用,并建立TFEB在AAA形成中的保护作用。
硝基-CLA是一种靶向VSMC TFEB治疗AAA的新策略。这种机械研究
将为硝基-CLA的快速转化为临床应用奠定坚实的基础,并可能导致
治疗或/和预防AAA的突破。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
ATG5 (autophagy related 5) in microglia controls hippocampal neurogenesis in Alzheimer disease.
- DOI:10.1080/15548627.2023.2277634
- 发表时间:2023-11
- 期刊:
- 影响因子:13.3
- 作者:Xin Tang;Ellen Walter;Eric S. Wohleb;Yanbo Fan;Chenran Wang
- 通讯作者:Xin Tang;Ellen Walter;Eric S. Wohleb;Yanbo Fan;Chenran Wang
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Yanbo Fan其他文献
Yanbo Fan的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Yanbo Fan', 18)}}的其他基金
Transcription Factor-EB and Postischemic Angiogenesis
转录因子-EB 与缺血后血管生成
- 批准号:
9368394 - 财政年份:2017
- 资助金额:
$ 53.84万 - 项目类别:
相似海外基金
Double Incorporation of Non-Canonical Amino Acids in an Animal and its Application for Precise and Independent Optical Control of Two Target Genes
动物体内非规范氨基酸的双重掺入及其在两个靶基因精确独立光学控制中的应用
- 批准号:
BB/Y006380/1 - 财政年份:2024
- 资助金额:
$ 53.84万 - 项目类别:
Research Grant
Quantifying L-amino acids in Ryugu to constrain the source of L-amino acids in life on Earth
量化 Ryugu 中的 L-氨基酸以限制地球生命中 L-氨基酸的来源
- 批准号:
24K17112 - 财政年份:2024
- 资助金额:
$ 53.84万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Molecular recognition and enantioselective reaction of amino acids
氨基酸的分子识别和对映选择性反应
- 批准号:
23K04668 - 财政年份:2023
- 资助金额:
$ 53.84万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Basic research toward therapeutic strategies for stress-induced chronic pain with non-natural amino acids
非天然氨基酸治疗应激性慢性疼痛策略的基础研究
- 批准号:
23K06918 - 财政年份:2023
- 资助金额:
$ 53.84万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Molecular mechanisms how arrestins that modulate localization of glucose transporters are phosphorylated in response to amino acids
调节葡萄糖转运蛋白定位的抑制蛋白如何响应氨基酸而被磷酸化的分子机制
- 批准号:
23K05758 - 财政年份:2023
- 资助金额:
$ 53.84万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Design and Synthesis of Fluorescent Amino Acids: Novel Tools for Biological Imaging
荧光氨基酸的设计与合成:生物成像的新工具
- 批准号:
2888395 - 财政年份:2023
- 资助金额:
$ 53.84万 - 项目类别:
Studentship
Collaborative Research: RUI: Elucidating Design Rules for non-NRPS Incorporation of Amino Acids on Polyketide Scaffolds
合作研究:RUI:阐明聚酮化合物支架上非 NRPS 氨基酸掺入的设计规则
- 批准号:
2300890 - 财政年份:2023
- 资助金额:
$ 53.84万 - 项目类别:
Continuing Grant
Structurally engineered N-acyl amino acids for the treatment of NASH
用于治疗 NASH 的结构工程 N-酰基氨基酸
- 批准号:
10761044 - 财政年份:2023
- 资助金额:
$ 53.84万 - 项目类别:
Lifestyle, branched-chain amino acids, and cardiovascular risk factors: a randomized trial
生活方式、支链氨基酸和心血管危险因素:一项随机试验
- 批准号:
10728925 - 财政年份:2023
- 资助金额:
$ 53.84万 - 项目类别:
Single-molecule protein sequencing by barcoding of N-terminal amino acids
通过 N 端氨基酸条形码进行单分子蛋白质测序
- 批准号:
10757309 - 财政年份:2023
- 资助金额:
$ 53.84万 - 项目类别: