Vascular Smooth Muscle Protein Quality Control and Aortic Aneurysm Formation
血管平滑肌蛋白质量控制与主动脉瘤形成
基本信息
- 批准号:10714562
- 负责人:
- 金额:$ 69.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-01 至 2027-04-30
- 项目状态:未结题
- 来源:
- 关键词:Abdominal Aortic AneurysmAddressAngiotensin IIAortic AneurysmBiochemicalBiological AssayBlood VesselsCell LineageCell NucleusComplicationCyclic AMPCyclic AMP-Dependent Protein KinasesCyclic GMPCyclic NucleotidesDevelopmentDilatation - actionDiseaseDisease ProgressionDissectionDown-RegulationDrug TargetingElastasesEtiologyFamily memberFunctional disorderGatekeepingGene set enrichment analysisGenesGenetic TranscriptionHumanHydrolysisImpairmentIn VitroInterventionKnock-outKnockout MiceMediatingModelingMorbidity - disease rateMouse StrainsMusMuscle ContractionMuscle ProteinsOperative Surgical ProceduresPathogenesisPathway AnalysisPathway interactionsPerformancePharmacologic SubstancePhenotypePlayPreventionProteasome InhibitorProteinsQuality ControlRegulationReporterRoleRuptureSignal TransductionSmooth Muscle MyocytesSystemTestingTimeTissuesTransgenic MiceTransgenic OrganismsUbiquitinVascular DiseasesVascular Smooth Muscleabdominal aortacell typecombatcostepigenomeglycogen synthase kinase 3 betahuman diseaseimprovedmisfolded proteinmortalitymouse modelmulticatalytic endopeptidase complexmultiple omicsmyocardinnoveloverexpressionphosphoric diester hydrolasepreventprogramsprotein degradationprotein expressionproteostasisproteotoxicitytherapeutic targettranscriptometranscriptome sequencingvirtual
项目摘要
PROJECT SUMMARY
Abdominal aortic aneurysm (AAA) is a devastating disease carrying high morbidity and mortality due to the high
likelihood of fatal dissection and rupture. There are currently no proven pharmaceutical treatments to prevent
AAA progression. VSMC degeneration contributes largely to AAA pathogenesis, but the mechanism remains
elusive. The ubiquitin proteasome system (UPS) serves as an essential protein quality control mechanism by
degrading misfolded proteins and surplus normal proteins. While proteotoxicity resulting from insufficient UPS
function has been widely accepted as an important mechanism for multiple degenerative human conditions, the
implication of UPS dysfunction in AAA is completely unknown. Our pathway analysis in human AAA tissues
revealed an association of UPS function with AAA. In a mouse model of AAA, accumulation of ubiquitinated
proteins, a hallmark of impaired UPS performance, precedes VSMC degeneration and AAA formation and is
exacerbated with disease progression. This suggests that inadequate UPS performance may act as a novel
mechanism underlying AAA etiology. MYOCD is a master switch of VSMC contractile gene program. How
MYOCD is regulated and functions in AAA is unknown. Bulk RNA-seq in VSMCs showed an enrichment of UPS-
related pathways in the top MYOCD-upregulated gene programs besides those relevant to VSMC contraction.
Forced expression of MYOCD improved UPS performance while suppressing VSMC degeneration in cultured
VSMCs and VSMC-specific MYOCD transgenic (Tg) mice at the early stage of AAA formation. MYOCD
increased the expression of NFE2L1 and KLHL3, two key players of UPS function. These lines of evidence
suggest a novel role of MYOCD in UPS function. Phosphodiesterases (PDEs), by catalyzing the hydrolysis of
cAMP and cGMP to specifically modulate cyclic nucleotide signaling, play critical roles in VSMC pathophysiology
and are proven drug targets for multiple human diseases. We found that PDE10A was the most induced PDE
family member during AAA formation, while MYOCD protein expression was suppressed. Inhibition of PDE10A
increased MYOCD protein, improved UPS performance, and suppressed AAA formation. These exciting
preliminary findings support a novel hypothesis that downregulation of MYOCD protein by PDE10A impairs UPS
performance, leading to VSMC degeneration and AAA. We propose three Aims to test this hypothesis. Aim 1
will use novel VSMC-specific Myocd knockout and Tg mice to determine the function of MYOCD in AngII-induced
AAA model. Aim 2 will use a novel UPS reporter mouse line and biochemical assays to determine the importance
of UPS function in MYOCD-regulated AAA and how MYOCD modulates UPS function. Aim 3 will determine how
PDE10 promotes MYOCD protein degradation and PDE10A functions in UPS performance and AAA formation.
This proposal will address for the first time the importance of UPS performance in VSMC degeneration and AAA
formation, and elucidate a novel regulatory cascade comprising a druggable upstream modulator (PDE10A) and
a downstream effector (MYOCD) in safeguarding UPS performance and proteostasis.
项目摘要
腹主动脉瘤(AAA)是一种毁灭性的疾病,由于高血压,
可能会造成致命的夹层和破裂目前还没有经过证实的药物治疗方法可以预防
AAA进展。血管平滑肌细胞变性在AAA发病机制中起重要作用,但其机制仍然存在
难以捉摸。泛素蛋白酶体系统(UPS)作为一种重要的蛋白质质量控制机制,
降解错误折叠的蛋白质和多余的正常蛋白质。虽然UPS不足导致蛋白毒性
功能已被广泛接受为多种退行性人类疾病的重要机制,
UPS功能障碍在AAA中意义完全未知。我们在人AAA组织中的通路分析
揭示了UPS功能与AAA的关联。在AAA小鼠模型中,泛素化的
蛋白,UPS性能受损的标志,先于VSMC变性和AAA形成,
随着疾病进展而加重。这表明,UPS性能不足可能是一种新的
AAA病因的潜在机制。MYOCD是VSMC收缩基因程序的主开关。如何
MYOCD是受调节的,在AAA中的功能未知。VSMC中的批量RNA-seq显示UPS-1的富集。
除了与VSMC收缩相关的途径外,MYOCD上调的基因程序中也存在相关途径。
MYOCD的强制表达改善了UPS的性能,同时抑制了培养的VSMC的变性。
AAA形成早期的VSMC和VSMC特异性MYOCD转基因(Tg)小鼠。MYOCD
增加了UPS功能的两个关键参与者NFE 2L 1和KLHL 3的表达。这些证据
提示MYOCD在UPS功能中新作用。磷酸二酯酶(PDE),通过催化
cAMP和cGMP特异性地调节环核苷酸信号,在VSMC病理生理学中起关键作用
并且被证明是多种人类疾病的药物靶标。我们发现PDE 10A是最易诱导的PDE
在AAA形成过程中,MYOCD家族成员的表达受到抑制。PDE 10A的抑制
增加MYOCD蛋白,改善UPS性能,并抑制AAA形成。这些令人兴奋
初步研究结果支持了一个新的假设,即PDE 10A下调MYOCD蛋白会损害UPS
性能,导致VSMC退化和AAA。我们提出了三个目标来检验这一假设。要求1
将使用新的VSMC特异性Myocd敲除和Tg小鼠来确定MYOCD在AngII诱导的血管紧张素Ⅱ(Ang Ⅱ)表达中的功能。
AAA型号。目的2将使用一种新的UPS报告小鼠系和生化测定来确定
MYOCD调节的AAA中的UPS功能以及MYOCD如何调节UPS功能。目标3将决定如何
PDE 10促进MYOCD蛋白降解,PDE 10A在UPS性能和AAA形成中起作用。
该提案将首次阐述UPS性能在VSMC退化和AAA中的重要性
形成,并阐明了一种新的调控级联,包括可药物化的上游调节剂(PDE 10A)和
保护UPS性能和蛋白质稳态的下游效应子(MYOCD)。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
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 }}
Xiaochun Long其他文献
Xiaochun Long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('Xiaochun Long', 18)}}的其他基金
Function and Regulation of TSPAN2 in Vascular Disease
TSPAN2在血管疾病中的功能和调控
- 批准号:
10083017 - 财政年份:2020
- 资助金额:
$ 69.26万 - 项目类别:
Function and Regulation of TSPAN2 in Vascular Disease
TSPAN2在血管疾病中的功能和调控
- 批准号:
10543854 - 财政年份:2020
- 资助金额:
$ 69.26万 - 项目类别:
Function and Regulation of TSPAN2 in Vascular Disease
TSPAN2在血管疾病中的功能和调控
- 批准号:
10323276 - 财政年份:2020
- 资助金额:
$ 69.26万 - 项目类别:
Novel Interplay of KILN and MKL1 in Vascular Pathophysiology
KILN 和 MKL1 在血管病理生理学中的新相互作用
- 批准号:
10445030 - 财政年份:2014
- 资助金额:
$ 69.26万 - 项目类别:
Novel Role of MAPK14 in Regulation of VSMC Contractile Phenotype
MAPK14 在 VSMC 收缩表型调节中的新作用
- 批准号:
8828776 - 财政年份:2014
- 资助金额:
$ 69.26万 - 项目类别:
Novel Interplay of KILN and MKL1 in Vascular Pathophysiology
KILN 和 MKL1 在血管病理生理学中的新相互作用
- 批准号:
10001073 - 财政年份:2014
- 资助金额:
$ 69.26万 - 项目类别:
Novel Interplay of KILN and MKL1 in Vascular Pathophysiology
KILN 和 MKL1 在血管病理生理学中的新相互作用
- 批准号:
10219334 - 财政年份:2014
- 资助金额:
$ 69.26万 - 项目类别:
Novel Role of MAPK14 in Regulation of VSMC Contractile Phenotype
MAPK14 在 VSMC 收缩表型调节中的新作用
- 批准号:
8670325 - 财政年份:2014
- 资助金额:
$ 69.26万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 69.26万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 69.26万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 69.26万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 69.26万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 69.26万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 69.26万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 69.26万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 69.26万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 69.26万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 69.26万 - 项目类别:
Research Grant