The role of endothelial connexins in vascular wound repair
内皮连接蛋白在血管伤口修复中的作用
基本信息
- 批准号:10751730
- 负责人:
- 金额:$ 4.25万
- 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:2023-08-10 至 2026-02-09
- 项目状态:未结题
- 来源:
- 关键词:AlanineAntibodiesAortaAreaArteriesBiologicalBiologyBiomedical ResearchBlood VesselsC-terminalCarotid ArteriesCell CommunicationCell Culture TechniquesCell LineCell ProliferationCell SeparationCellsCessation of lifeCommunicationConfocal MicroscopyConnexin 43ConnexinsCoronary ThrombosisCoronary arteryDataData AnalysesDefectDeoxyuridineDiseaseEndothelial CellsEndotheliumEnsureEnvironmentEquipmentFailureFellowshipFemaleGap JunctionsGeneticGoalsHealthHeartHomeHourHumanImmunofluorescence ImmunologicImpaired healingImpairmentInjectionsInjuryInvestigationKnock-outKnockout MiceLegal patentLifeLigationLinkMeasuresMediatingMentorshipMicroscopeMissionModelingModernizationModificationMusMutationMyocardial InfarctionOperative Surgical ProceduresPathway interactionsPatientsPharmaceutical PreparationsPhosphorylationPhosphorylation InhibitionPhosphorylation SitePhosphotransferasesPlasmidsPost-Translational Protein ProcessingPreparationProcessProliferatingProliferation MarkerProto-Oncogene Proteins c-aktResearchResearch InstituteResearch PersonnelRoleSaphenous VeinSerineSignal PathwaySignal TransductionSiteStentsSurvival RateTechnical ExpertiseTechniquesTestingTherapeuticThrombusTissuesTrainingTransfectionTravelUnited States National Institutes of HealthUniversitiesUp-RegulationVascular DiseasesVascular Endothelial CellVascular GraftVirginiaWestern BlottingWorkanimal facilityburden of illnesscell growthcell injurycell motilitydesignendothelial regenerationendothelial repairexperienceexperimental studyhealingimprovedin vivoin vivo Modelinjuredmalemigrationmimeticsnovelpharmacologicprotein expressionrepairedresponserestenosissexstroke risktherapeutic targettranscriptome sequencingvascular injurywound closurewound healing
项目摘要
|| Project Summary .
Impaired endothelial wound healing in blood vessels like the coronary artery and saphenous vein is a primary
contributor to vascular stent failure and deadly coronary thrombosis. Identifying the mechanism of delayed
endothelial repair is essential for improving vessel patency and patient survival rates. As such, this proposal
focuses on identifying regulators of normal endothelial healing and understanding how these factors are
dysregulated when healing is impaired. Previous studies have shown connexin 43 (Cx43) gap junctions may
regulate wound healing. However, the specific role of connexin 43 in endothelial cell (EC) healing is unknown.
Preliminary data in this proposal indicates that ligation-induced vascular injury promotes increases in the
expression of EC Cx43 surrounding the damaged area in the aorta and carotid arteries in mice. Cx43-mediated
gap junction intracellular communication is controlled by phosphorylation at the Cx43 C-terminus. My preliminary
data demonstrate that specific Cx43 phosphorylation at its serine (s) 368, associated with gap junction closure,
is present during the final stages of EC wound healing in vivo. Cx43-s368 also reduced the rate of wound closure
in cultured human EC. These findings inform the hypothesis that Cx43 expression and channel functions are
critical for EC wound healing in large arteries. The aims of this proposal are to define the role of connexin 43 in
endothelial wound healing (Aim 1), investigate if a loss of Cx43 limits healing in vivo (Aim 1), and test if channel
functions, regulated by posttranslational modifications, improve/delay vascular repair (Aim 2). This investigation
will be completed using a novel mouse carotid EC injury survival surgery in mice I developed, which will allow
for the assessment of Cx43 expression in carotid EC during the healing process. Both genetic and
pharmacological strategies will be used to alter Cx43 expression and phosphorylation in mouse injury models
and in cultured human EC, and the impact of these modifications on the rate and quality of EC healing will be
quantified. Additionally, RNAseq approaches will be used to identify Cx43 gap junction-dependent signaling in
the regenerating endothelium. These aims will be accomplished under the mentorship of researchers with
extensive experience in vascular biology, Dr. Scott Johnstone, Dr. Robert Gourdie, and Dr. Brant Isakson, at
Virginia Tech’s Fralin Biomedical Research Institute (FBRI). The FBRI is home to research equipment including
but not limited to animal facilities, confocal microscopes, flow cytometers, and cell culture equipment. This state-
of-the-art research environment will allow for a detailed and mechanistic investigation. Ultimately, this study will
characterize a novel role for Cx43 in vascular EC. This project is designed to identify new potential therapeutic
targets in vascular disease that will promote the mission of the NIH to enhance patient health and to promote
longer life free of illness.
|| 项目摘要。
冠状动脉和大隐静脉等血管的内皮损伤愈合受损是主要的
导致血管支架失效和致命的冠状动脉血栓形成。识别延迟的机制
内皮修复对于改善血管开放性和患者存活率是必不可少的。因此,本提案
重点是确定正常内皮愈合的调节因子,并了解这些因子是如何
当愈合受损时,调节失调。先前的研究表明,连接蛋白43(Cx43)间隙连接可能
调节伤口愈合。然而,连接蛋白43在内皮细胞(EC)愈合中的具体作用尚不清楚。
该提案中的初步数据表明,结扎诱导的血管损伤促进了
小鼠主动脉和颈动脉损伤区周围EC Cx43的表达。Cx43介导
间隙连接细胞内通讯由Cx43 C-末端的磷酸化控制。我的初步
数据表明,与间隙连接闭合相关的,
存在于体内EC伤口愈合的最后阶段。Cx43-s368还降低了伤口闭合率
在培养的人EC中。这些发现提示了Cx43表达和通道功能是
对于大动脉中的EC伤口愈合至关重要。该提议的目的是确定连接蛋白43在以下方面的作用:
内皮伤口愈合(目标1),研究Cx43的缺失是否限制体内愈合(目标1),并测试通道
通过翻译后修饰调节的功能,改善/延迟血管修复(目的2)。这次调查
将使用我开发的一种新型小鼠颈动脉EC损伤存活手术来完成,
用于评估愈合过程中颈动脉EC中Cx43的表达。遗传和
药理学策略将用于改变小鼠损伤模型中Cx43的表达和磷酸化
以及在培养的人EC中,这些修饰对EC愈合的速率和质量的影响将是
量化。此外,RNAseq方法将用于鉴定Cx43间隙连接依赖性信号传导,
再生的内皮细胞这些目标将在研究人员的指导下实现,
Scott Johnstone博士、Robert Gourdie博士和Brant Isakson博士在血管生物学方面拥有丰富的经验,
弗吉尼亚理工大学Fralin生物医学研究所(FBRI)。FBRI是研究设备的所在地,
但不限于动物设施、共聚焦显微镜、流式细胞仪和细胞培养设备。这个州-
最先进的研究环境将允许详细和机械的调查。最终,这项研究将
描述了Cx43在血管EC中的新作用。该项目旨在确定新的潜在治疗方法,
血管疾病的目标,这将促进国家卫生研究院的使命,以提高病人的健康和促进
更长的寿命免于疾病。
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 }}
Meghan Sedovy其他文献
Meghan Sedovy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 }}
相似海外基金
University of Aberdeen and Vertebrate Antibodies Limited KTP 23_24 R1
阿伯丁大学和脊椎动物抗体有限公司 KTP 23_24 R1
- 批准号:
10073243 - 财政年份:2024
- 资助金额:
$ 4.25万 - 项目类别:
Knowledge Transfer Partnership
Role of Natural Antibodies and B1 cells in Fibroproliferative Lung Disease
天然抗体和 B1 细胞在纤维增生性肺病中的作用
- 批准号:
10752129 - 财政年份:2024
- 资助金额:
$ 4.25万 - 项目类别:
CAREER: Next-generation protease inhibitor discovery with chemically diversified antibodies
职业:利用化学多样化的抗体发现下一代蛋白酶抑制剂
- 批准号:
2339201 - 财政年份:2024
- 资助金额:
$ 4.25万 - 项目类别:
Continuing Grant
Isolation and characterisation of monoclonal antibodies for the treatment or prevention of antibiotic resistant Acinetobacter baumannii infections
用于治疗或预防抗生素耐药鲍曼不动杆菌感染的单克隆抗体的分离和表征
- 批准号:
MR/Y008693/1 - 财政年份:2024
- 资助金额:
$ 4.25万 - 项目类别:
Research Grant
Discovery of novel nodal antibodies in the central nervous system demyelinating diseases and elucidation of the mechanisms through an optic nerve demyelination model
发现中枢神经系统脱髓鞘疾病中的新型节点抗体并通过视神经脱髓鞘模型阐明其机制
- 批准号:
23K14783 - 财政年份:2023
- 资助金额:
$ 4.25万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Elucidation of the mechanisms controlling the physicochemical properties and functions of supercharged antibodies and development of their applications
阐明控制超电荷抗体的理化性质和功能的机制及其应用开发
- 批准号:
23KJ0394 - 财政年份:2023
- 资助金额:
$ 4.25万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Developing first-in-class aggregation-specific antibodies for a severe genetic neurological disease
开发针对严重遗传神经系统疾病的一流聚集特异性抗体
- 批准号:
10076445 - 财政年份:2023
- 资助金额:
$ 4.25万 - 项目类别:
Grant for R&D
PLA2G2D Antibodies for Cancer Immunotherapy
用于癌症免疫治疗的 PLA2G2D 抗体
- 批准号:
10699504 - 财政年份:2023
- 资助金额:
$ 4.25万 - 项目类别:
Genetic adjuvants to elicit neutralizing antibodies against HIV
基因佐剂可引发抗艾滋病毒中和抗体
- 批准号:
10491642 - 财政年份:2023
- 资助金额:
$ 4.25万 - 项目类别:
Novel Immunogens to Elicit Broadly Cross-reactive Antibodies That Target the Hemagglutinin Head Trimer Interface
新型免疫原可引发针对血凝素头三聚体界面的广泛交叉反应抗体
- 批准号:
10782567 - 财政年份:2023
- 资助金额:
$ 4.25万 - 项目类别:














{{item.name}}会员




