SOD3 regulation of redox sensitive signaling in pulmonary vascular diseases
SOD3 对肺血管疾病中氧化还原敏感信号的调节
基本信息
- 批准号:10610425
- 负责人:
- 金额:$ 57.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-06-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AgeAnimal ModelAwardBindingBiologyBlood VesselsCD44 geneCell CommunicationCellsDevelopmentDiseaseElectron Spin Resonance SpectroscopyExtracellular MatrixFibroblastsFibrosisFoundationsFundingFutureGene ExpressionGenetic PolymorphismGrowthHalf-LifeHomeostasisHumanHyaluronanIn VitroIndividualInflammasomeInflammationKnock-inKnowledgeLocationLungMacrophageMetabolismMissionModificationMouse StrainsMusNatural ImmunityOxidation-ReductionPathogenesisPathologicPrecision Medicine InitiativePredispositionPropertyPulmonary CirculationPulmonary HypertensionRegulationResearchResearch InfrastructureResearch Project GrantsResource SharingSeriesSeveritiesSignal PathwaySignal TransductionSuperoxide DismutaseTestingTransforming Growth Factor betaTranslatingTranslationsVascular remodelingWorkantioxidant enzymedesignenzyme activityepigenetic regulationexperimental studyextracellularimprovedin vivoindividual variationinsightmitochondrial dysfunctionnew therapeutic targetnovel therapeutic interventionprogramspulmonary vascular disorderreceptorresponsetool
项目摘要
The overall mission of this research program is to determine how the antioxidant enzyme, extracellular
superoxide dismutase (EC-SOD or SOD3) regulates redox-sensitive signaling pathways responsible for
inflammation and fibrosis in pulmonary vascular diseases across the age span, and harness this knowledge to
design new and precise therapies. The different research projects are based on three complementary themes.
Theme 1 interrogates the regulation of SOD3 expression, activity and distribution in the healthy and diseased
pulmonary circulation in the mature and immature lung. These studies would include in vitro, and in vivo
studies using animal models, as well as activity translating the work through new human studies. They will
address the multiple levels of SOD3 regulation, including genetic polymorphisms, epigenetic regulation, or
other post-translation SOD3 modifications, that can influence gene expression, enzyme activity, half-life and
localization. Theme 2 evaluates how changes in SOD3 activity or binding properties impact redox sensitive
signaling pathways that are responsible for the development of pulmonary vascular disease, in particular,
inflammation and subsequent vascular remodeling and fibrosis. These experiments utilize a unique series of
SOD3 mouse strains, including a mouse with knock-in of a known human SOD3 polymorphism, to interrogate
how individual changes in SOD3 location or content can influence disease pathogenesis and severity. Based
on the unique extracellular localization of SOD3, studies will test the effects of insufficient SOD3 on matrix
integrity, matrix-cell interactions, cell-cell interactions and communication between extracellular signals and
intracellular cellular responses. Ongoing studies are testing how the loss of vascular SOD3 increases the
susceptibility of two key redox-sensitive targets localized to the extracellular matrix (ECM): activation of latent
TGF-β, which enhances PASMC and fibroblast growth, inflammation and synthetic function, or oxidative
fragmentation of hyaluronan, which binds to macrophage CD44 receptors and activates the NLRP3
inflammasome. Future planned studies will test how altered SOD3 impacts the redox landscape to modulate
innate immunity, cellular metabolism and mitochondrial dysfunction responsible for vascular fibrosis in PH.
Theme 3 translates the findings into new therapeutic strategies to replenish deficient SOD3 to restore redox
homeostasis. This framework is supported by a new initiative, funded by a Dean's Strategic Infrastructure
Research Committee Award for the purchase of an electron paramagnetic resonance spectrometer, to develop
a collaborative and interdisciplinary UCD Redox Biology Shared Resource Facility to advance the study of
Redox Biology. These studies collectively will provide new insight relevant to the mission of the Precision
Medicine Initiative, as they will uncover how individual variables that influence SOD3 impact the development
of inflammation and fibrosis in pulmonary hypertension.
这项研究计划的总体使命是确定细胞外抗氧化酶
超氧化物歧化酶(EC-SOD或SOD 3)调节氧化还原敏感的信号通路,
炎症和纤维化在肺血管疾病的年龄跨度,并利用这些知识,
设计新的精确疗法不同的研究项目基于三个互补的主题。
主题1探讨SOD 3在健康和疾病中的表达、活性和分布的调节,
成熟和未成熟肺的肺循环。这些研究将包括体外和体内
使用动物模型的研究,以及通过新的人类研究转化工作的活动。他们将
解决SOD 3调节的多个水平,包括遗传多态性,表观遗传调节,或
其他翻译后SOD 3修饰,可以影响基因表达,酶活性,半衰期和
本地化主题2评估了SOD 3活性或结合特性的变化如何影响氧化还原敏感性
导致肺血管疾病发展的信号通路,特别是,
炎症和随后的血管重塑和纤维化。这些实验利用了一系列独特的
SOD 3小鼠品系,包括具有已知人SOD 3多态性的敲入的小鼠,以询问
SOD 3位置或含量的个体变化如何影响疾病的发病机制和严重程度。基于
关于SOD 3独特的细胞外定位,研究将测试SOD 3不足对基质的影响,
完整性、基质-细胞相互作用、细胞-细胞相互作用和细胞外信号之间的通信,
细胞内的细胞反应。正在进行的研究正在测试血管SOD 3的损失如何增加血管内皮细胞的功能。
细胞外基质(ECM)中两个关键的氧化还原敏感靶点的敏感性:
TGF-β,其增强PASMC和成纤维细胞生长、炎症和合成功能,或氧化
透明质酸片段,与巨噬细胞CD 44受体结合并激活NLRP 3
炎性小体未来计划的研究将测试改变的SOD 3如何影响氧化还原景观,以调节
先天性免疫、细胞代谢和线粒体功能障碍是PH血管纤维化的原因。
主题3将这些发现转化为新的治疗策略,以补充缺乏的SOD 3,以恢复氧化还原
体内平衡该框架得到了一项新倡议的支持,该倡议由院长的战略基础设施资助
研究委员会奖购买电子顺磁共振光谱仪,开发
一个协作和跨学科的UCD氧化还原生物学共享资源设施,以促进研究
氧化还原生物学这些研究将共同为Precision的使命提供新的见解
医学倡议,因为他们将揭示影响SOD 3的个体变量如何影响发展
肺动脉高压的炎症和纤维化
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)
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Eva S. Nozik其他文献
Nbeal2 knockout mice are not protected against hypoxia-induced pulmonary vascular remodeling and pulmonary hypertension
Nbeal2基因敲除小鼠对缺氧诱导的肺血管重构和肺动脉高压没有保护作用
- DOI:
10.1182/bloodadvances.2024013880 - 发表时间:
2025-04-08 - 期刊:
- 影响因子:7.100
- 作者:
Janelle N. Posey;Mariah Jordan;Caitlin V. Lewis;Christina Sul;Evgenia Dobrinskikh;Delaney Swindle;Frederik Denorme;David Irwin;Jorge Di Paola;Kurt Stenmark;Eva S. Nozik;Cassidy Delaney - 通讯作者:
Cassidy Delaney
Eva S. Nozik的其他文献
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{{ truncateString('Eva S. Nozik', 18)}}的其他基金
R35 Administrative Supplements to Recognize Excellencein Diversity, Equity, Inclusion, and Accessibility (DEIA)Mentorship
R35 表彰多元化、公平、包容性和可及性 (DEIA) 指导方面卓越表现的行政补充
- 批准号:
10630461 - 财政年份:2022
- 资助金额:
$ 57.14万 - 项目类别:
Collaborative Pediatric Critical Care Research Network - Clinical Site
儿科重症监护协作研究网络 - 临床网站
- 批准号:
10470946 - 财政年份:2021
- 资助金额:
$ 57.14万 - 项目类别:
Collaborative Pediatric Critical Care Research Network - Clinical Site
儿科重症监护协作研究网络 - 临床网站
- 批准号:
10667490 - 财政年份:2021
- 资助金额:
$ 57.14万 - 项目类别:
SOD3 regulation of redox sensitive signaling in pulmonary vascular diseases
SOD3 对肺血管疾病中氧化还原敏感信号的调节
- 批准号:
10847902 - 财政年份:2018
- 资助金额:
$ 57.14万 - 项目类别:
SOD3 regulation of redox sensitive signaling in pulmonary vascular diseases
SOD3 对肺血管疾病中氧化还原敏感信号的调节
- 批准号:
10433989 - 财政年份:2018
- 资助金额:
$ 57.14万 - 项目类别:
SOD3 regulation of redox sensitive signaling in pulmonary vascular diseases
SOD3 对肺血管疾病中氧化还原敏感信号的调节
- 批准号:
10237868 - 财政年份:2018
- 资助金额:
$ 57.14万 - 项目类别:
DNA methylation of extracellular superoxide dismutase in pulmonary hypertension
肺动脉高压细胞外超氧化物歧化酶 DNA 甲基化
- 批准号:
8335465 - 财政年份:2011
- 资助金额:
$ 57.14万 - 项目类别:
Regulation of extracellular superoxide dismutase in human pulmonary arterial hype
细胞外超氧化物歧化酶在人肺动脉高压中的调节
- 批准号:
8210797 - 财政年份:2011
- 资助金额:
$ 57.14万 - 项目类别:
Extracellular superoxide induces Egr-1 in the hypoxic pulmonary artery
细胞外超氧化物在缺氧肺动脉中诱导 Egr-1
- 批准号:
7841072 - 财政年份:2009
- 资助金额:
$ 57.14万 - 项目类别:
Extracellular superoxide induces Egr-1 in the hypoxic pulmonary artery
细胞外超氧化物在缺氧肺动脉中诱导 Egr-1
- 批准号:
8197441 - 财政年份:2007
- 资助金额:
$ 57.14万 - 项目类别:
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