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
• 负责人: Eva S. Nozik
• 金额: $ 57.14万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10433989
• 关键词: Address; Age; Animal Model; Award; Binding; Biology; Blood Vessels; CD44 gene; Cell Communication; Cells; Development; Disease; Electron Spin Resonance Spectroscopy; Extracellular Matrix; Fibroblasts; Fibrosis; Foundations; Funding; Future; Gene Expression; Genetic Polymorphism; Growth; Half-Life; Homeostasis; Human; Hyaluronan; In Vitro; Individual; Inflammasome; Inflammation; Knock-in; Knowledge; Location; Lung; Metabolism; Mission; Modification; Mouse Strains; Mus; Natural Immunity; Oxidation-Reduction; Pathogenesis; Pathologic; Precision Medicine Initiative; Predisposition; Property; Pulmonary Circulation; Pulmonary Hypertension; Regulation; Research; Research Infrastructure; Research Project Grants; Resource Sharing; Series; Severities; Signal Pathway; Signal Transduction; Superoxide Dismutase; Testing; Transforming Growth Factor beta; Translating; Translations; Vascular remodeling; Work; antioxidant enzyme; base; design; enzyme activity; epigenetic regulation; experimental study; extracellular; improved; in vivo; insight; macrophage; mitochondrial dysfunction; new therapeutic target; novel therapeutic intervention; programs; pulmonary vascular disorder; receptor; response; tool

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