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.

该研究计划的总体任务是确定抗氧化酶、细胞外酶如何 超氧化物歧化酶（EC-SOD 或 SOD3）调节氧化还原敏感信号通路，负责 不同年龄段肺血管疾病的炎症和纤维化，并利用这些知识 设计新的、精确的疗法。不同的研究项目基于三个互补的主题。 主题 1 探讨健康人和患病者中 SOD3 表达、活性和分布的调节 成熟肺和未成熟肺的肺循环。这些研究将包括体外和体内 使用动物模型进行的研究，以及通过新的人体研究转化工作的活动。他们会 解决 SOD3 调控的多个层面，包括遗传多态性、表观遗传调控或 其他翻译后 SOD3 修饰，可以影响基因表达、酶活性、半衰期和 本土化。主题 2 评估 SOD3 活性或结合特性的变化如何影响氧化还原敏感性 导致肺血管疾病发生的信号通路，特别是 炎症以及随后的血管重塑和纤维化。这些实验利用了一系列独特的 SOD3 小鼠品系，包括敲入已知人类 SOD3 多态性的小鼠，用于询问 SOD3 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 基于SOD3独特的细胞外定位，研究将测试SOD3不足对基质的影响 完整性、基质-细胞相互作用、细胞-细胞相互作用以及细胞外信号和细胞之间的通信 细胞内的细胞反应。正在进行的研究正在测试血管 SOD3 的缺失如何增加 位于细胞外基质（ECM）的两个关键氧化还原敏感靶点的敏感性：潜在的激活 TGF-β，增强 PASMC 和成纤维细胞生长、炎症和合成功能或氧化 透明质酸碎片，与巨噬细胞 CD44 受体结合并激活 NLRP3 炎症小体。未来计划的研究将测试改变的 SOD3 如何影响氧化还原景观以进行调节 先天免疫、细胞代谢和线粒体功能障碍是导致 PH 血管纤维化的原因。 主题 3 将研究结果转化为新的治疗策略，以补充 SOD3 缺陷以恢复氧化还原 体内平衡。该框架得到了一项新举措的支持，该举措由院长战略基础设施资助 研究委员会奖励购买电子顺磁共振波谱仪，开发 一个协作和跨学科的都柏林大学氧化还原生物学共享资源设施，以推进以下研究 氧化还原生物学。这些研究共同将为 Precision 的使命提供新的见解 Medicine Initiative，他们将揭示影响 SOD3 的个体变量如何影响发育 肺动脉高压中的炎症和纤维化。