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: 10610425
• 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/10610425
• 关键词: 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; Macrophage; 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; design; enzyme activity; epigenetic regulation; experimental study; extracellular; improved; in vivo; individual variation; insight; 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任务是确定细胞外的抗氧化酶是如何