SSH1-Nrf2 nexus in tipping the balance between degeneration and protection in tauopathies.

SSH1-Nrf2 关系打破了 tau蛋白病中退化和保护之间的平衡。

• 批准号: 10605657
• 负责人: David E Kang
• 金额: $ 50.57万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605657
• 关键词: APP-PS1; Actins; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid; Animal Model; Astrocytes; Autophagocytosis; Autopsy; Binding; Binding Sites; Biochemical; Biological Assay; Brain; Cell Fractionation; Cell Nucleus; Cell model; Cells; Cognitive deficits; Cytoskeleton; Defect; Deposition; Equilibrium; Exhibits; F-Actin; Frontotemporal Lobar Degenerations; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Homologous Gene; Human; Impaired cognition; In Situ; In Vitro; Induction of Apoptosis; Knowledge; Lentivirus; Ligation; Mediating; Microfilaments; Mitochondria; Molecular; Mus; Nerve Degeneration; Neurons; Nuclear; Outcome; Oxidative Stress; Pathogenesis; Pathologic; Pathology; Pathway interactions; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Physiological; Process; Protein Dephosphorylation; Proteins; Proteome; Proteomics; Recombinant Proteins; Regulation; Repression; Rod; Severities; Signal Transduction; Synapses; Tauopathies; Testing; Titrations; Transfection; cofilin; cohort; immunoreactivity; insight; mind control; mutant; neuroinflammation; neuroprotection; oxidation; oxidative damage; proteotoxicity; response; sensor; small hairpin RNA; tau Proteins; tau aggregation; transcriptome; transcriptome sequencing; ubiquitin-protein ligase; APP-PS1; Actins; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid; Animal Model; Astrocytes; Autophagocytosis; Autopsy; Binding; Binding Sites; Biochemical; Biological Assay; Brain; Cell Fractionation; Cell Nucleus; Cell model; Cells; Cognitive deficits; Cytoskeleton; Defect; Deposition; Equilibrium; Exhibits; F-Actin; Frontotemporal Lobar Degenerations; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Homologous Gene; Human; Impaired cognition; In Situ; In Vitro; Induction of Apoptosis; Knowledge; Lentivirus; Ligation; Mediating; Microfilaments; Mitochondria; Molecular; Mus; Nerve Degeneration; Neurons; Nuclear; Outcome; Oxidative Stress; Pathogenesis; Pathologic; Pathology; Pathway interactions; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Physiological; Process; Protein Dephosphorylation; Proteins; Proteome; Proteomics; Recombinant Proteins; Regulation; Repression; Rod; Severities; Signal Transduction; Synapses; Tauopathies; Testing; Titrations; Transfection; cofilin; cohort; immunoreactivity; insight; mind control; mutant; neuroinflammation; neuroprotection; oxidation; oxidative damage; proteotoxicity; response; sensor; small hairpin RNA; tau Proteins; tau aggregation; transcriptome; transcriptome sequencing; ubiquitin-protein ligase

Project Summary Accumulating evidence indicates that the ability to mount an effective Nrf2-mediated gene expression response to oxidative stress declines during the aging process. In particular, nuclear but not cytoplasmic Nrf2 is depleted in neurons of AD patients. In animal models, loss of Nrf2 signaling exacerbates amyloid and tau deposition, neuroinflammation, and cognitive deficits, whereas induction of Nrf2 signaling protects against these phenotypes. While toxic tau assemblies, oxidative stress, cytoskeletal disruption, and autophagy defects are cardinal features of tauopathies, including AD, how these cellular brain phenotypes integrate at the molecular level to produce physiological or pathological responses during tau pathogenesis is unknown. In addition to the known regulation of the cytoskeleton, mitochondria, and autophagy by SSH1, our new preliminary studies show that the SSH1 pathway intersects with the Nrf2 to inhibit and titrate Nrf2 signaling. Our overarching hypothesis is that the nexus between the SSH1 and Nrf2 pathways represents a tipping point that tips the balance between degeneration and protection during proteotoxic and oxidative stress in tauopathies. As both Nrf2 and SSH1 are activated under oxidative stress, understanding how the nexus between Nrf2 and SSH1 is physiologically and pathologically regulated will provide key insights into treating AD and other tauopathies. Utilizing in vitro recombinant proteins, cellular models, animal models, and postmortem brains combined with mechanistic biochemical, immunochemical, in situ proximity ligation assays, RNA- seq, and proteomics studies, we will define and dissect how the SSH1-Nrf2 nexus tips the balance between neurodegeneration vs. neuroprotection in tauopathies.

项目摘要 积累的证据表明，安装有效的NRF2介导的基因的能力 对氧化应激的表达反应在衰老过程中下降。特别是核 但是，在AD患者的神经元中，细胞质NRF2耗尽。在动物模型中，NRF2的损失 信号加剧淀粉样蛋白和TAU沉积，神经炎症和认知缺陷， 而诱导NRF2信号传导可以防止这些表型。而有毒的tau 组件，氧化应激，细胞骨架破坏和自噬缺陷是基本特征 这些细胞脑表型如何在分子水平积分 在tau发病机理期间产生生理或病理反应是未知的。在 除了SSH1的已知调节，线粒体和自噬的已知调节 新的初步研究表明，SSH1途径与NRF2相交以抑制和滴定 NRF2信号。我们的总体假设是SSH1和NRF2之间的联系 途径代表一个转折点，可以使变性与保护之间的平衡 在蛋白毒性和氧化应激期间。由于NRF2和SSH1在 氧化应激，了解NRF2和SSH1之间的联系在生理和 病理调节将为治疗AD和其他tauopathies提供关键见解。 利用体外重组蛋白，细胞模型，动物模型和事后大脑 结合机械生化，免疫化学，原位接近结扎结合测定，RNA- SEQ和蛋白质组学研究，我们将定义和剖析SSH1-NRF2 Nexus如何提示平衡 在扭曲病中的神经变性与神经保护之间。