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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。

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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.

项目总结