Genetic inactivation of RIP1 kinase activity in rats protects against ischemic brain injury
| العنوان: | Genetic inactivation of RIP1 kinase activity in rats protects against ischemic brain injury |
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| المؤلفون: | Baris Bingol, Kimberly L. Stark, Hai Ngu, Brent S. McKenzie, Donald S. Kirkpatrick, Luke Xie, Ivan Peng, Amy Easton, Erik Verschueren, Tatiana Goncharov, Eugene Varfolomeev, Keith R. Anderson, Domagoj Vucic, Meena Choi, Joshua D. Webster |
| المصدر: | Cell Death & Disease Cell Death and Disease, Vol 12, Iss 4, Pp 1-15 (2021) |
| بيانات النشر: | Nature Publishing Group UK, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Nervous system, Male, Cancer Research, Programmed cell death, Immunology, Cell death in the nervous system, Inflammation, Pharmacology, Protein Serine-Threonine Kinases, medicine.disease_cause, Article, Rats, Sprague-Dawley, Cellular and Molecular Neuroscience, Ischemia, medicine, Animals, lcsh:QH573-671, Kinase activity, Mutation, Cell Death, lcsh:Cytology, Kinase, business.industry, Cell Biology, Phenotype, Rats, Disease Models, Animal, medicine.anatomical_structure, Brain Injuries, Receptor-Interacting Protein Serine-Threonine Kinases, Biomarker (medicine), Diseases of the nervous system, medicine.symptom, business |
| الوصف: | RIP1 kinase-mediated inflammatory and cell death pathways have been implicated in the pathology of acute and chronic disorders of the nervous system. Here, we describe a novel animal model of RIP1 kinase deficiency, generated by knock-in of the kinase-inactivating RIP1(D138N) mutation in rats. Homozygous RIP1 kinase-dead (KD) rats had normal development, reproduction and did not show any gross phenotypes at baseline. However, cells derived from RIP1 KD rats displayed resistance to necroptotic cell death. In addition, RIP1 KD rats were resistant to TNF-induced systemic shock. We studied the utility of RIP1 KD rats for neurological disorders by testing the efficacy of the genetic inactivation in the transient middle cerebral artery occlusion/reperfusion model of brain injury. RIP1 KD rats were protected in this model in a battery of behavioral, imaging, and histopathological endpoints. In addition, RIP1 KD rats had reduced inflammation and accumulation of neuronal injury biomarkers. Unbiased proteomics in the plasma identified additional changes that were ameliorated by RIP1 genetic inactivation. Together these data highlight the utility of the RIP1 KD rats for target validation and biomarker studies for neurological disorders. |
| اللغة: | English |
| تدمد: | 2041-4889 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::aef4690f118255b62df548cee4af5d22 http://europepmc.org/articles/PMC8026634 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....aef4690f118255b62df548cee4af5d22 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20414889 |
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