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Genetic inactivation of RIP1 kinase activity in rats protects against ischemic brain injury.
Stark, Kimberly; Goncharov, Tatiana; Varfolomeev, Eugene; Xie, Luke; Ngu, Hai; Peng, Ivan; Anderson, Keith R; Verschueren, Erik; Choi, Meena; Kirkpatrick, Donald S; Easton, Amy; Webster, Joshua D; McKenzie, Brent S; Vucic, Domagoj; Bingol, Baris.
Afiliação
  • Stark K; Department of Neuroscience, Genentech, South San Francisco, 94080, CA, USA.
  • Goncharov T; Department of Early Discovery Biochemistry, Genentech, South San Francisco, 94080, CA, USA.
  • Varfolomeev E; Department of Early Discovery Biochemistry, Genentech, South San Francisco, 94080, CA, USA.
  • Xie L; Department of Biomedical Imaging, Genentech, South San Francisco, 94080, CA, USA.
  • Ngu H; Department of Pathology, Genentech, South San Francisco, 94080, CA, USA.
  • Peng I; Department of Translational Immunology, Genentech, South San Francisco, 94080, CA, USA.
  • Anderson KR; Department of Molecular Biology, Genentech, South San Francisco, 94080, CA, USA.
  • Verschueren E; Department of Microchemistry, Proteomics and Lipidomics, Genentech, South San Francisco, 94080, CA, USA.
  • Choi M; Department of Microchemistry, Proteomics and Lipidomics, Genentech, South San Francisco, 94080, CA, USA.
  • Kirkpatrick DS; Department of Microchemistry, Proteomics and Lipidomics, Genentech, South San Francisco, 94080, CA, USA.
  • Easton A; Department of Neuroscience, Genentech, South San Francisco, 94080, CA, USA.
  • Webster JD; Department of Pathology, Genentech, South San Francisco, 94080, CA, USA.
  • McKenzie BS; Department of Translational Immunology, Genentech, South San Francisco, 94080, CA, USA.
  • Vucic D; Department of Early Discovery Biochemistry, Genentech, South San Francisco, 94080, CA, USA. vucic.domagoj@gene.com.
  • Bingol B; Department of Neuroscience, Genentech, South San Francisco, 94080, CA, USA. bingol.baris@gene.com.
Cell Death Dis ; 12(4): 379, 2021 04 07.
Article em En | MEDLINE | ID: mdl-33828080
ABSTRACT
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Lesões Encefálicas / Morte Celular / Proteínas Serina-Treonina Quinases / Isquemia Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Lesões Encefálicas / Morte Celular / Proteínas Serina-Treonina Quinases / Isquemia Idioma: En Ano de publicação: 2021 Tipo de documento: Article