MassIVE MSV000086623

Partial Public PXD023255

Genetic inactivation of RIP1 kinase activity in rats protects against ischemic brain injury

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Description

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. For mass spectrometry experiment, please check the method section in the manuscript. [doi:10.25345/C55F6T] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: DIA ; Thermo Fusion Lumos ; HRM ; rat plasma ; RIP1 kinase ; ischemic brain injury

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Principal Investigators:
(in alphabetical order) 		Baris Bingol, Genentech, Inc., USA
Submitting User: mnchoi
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