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基因敲除大鼠 RIP1 激酶活性可对抗脑缺血损伤。

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

机构信息

Department of Neuroscience, Genentech, South San Francisco, 94080, CA, USA.

Department of Early Discovery Biochemistry, Genentech, South San Francisco, 94080, CA, USA.

出版信息

Cell Death Dis. 2021 Apr 7;12(4):379. doi: 10.1038/s41419-021-03651-6.

DOI:10.1038/s41419-021-03651-6
PMID:33828080
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8026634/
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.

摘要

RIP1 激酶介导的炎症和细胞死亡途径与神经系统的急性和慢性疾病的病理学有关。在这里，我们描述了一种新型的 RIP1 激酶缺陷动物模型，该模型通过在大鼠中敲入激酶失活的 RIP1(D138N)突变而产生。RIP1 激酶完全缺失（KD）的杂合子大鼠发育正常，繁殖正常，在基线时没有表现出任何明显的表型。然而，源自 RIP1 KD 大鼠的细胞对坏死性细胞死亡具有抗性。此外，RIP1 KD 大鼠对 TNF 诱导的全身休克具有抗性。我们通过测试在短暂性大脑中动脉闭塞/再灌注脑损伤模型中基因缺失的疗效，研究了 RIP1 KD 大鼠在神经疾病中的应用。在一系列行为、成像和组织病理学终点方面，RIP1 KD 大鼠在该模型中得到了保护。此外，RIP1 KD 大鼠的炎症和神经元损伤生物标志物的积累减少。在血浆中的无偏蛋白质组学鉴定到了其他由 RIP1 基因缺失改善的变化。这些数据共同强调了 RIP1 KD 大鼠在神经疾病的靶标验证和生物标志物研究中的应用价值。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63e9/8026634/6191ecb9bf9b/41419_2021_3651_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63e9/8026634/cd9a4f622761/41419_2021_3651_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63e9/8026634/dbc2e546d34e/41419_2021_3651_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63e9/8026634/8fd5d00882ad/41419_2021_3651_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63e9/8026634/e55c364e60e2/41419_2021_3651_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63e9/8026634/6191ecb9bf9b/41419_2021_3651_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63e9/8026634/cd9a4f622761/41419_2021_3651_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63e9/8026634/dbc2e546d34e/41419_2021_3651_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63e9/8026634/8fd5d00882ad/41419_2021_3651_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63e9/8026634/e55c364e60e2/41419_2021_3651_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63e9/8026634/6191ecb9bf9b/41419_2021_3651_Fig5_HTML.jpg

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