Hepatic kinome atlas: An in-depth identification of kinase pathways in liver fibrosis of humans and rodents.
Hepatic kinome atlas: An in-depth identification of kinase pathways in liver fibrosis of humans and rodents.
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DOI：
10.1002/hep.32467
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发表时间：
2022-11
期刊：
影响因子：
13.5
通讯作者：
Hinds, Terry D., Jr.
中科院分区：
文献类型：
--
作者：
Creeden, Justin F.;Kipp, Zachary A.;Xu, Mei;Flight, Robert M.;Moseley, Hunter N. B.;Martinez, Genesee J.;Lee, Wang-Hsin;Alganem, Khaled;Imami, Ali S.;McMullen, Megan R.;Roychowdhury, Sanjoy;Nawabi, Atta M.;Hipp, Jennifer A.;Softic, Samir;Weinman, Steven A.;McCullumsmith, Robert;Nagy, Laura E.;Hinds, Terry D., Jr.
解决在肝病中（例如在后期阶段）汇聚导致有害影响的途径具有潜在的抗纤维化作用，可以改善结果。我们的目的是探索人类和啮齿动物是否表现出相似的纤维化信号网络。我们使用 340 个底物靶标、激酶通路的上游生物信息学分析以及使用 PamGene PamStation 激酶组微阵列芯片技术的 2000 多次随机采样迭代，精心绘制了激酶通路图。利用这项技术，我们鉴定了大量在这两个物种的肝纤维化中活性发生改变的激酶。基因表达和免疫染色分析验证了许多这些激酶是真正的信号事件。令人惊讶的是，胰岛素受体作为一种重要的蛋白酪氨酸激酶出现，在人类和啮齿动物的纤维化肝病中高度活跃。盘状结构域受体酪氨酸激酶由纤维化过程中增加的胶原蛋白激活，是患有纤维化的人类和啮齿动物中另一种高度活跃的蛋白酪氨酸激酶。发现在纤维化中最活跃的丝氨酸/苏氨酸激酶是营养不良型1蛋白激酶和蛋白激酶激酶家族的成员。我们比较了四种模型的纤维化事件：患有肝硬化的人类模型和三种具有不同纤维化水平的小鼠模型，其中包括两种出现纤维化的脂肪肝模型。数据表明，人类和啮齿动物肝脏激酶组信号传导之间存在高度一致性，正如我们对有害途径的网络分析所示。我们的研究结果建立了一个全面的肝纤维化激酶图谱，它识别了人类和啮齿动物中保守的类似信号事件。我们使用 PamGene PamStation 技术和生物信息分析将人和小鼠的肝纤维化与激酶活性测量进行了比较。胰岛素受体 (INSR)、DDR、DMPK 和 PKA 是人类肝硬化和纤维化动物模型中最活跃的激酶。
Resolution of pathways that converge to induce deleterious effects in hepatic diseases, such as in the later stages, have potential antifibrotic effects that may improve outcomes. We aimed to explore whether humans and rodents display similar fibrotic signaling networks. We assiduously mapped kinase pathways using 340 substrate targets, upstream bioinformatic analysis of kinase pathways, and over 2000 random sampling iterations using the PamGene PamStation kinome microarray chip technology. Using this technology, we characterized a large number of kinases with altered activity in liver fibrosis of both species. Gene expression and immunostaining analyses validated many of these kinases as bona fide signaling events. Surprisingly, the insulin receptor emerged as a considerable protein tyrosine kinase that is hyperactive in fibrotic liver disease in humans and rodents. Discoidin domain receptor tyrosine kinase, activated by collagen that increases during fibrosis, was another hyperactive protein tyrosine kinase in humans and rodents with fibrosis. The serine/threonine kinases found to be the most active in fibrosis were dystrophy type 1 protein kinase and members of the protein kinase family of kinases. We compared the fibrotic events over four models: humans with cirrhosis and three murine models with differing levels of fibrosis, including two models of fatty liver disease with emerging fibrosis. The data demonstrate a high concordance between human and rodent hepatic kinome signaling that focalizes, as shown by our network analysis of detrimental pathways. Our findings establish a comprehensive kinase atlas for liver fibrosis, which identifies analogous signaling events conserved among humans and rodents. We compared human and mouse liver fibrosis with kinase activity measurements using the PamGene PamStation technology and bioinformatic analysis. The Insulin Receptor (INSR), DDR, DMPK, and PKA are the most active kinases among humans with cirrhosis and animal models of fibrosis.
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影响因子：
5.6
作者：
Hinds TD Jr;Creeden JF;Gordon DM;Stec DF;Donald MC;Stec DE
通讯作者：
Stec DE
DOI：
10.3390/ijerph18041794
发表时间：
2021-02-12
影响因子：
--
作者：
Mateus T;Martins F;Nunes A;Herdeiro MT;Rebelo S
通讯作者：
Rebelo S
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
3.2
作者：
Lee, Ursula E.;Friedman, Scott L.
通讯作者：
Friedman, Scott L.
影响因子：
29.4
作者：
Eslam, Mohammed;Sanyal, Arun J.;George, Jacob
通讯作者：
George, Jacob