Siddiqui Sana, Lustig Ana, Carter Arnell, Sankar Mathavi, Daimon Caitlin M, Premont Richard T, Etienne Harmonie, van Gastel Jaana, Azmi Abdelkrim, Janssens Jonathan, Becker Kevin G, Zhang Yongqing, Wood William, Lehrmann Elin, Martin James G, Martin Bronwen, Taub Dennis D, Maudsley Stuart
Receptor Pharmacology Unit, Laboratory of Neurosciences, National Institute on Aging (NIA), National Institutes of Health (NIH), Baltimore, MD 21224, USA.
Laboratory of Molecular Biology and Immunology, NIA, NIH, Baltimore, MD 21224, USA.
Aging (Albany NY). 2017 Mar 4;9(3):706-740. doi: 10.18632/aging.101185.
Recent research has proposed that GIT2 (G protein-coupled receptor kinase interacting protein 2) acts as an integrator of the aging process through regulation of 'neurometabolic' integrity. One of the commonly accepted hallmarks of the aging process is thymic involution. At a relatively young age, 12 months old, GIT2 mice present a prematurely distorted thymic structure and dysfunction compared to age-matched 12 month-old wild-type control (C57BL/6) mice. Disruption of thymic structure in GIT2 (GIT2KO) mice was associated with a significant reduction in the expression of the cortical thymic marker, (cytokeratin 8). Double positive (CD4CD8) and single positive CD4 T cells were also markedly reduced in 12 month-old GIT2KO mice compared to age-matched control wild-type mice. Coincident with this premature thymic disruption in GIT2KO mice was the unique generation of a novel cervical 'organ', . 'parathymic lobes'. These novel organs did not exhibit classical peripheral lymph node-like characteristics but expressed high levels of T cell progenitors that were reflexively reduced in GIT2KO thymi. Using signaling pathway analysis of GIT2KO thymus and parathymic lobe transcriptomic data we found that the molecular signaling functions lost in the dysfunctional GIT2KO thymus were selectively reinstated in the novel parathymic lobe - suggestive of a compensatory effect for the premature thymic disruption. Broader inspection of high-dimensionality transcriptomic data from GIT2KO lymph nodes, spleen, thymus and parathymic lobes revealed a systemic alteration of multiple proteins (Dbp, Tef, Per1, Per2, Fbxl3, Ddit4, Sin3a) involved in the multidimensional control of cell cycle clock regulation, cell senescence, cellular metabolism and DNA damage. Altered cell clock regulation across both immune and non-immune tissues therefore may be responsible for the premature 'aging' phenotype of GIT2KO mice.
最近的研究表明，GIT2（G蛋白偶联受体激酶相互作用蛋白2）通过调节“神经代谢”完整性，作为衰老过程的整合因子发挥作用。衰老过程中一个普遍公认的标志是胸腺退化。在相对年轻的12个月龄时，与年龄匹配的12个月龄野生型对照（C57BL/6）小鼠相比，GIT2小鼠呈现出过早扭曲的胸腺结构和功能障碍。GIT2（GIT2KO）小鼠胸腺结构的破坏与皮质胸腺标志物（细胞角蛋白8）表达的显著降低有关。与年龄匹配的对照野生型小鼠相比，12个月龄的GIT2KO小鼠中双阳性（CD4CD8）和单阳性CD4 T细胞也明显减少。与GIT2KO小鼠中这种过早的胸腺破坏同时发生的是一种新型颈部“器官”——“副胸腺叶”的独特产生。这些新型器官没有表现出典型的外周淋巴结样特征，但表达高水平的T细胞祖细胞，而这些祖细胞在GIT2KO胸腺中反射性减少。通过对GIT2KO胸腺和副胸腺叶转录组数据进行信号通路分析，我们发现功能失调的GIT2KO胸腺中丧失的分子信号功能在新型副胸腺叶中被选择性恢复——这暗示了对过早胸腺破坏的一种补偿作用。对来自GIT2KO淋巴结、脾脏、胸腺和副胸腺叶的高维转录组数据进行更广泛的检查发现，参与细胞周期时钟调节、细胞衰老、细胞代谢和DNA损伤多维控制的多种蛋白质（Dbp、Tef、Per1、Per2、Fbxl3、Ddit4、Sin3a）发生了系统性改变。因此，免疫和非免疫组织中细胞时钟调节的改变可能是GIT2KO小鼠过早“衰老”表型的原因。
