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Lin, Zhiqiang

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Zhiqiang

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Lin, Zhiqiang

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2015 - 20173

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Author's Publications: search.filters.isAuthorOfPublication.38089fab-741e-4841-b9f3-539e56a6a185

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    Trbp regulates heart function through miRNA-mediated Sox6 repression
    (2015) Ding, Jian; Chen, Jinghai; Wang, Yanqun; Kataoka, Masaharu; Ma, Lixin; Zhou, Pingzhu; Hu, Xiaoyun; Lin, Zhiqiang; Nie, Mao; Deng, Zhong-Liang; Pu, William; Wang, Da-Zhi
    Cardiomyopathy is associated with altered expression of genes encoding contractile proteins. Here we show that Trbp (Tarbp2), an RNA binding protein, is required for normal heart function. Cardiac-specific inactivation of Trbp (TrbpcKO) caused progressive cardiomyopathy and lethal heart failure. Trbp loss of function resulted in upregulation of Sox6, repression of genes encoding normal cardiac slow-twitch myofiber proteins, and pathologically increased expression of skeletal fast-twitch myofiber genes. Remarkably, knockdown of Sox6 fully rescued the Trbp mutant phenotype, whereas Sox6 overexpression phenocopied the TrbpcKO phenotype. Trbp inactivation was mechanistically linked to Sox6 upregulation through altered processing of miR-208a, which is a direct inhibitor of Sox6. Transgenic overexpression of miR-208a sufficiently repressed Sox6, restored the balance of fast- and slow- twitch myofiber gene expression, and rescued cardiac function in TrbpcKO mice. Together, our studies reveal a novel Trbp-mediated microRNA processing mechanism in regulating a linear genetic cascade essential for normal heart function.
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    SOCS3 in retinal neurons and glial cells suppresses VEGF signaling to prevent pathological neovascular growth
    (American Association for the Advancement of Science (AAAS), 2015) Sun, Ye; Ju, Meihua; Lin, Zhiqiang; Fredrick, T. W.; Evans, L. P.; Tian, Katherine; Saba, N. J.; Morss, P. C.; Pu, William; Chen, Jing; Stahl, A.; Joyal, Jean; Smith, Lois
    Accumulating evidence indicates that retinal neuroglia and neural cells contribute to neovascularization in proliferative retinopathy, but the controlling molecular interactions are not well known. We identified a mechanism by which neurons influence neovascularization through suppressor of cytokine signaling 3 (SOCS3) in neurons and glial cells. We found that Socs3 expression was increased in the retinal ganglion cell layer and inner nuclear layer after oxygen- induced retinopathy. Neuronal/glial Socs3 deficient mice with oxygen-induced retinopathy had significantly increased pathologic retinal neovascularization and reduced vaso-obliterated retinal areas, suggesting that loss of neuronal/glial SOCS3 increased both retinal vascular re-growth and pathological neovascularization. In response to oxygen-induced retinopathy, retinal vascular endothelial growth factor A (Vegfa) expression was higher in neuronal/glial Socs3 deficient mice than in than Socs3 flox/flox controls indicating that neuronal and glial Socs3 suppressed Vegfa during pathologic conditions. Lack of neuronal/glial SOCS3 resulted in greater phosphorylation and activation of STAT3, which led to increased expression of its gene target Vegfa, and increased endothelial cell proliferation. In summary, neuronal/glial SOCS3 suppresses endothelial cell activation through suppression of STAT3-mediated neuronal/glia VEGF secretion, resulting in less endothelial proliferation and angiogenesis. These results show that neuronal/glial SOCS3 regulates neurovascular interaction and pathologic retinal angiogenesis by titrating VEGF signaling.
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    Inflammatory signals from photoreceptor modulate pathological retinal angiogenesis via c-Fos
    (The Rockefeller University Press, 2017) Sun, Ye; Lin, Zhiqiang; Liu, Chi-Hsiu; Gong, Yan; Liegl, Raffael; Fredrick, Thomas W.; Meng, Steven S.; Burnim, Samuel B.; Wang, Zhongxiao; Akula, James; Pu, William; Chen, Jing; Smith, Lois E.H.
    Pathological neovessels growing into the normally avascular photoreceptors cause vision loss in many eye diseases, such as age-related macular degeneration and macular telangiectasia. Ocular neovascularization is strongly associated with inflammation, but the source of inflammatory signals and the mechanisms by which these signals regulate the disruption of avascular privilege in photoreceptors are unknown. In this study, we found that c-Fos, a master inflammatory regulator, was increased in photoreceptors in a model of pathological blood vessels invading photoreceptors: the very low-density lipoprotein receptor–deficient (Vldlr−/−) mouse. Increased c-Fos induced inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor (TNF), leading to activation of signal transducer and activator of transcription 3 (STAT3) and increased TNFα–induced protein 3 (TNFAIP3) in Vldlr−/− photoreceptors. IL-6 activated the STAT3/vascular endothelial growth factor A (VEGFA) pathway directly, and elevated TNFAIP3 suppressed SOCS3 (suppressor of cytokine signaling 3)–activated STAT3/VEGFA indirectly. Inhibition of c-Fos using photoreceptor-specific AAV (adeno-associated virus)-hRK (human rhodopsin kinase)–sh_c-fos or a chemical inhibitor substantially reduced the pathological neovascularization and rescued visual function in Vldlr−/− mice. These findings suggested that the photoreceptor c-Fos controls blood vessel growth into the normally avascular photoreceptor layer through the inflammatory signal–induced STAT3/VEGFA pathway.