國家衛生研究院 NHRI:Item 3990099045/15097
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    题名: Targeting Ca(2+)-dependent pathways to promote corneal epithelial wound healing induced by CISD2 deficiency
    作者: Sun, CC;Lee, SY;Chen, LH;Lai, CH;Shen, ZQ;Chen, NN;Lai, YS;Tung, CY;Tzeng, TY;Chiu, WT;Tsai, TF
    贡献者: Institute of Molecular and Genomic Medicine
    摘要: Chronic epithelial defects of the cornea, which are usually associated with severe dry eye disease, diabetes mellitus, chemical injuries or neurotrophic keratitis, as well as aging, are an unmet clinical need. CDGSH Iron Sulfur Domain 2 (CISD2) is the causative gene for Wolfram syndrome 2 (WFS2; MIM 604928). CISD2 protein is significantly decreased in the corneal epithelium of patients with various corneal epithelial diseases. Here we summarize the most updated publications and discuss the central role of CISD2 in corneal repair, as well as providing new results describing how targeting Ca(2+)-dependent pathways can improve corneal epithelial regeneration. This review mainly focuses on the following topics. Firstly, an overview of the cornea and of corneal epithelial wound healing. The key players involved in this process, such as Ca(2+), various growth factors/cytokines, extracellular matrix remodeling, focal adhesions and proteinases, are briefly discussed. Secondly, it is well known that CISD2 plays an essential role in corneal epithelial regeneration via the maintenance of intracellular Ca(2+) homeostasis. CISD2 deficiency dysregulates cytosolic Ca(2+), impairs cell proliferation and migration, decreases mitochondrial function and increases oxidative stress. As a consequence, these abnormalities bring about poor epithelial wound healing and this, in turn, will lead to persistent corneal regeneration and limbal progenitor cell exhaustion. Thirdly, CISD2 deficiency induces three distinct Ca(2+)-dependent pathways, namely the calcineurin, CaMKII and PKCα signaling pathways. Intriguingly, inhibition of each of the Ca(2+)-dependent pathways seems to reverse cytosolic Ca(2+) dysregulation and restore cell migration during corneal wound healing. Notably, cyclosporin, an inhibitor of calcineurin, appears to have a dual effect on both inflammatory and corneal epithelial cells. Finally, corneal transcriptomic analyses have revealed that there are six major functional groupings of differential expression genes when CISD2 deficiency is present: (1) inflammation and cell death; (2) cell proliferation, migration and differentiation; (3) cell adhesion, junction and interaction; (4) Ca(2+) homeostasis; (5) wound healing and extracellular matrix; and (6) oxidative stress and aging. This review highlights the importance of CISD2 in corneal epithelial regeneration and identifies the potential of repurposing venerable FDA-approved drugs that target Ca(2+)-dependent pathways for new uses, namely treating chronic epithelial defects of the cornea.
    日期: 2023-09
    關聯: Cellular Signalling. 2023 Sep;109:Article number 110755.
    Link to: http://dx.doi.org/10.1016/j.cellsig.2023.110755
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0898-6568&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:001023630000001
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85163735132
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