COBRE P3: ROLE OF HEXOSAMINE BIOSYNTHETIC PATHWAY AND POSTRANSLATIONAL O-GLCNAC

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本项目的长期目标是阐明蛋白质Ser/Thr的翻译后O-GlcNAc修饰在调节与糖尿病并发症相关的信号转导事件中的作用。 我们推测，高葡萄糖诱导的O-GlcNAc糖基化的细胞质和/或核蛋白的升高有助于延迟愈合的牙周组织和夸大的反应感染观察糖尿病患者。 我们的第一个目的是阐明胰岛素/IGF-1受体信号传导途径的关键组分IRS-1和IRS-2的O-GlcNAc修饰减弱胰岛素信号传导的机制，并测试这些蛋白质的O-GlcNAc修饰减弱IGF-1受体信号传导的假设。第二个目标将测试的假设，IGF-1信号在牙周膜成纤维细胞（PDLF）是由高葡萄糖诱导的O-GlcNAc修饰减弱。 如果这一假设是正确的，我们预计，葡萄糖诱导的IGF-1信号转导的损害可能会减轻操纵的酶负责这种修改，O-GlcNAc酶和O-GlcNAc转移酶。第三个目标将确定葡萄糖诱导的LPS刺激的MMP-1从巨噬细胞分泌的增强是否可以通过酶O-GlcNAc酶的过表达来减少。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long-term goal of this project is to elucidate the role of posttranslational O-GlcNAc modification of protein Ser/Thr in the regulation of signal transduction events relevant to the complications associated with diabetes. We hypothesize that high glucose-induced elevation in O-GlcNAc glycosylation of cytoplasmic and/or nuclear proteins contributes to delayed healing of the periodontium and to the exaggerated response to infection observed in diabetic patients. Our first aim is to elucidate the mechanism by which O-GlcNAc modification of critical components of the insulin/IGF-1 receptor signaling pathways, IRS-1 and IRS-2, attenuates insulin signaling and to test the hypothesis that O-GlcNAc modification of these proteins attenuates IGF-1 receptor signaling. The second aim will test the hypothesis that IGF-1 signaling in periodontal ligament fibroblasts (PDLF) is attenuated by high glucose-induced O-GlcNAc modification. If this hypothesis is correct we anticipate that glucose-induced impairment of IGF-1 signaling may be alleviated by manipulation of the enzymes responsible for this modification, O-GlcNAcase and O-GlcNAc transferase. The third aim will determine whether the glucose-induced augmentation of LPS-stimulated secretion of MMP-1 from macrophages can be reduced by overexpression of the enzyme, O-GlcNAcase.