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利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 该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相关并发症相关的信号转导事件中的作用。我们假设，高糖诱导细胞质和/或核蛋白O-GlcNAc糖基化的升高导致牙周组织延迟愈合，并导致糖尿病患者对感染的夸大反应。 我们的第一个目标是阐明胰岛素/IGF-1受体信号通路的关键成分IRS-1和IRS-2的O-GlcNAc修饰减弱胰岛素信号的机制，并验证这些蛋白的O-GlcNAc修饰减弱IGF-1受体信号的假设。第二个目的将验证高糖诱导的O-GlcNAc修饰减弱牙周膜成纤维细胞(PDLF)中IGF-1信号的假设。如果这一假设是正确的，我们预计葡萄糖诱导的IGF-1信号通路的损伤可以通过操纵负责这一修饰的酶，O-GlcNAcase和O-GlcNAc转移酶来缓解。第三个目的将确定是否可以通过过表达O-GlcNAcase来减少葡萄糖诱导的内毒素刺激的巨噬细胞分泌基质金属蛋白酶-1的增加。

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.