Exploring novel molecular mechanisms of TSC22D4 action in development of diabetes mellitus

探索 TSC22D4 在糖尿病发展中作用的新分子机制

• 批准号: 404084161
• 负责人: Dr. Bilgen Ekim, Ph.D.
• 金额: --
• 依托单位: Klinik für Endokrinologie, Diabetologie, Stoffwechselkrankheiten und Klinische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/404084161?language=en
• 关键词: Exploring; novel; molecular; mechanisms; TSC22D4

Type 2 diabetes is the disease of the modern world which is associated with unhealthy eating habits and sedentary life style. Although anti-diabetes medications exist, they all have their own limitations and side effects. Hence, type 2 diabetic patients are in need of novel therapeutics, which requires a better understanding of the disease.We identified TSC22D4 as a novel regulator of insulin sensitivity and glucose metabolism and showed that human type 2 diabetic patients have elevated hepatic TSC22D4 levels that negatively correlate with insulin sensitivity. Yet the molecular mechanism of TSC22D4 action in controlling glucose homeostasis remains elusive. More recently, we could show that TSC22D4 interacts with Akt1 in a regulatory manner. While energy availability weakens the TSC22D4-Akt1 interaction, oxidative stress and mitochondrial inhibition promote it, suggesting that the TSC22D4-Akt1 interaction might inhibit Akt function. Interestingly, JNK signaling also promotes the TSC22D4-Akt1 interaction and introduces phosphorylation(s) on TSC22D4 at yet-to-be identified threonine residues(s). Additionally, we identified S62 as a novel phosphorylation site on TSC22D4 and showed that phospho-defective TSC22D4-S62A mutant impairs insulin stimulated Akt1 phosphorylation.Based on our preliminary data, my proposal will explore the functional implications of TSC22D4-Akt1 interaction in glucose metabolism and its state of regulation in healthy vs. diabetic state both in mice and humans. By employing p-S62 antibodies, we will also investigate the regulation and function of TSC22D4 S62 phosphorylation in maintenance of glucose homeostasis and insulin sensitivity. Importantly, we will examine the JNK-TSC22D4 connection in the context of oxidative stress and insulin resistance and identify JNK regulated threonine phosphorylation(s) on TSC22D4.Overall, this proposal will reveal the novel function of TSC22D4 action in controlling blood glucose levels and insulin sensitivity at the intersection of Akt and JNK signaling pathways, both of which are highly implicated in type 2 diabetes. Our findings will significantly contribute to our understanding of pathogenesis of type 2 diabetes and might promote development of novel therapeutics to treat this modern world disease.

2型糖尿病是现代世界的疾病，与不健康的饮食习惯和久坐不动的生活方式有关。虽然抗糖尿病药物存在，但它们都有自己的局限性和副作用。因此，2型糖尿病患者需要新的治疗方法，这需要更好地了解疾病。我们确定了TSC 22 D4作为胰岛素敏感性和葡萄糖代谢的新调节剂，并表明人类2型糖尿病患者肝脏TSC 22 D4水平升高，与胰岛素敏感性呈负相关。然而，TSC 22 D4在控制葡萄糖稳态中作用的分子机制仍然难以捉摸。最近，我们可以证明TSC 22 D4以调节方式与Akt 1相互作用。虽然能量供应减弱了TSC 22 D4-Akt 1相互作用，但氧化应激和线粒体抑制促进了它，这表明TSC 22 D4-Akt 1相互作用可能抑制Akt功能。有趣的是，JNK信号传导还促进TSC 22 D4-Akt 1相互作用，并在TSC 22 D4上尚未鉴定的苏氨酸残基处引入磷酸化。此外，我们发现了TSC 22 D4上的一个新的磷酸化位点S62，并发现磷酸缺陷的TSC 22 D4-S62 A突变体损害胰岛素刺激的Akt 1磷酸化。基于我们的初步数据，我的建议将探讨TSC 22 D4-Akt 1相互作用在糖代谢中的功能意义，以及它在健康和糖尿病状态下的调节状态。通过使用p-S62抗体，我们还将研究TSC 22 D4 S62磷酸化在维持葡萄糖稳态和胰岛素敏感性中的调节和功能。重要的是，我们将在氧化应激和胰岛素抵抗的背景下研究JNK-TSC 22 D4的联系，并鉴定JNK调节的TSC 22 D4上的苏氨酸磷酸化。总体而言，该提议将揭示TSC 22 D4在控制血糖水平和胰岛素敏感性方面的新功能Akt和JNK信号通路的交叉点，这两者都与2型糖尿病密切相关。我们的发现将大大有助于我们对2型糖尿病发病机制的理解，并可能促进治疗这种现代世界疾病的新疗法的开发。