Investigating Autophagy in GSD-Ia

糖原沉积病Ia型(GSD Ia)是一种遗传性疾病，以葡萄糖-6-缺乏为特征。 磷酸酶(G6Pase)。虽然改变饮食可以预防患者的低血糖，但目前的治疗方法失败了 为了预防许多患者的长期并发症，包括与肝脏脂肪堆积相关的 可能发展为肝细胞癌的肝腺瘤的高风险。我们的近期目标是 开发治疗GSD Ia模型中脂肪变性的新方法。根据我们对以下方面的初步研究 在GSD Ia中，我们试图检验我们的中心假设：逆转GSD Ia的异常 自噬将减少GSD Ia肝脏中积累的脂质。因此，我们建议研究 GSD Ia的肝细胞异常，目标是通过实现以下目标开发脂肪肝的新疗法 以下两个具体目标：1)确定脂肪变性抑制GSD自噬的机制 以及2)评估基因组编辑以预防GSD Ia的长期并发症。这些目标可能会提供 通过重新调整已批准的具有已知安全性的药物的用途来进行新的治疗。此外，药物之间的相互作用 将研究具有潜在治愈作用的基因组编辑疗法，目标是永久逆转 GSD Ia的肝细胞异常。如果在GSD Ia取得成功，开发降低肝脂的治疗方法 在其他情况下，蓄积也可以有效逆转脂肪变性，包括代谢性肝脏。 疾病和非酒精性脂肪性肝病。

Glycogen storage disease type Ia (GSD Ia) is an inherited condition characterized by deficiency of glucose-6- phosphatase (G6Pase). While dietary modification can prevent hypoglycemia in patients, current therapy fails to prevent long-term complications in many patients, including hepatic lipid accumulation associated with a high risk for hepatic adenomas that can develop into hepatocellular carcinoma. Our immediate goal is to develop new therapy for steatosis in models of GSD Ia. Based upon our preliminary studies of macroautophagy (autophagy) in GSD Ia, we seek to test our central hypothesis: Reversal of abnormalities of autophagy will reduce accumulated lipids in the GSD Ia liver. Therefore, we propose to study the hepatocellular abnormalities of GSD Ia, with the goal of developing new therapies for fatty liver by achieving the following two Specific Aims: 1) Identify the mechanism by which steatosis suppresses autophagy in GSD Ia, and 2) Evaluate genome editing to prevent long-term complications of GSD Ia. These aims may provide new treatments by repurposing approved drugs with known safety profiles. Furthermore, the interaction of drug therapy with potentially curative genome editing will be investigated, with the goal of permanently reversing the hepatocellular abnormalities of GSD Ia. If successful in GSD Ia, developing therapies that reduce hepatic lipid accumulations also could be effective at reversing steatosis in other conditions, including metabolic liver diseases and non-alcoholic fatty liver disease.