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Investigating Autophagy in GSD-Ia

研究 GSD-Ia 中的自噬

基本信息

批准号：
10241856
负责人：
Dwight D Koeberl
金额：
$ 15.92万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-15 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10241856
关键词：
Adenosine Monophosphate Adult Adverse effects Apoptosis Autophagocytosis Biochemical Biological Markers Canis familiaris Carbohydrates Corn starch preparation Data Diet Diet Modification Disease Disease Progression End stage renal failure Environment Fatty Liver Genes Glycogen Glycogen Storage Disease Type I Goals Grant Hepatic Hypoglycemia Inherited Life Life Expectancy Lipids Liver Liver diseases Medical Metabolic Modeling Mutation Nutrient Pathogenesis Patients Pharmaceutical Preparations Pharmacotherapy Phosphotransferases Population Prevalence Prevention Primary carcinoma of the liver cells Publishing Rare Diseases Regimen SIRT1 gene Safety Signal Transduction Testing Therapeutic Tissues Triglycerides United States adenoma base cellular pathology comparative efficacy curative treatments gene replacement therapy gene therapy genome editing high risk improved in vivo mitochondrial dysfunction mouse model non-alcoholic fatty liver disease novel novel therapeutics prevent renal epithelium therapy development uncooked

项目摘要

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.

Ia型糖原储存病（GSD Ia）是一种以葡萄糖-6-缺乏为特征的遗传性疾病