Insights into pathogenic mechanisms and biomarkers for prognosis and monitoring of glycogen storage disease type I (GSD I)
Insights into pathogenic mechanisms and biomarkers for prognosis and monitoring of glycogen storage disease type I (GSD I)
This thesis van Ruiqi Xiao presents a multi-omics translational study to investigate the pathological mechanisms and potential biomarkers of glycogen storage disease type I (GSD Ia and Ib).
In Chapter 2, CRISPR/Cas9-generated hepatocyte-specific GSD Ia and Ib mouse models were systematically compared using physiological, biochemical, metabolomic, proteomic, and transcriptomic analyses. Both subtypes showed hepatomegaly, fasting hypoglycemia, and metabolic disturbances, but these alterations were more severe in GSD Ia, consistent with clinical phenotypes.
Chapter 3 focused on GSD Ia mice and examined liver and plasma proteomic changes under fed and fasted conditions, representing controlled and poorly controlled metabolic states. Pronounced alterations were observed in pathways related to carbohydrate and lipid metabolism, mitochondrial function, and coagulation, particularly during fasting, and several circulating proteins were identified as potential non-invasive biomarkers of hepatic dysfunction.
To assess clinical relevance, Chapter 4 extended the analysis to retrospective human samples from GSD Ia and Ib patients, including those with hepatocellular adenoma or carcinoma. Distinct circulating and hepatic protein changes associated with bleeding risk, inflammation, liver injury, and tumor development were identified.
In Chapter 5, N-linked glycosylation profiles of patient serum and plasma were characterized, revealing subtype-specific alterations in sialylation, fucosylation, and branching, as well as tumor-associated glycan remodeling in GSD Ia.
Overall, this study provides novel insights into GSD I pathophysiology and identifies promising biomarkers for disease monitoring, prognosis, and individualized risk assessment.