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Gene expression profiling of liver from GSD1a patients: evidence of an inflammatory process

Gene expression profiling of liver from GSD1a patients: evidence of an inflammatory process. The world of “omics”. International meeting Glycogen Storage Diseases associations Milan October 2 nd 2010. Luigi Varesio. The chip. 54000 probsets. Gene expression profile of GSD1a liver.

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Gene expression profiling of liver from GSD1a patients: evidence of an inflammatory process

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  1. Gene expression profiling of liver from GSD1a patients: evidence of an inflammatory process The world of “omics” International meeting Glycogen Storage Diseases associations Milan October 2nd 2010 Luigi Varesio

  2. The chip 54000 probsets

  3. Gene expression profile of GSD1a liver • Gene expression profile of the liver of three patients who underwent liver transplantation and of three normal tissues. • Data analysis with Bibliosphere (Genomatics) to study metabolic pathways.

  4. Clinical manifestations hepatomegaly hypoglycemia hyperuricemia hyperlipidemia growth retardation Complications lack of growth delay of puberty gout juvenile pancreatitis arteriosclerosis hepatomas hypertension adenomas kidney diseases sugars proteins fat GSD1a ? G6Pase What causes complications?

  5. GSD1a patients have higher levels of IL-6 Possible state of chronic inflammation

  6. GSD1a can be associated with an inflammatory state

  7. IL-6 transgenic mice 12 day-old littermates De Benedetti, J Clin Invest 1997

  8. Clinical manifestations hepatomegaly hypoglycemia hyperuricemia hyperlipidemia growth retardation Complications lack of gowth delay of puberty gout juvenile pancreatitis arteriosclerosis hepatomas hypertension adenomas kidney diseases GSD1a Inflammation sugars proteins what causes inflammation? G6Pase fats Cytokines IL-6, IL-8

  9. Hypoxia in patho-physiological processes Growing tumors Myocardial ischemia Cerebral ischemia Energy metabolism Diabetic retinopathy Pulmonary hypertension Cell survival Angiogenesis HYPOXIA (pO2 0-20mm Hg) Rheumatoid arthritis Wound healing Erytropoiesis Cell migration Cell proliferation/ survival Aherosclerosis Microbial infections Preeclampsia Intrauterine growth retardation

  10. Hypoxia in the liver of GSD1a patients GSD-1a is associated with liver hypoxia

  11. Hypoxic tissue Monocyte Monocyte trapping CXC-Chemokines ↑ Neutrophils recruitment CC-chemokine receptors ↓ Gro-chemokines ↑ Mn migration inhibiting factor (MIF) ↑ G-protein deactivator (RGS1) ↑ Circulation Motility-promoting factor (ENPP2) ↓ O2

  12. What causes these effects? Liver hypoxia can Necrotic foci, elevated chemokines and infiltrating neutrophils in the liver of glycogen storage disease type Ia. Kim DY et al, J Hepatol. 2008

  13. GSD1a Clinical manifestations hepatomegaly hypoglycemia hyperuricemia hyperlipidemia growth retardation Complications lack of gowth delay of puberty gout juvenile pancreatitis arteriosclerosis hepatomas hypertension adenomas kidney diseases Inflammation sugars proteins what causes inflammation? G6Pase fats Liver Hypoxia Cytokines IL-6, IL-8

  14. MRA (Tocilizumab) a humanized moAb to the IL-6R Y Y Y Y MRA Y IL-6 Y sIL-6R IL-6R gp130 gp130

  15. Collaborators Molecular Biology Gaslini R. Lavieri A. Eva P. Fardin R.Resaz L. Varesio NationalInstitutesofHealth(USA) J.Chou D. Munroe S.K.Arya Associazione Italiana Glicogenosi ____ ___ ___ ____ _________ Clinical Departments • Dr. M. Di Rocco • G.Gaslini Institute (Genova) • Dr. D. Melis • Federico II University (Napoli) • Dr. R.Parini • S.Gerardo Hospital (Monza) • Dr. S. Paci • S.Paolo Hospital (Milano) • Dr. E. Procopio • Meyer Hospital (Firenze) • Dr. C. Dionisi • Bambin Gesù Hospital (Roma) • IST Genova • O. Barbieri

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