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Thesis (Doctoral)

University of Iceland > Verkfræði- og náttúruvísindasvið > Doktorsritgerðir - Verkfræði- og náttúruvísindasvið >

Please use this identifier to cite or link to this item: http://hdl.handle.net/1946/17423

Title: 
  • Systems biology of inborn errors of metabolism
Degree: 
  • Doctoral
Advisor: 
Keywords: 
Abstract: 
  • Inborn errors of metabolism (IEMs) are the hereditary metabolic disorders often leading to life threatening conditions when left un-treated. IEMs not only demand better diagnostic methods and efficient therapeutic regimen, but also, a high level understanding of the precise biochemical pathology involved. Constraint-based metabolic network reconstruction and modeling is the core systems biology methods to analyze the complex interactions between cellular components that maintain cellular homeostasis. Simultaneously, the global human metabolic networks, Recon 1 and Recon 2, are landmarks in this regard. The work presented in this thesis discusses the combined bottom-up and module approaches to expand and refine the mother networks. It also highlights the importance of transport proteins in network reconstruction, their associated properties, and their involvement in various IEMs. Thereafter, we focused on expansion of Recon 1 with acylcarnitine metabolism, via the Ac/FAO module, which enabled mapping of newborn screening data, facilitating the use of in silico models in IEMs diagnosis. Additionally, a compendium of IEMs was assembled for interrogation of 235 IEMs using this expanded network. IEMs are mainly treated by specific diet and medication. The impact of diet and IEMs on cellular metabolism was explored by manually building a metabolic network of small intestinal epithelial cells (sIEC), taking into account the correct representation of the biochemical, anatomical and physiological attributes of the human small intestine. Limiting constituent of specific diets that deranged the metabolic capability of sIEC was revealed. Subjecting the sIEC to particular diet and IEM, lead to further understanding of the biochemical relatedness to the clinical picture of IEMs, identification of novel comorbid patterns, as well as, studying cellular adaptive mechanisms employed by cells to bypass the metabolic block. The role of medications was analyzed through a drug module; further expanding Recon 2 to account for the metabolism of commonly used drugs. Administering a defined combination of diet and drug under IEMs, their effect on drug metabolism and elimination was studied. Further, statin-associated myopathy in mitochondrial energy disorders was found to be linked to hindrance of statin metabolism. The statin-cyclosporine interaction in IEMs cases was predicted to be related to common metabolic and transport proteins involved in their metabolism. Finally, we observed that the cellular energy level being compromised in order to enable elimination of drugs, like antihypertensives, analgesics and midazolam. This signifies the potential of metabolic modeling for biomedical applications, and the presented work can be extended to predict better therapy in terms of diet and medications, as well as their combination to combat various enzyme deficiencies.

Sponsor: 
  • Icelandic Research Fund (No.100406022)
Accepted: 
  • Mar 4, 2014
URI: 
  • http://hdl.handle.net/1946/17423


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