Construction of adenoviruses and retroviruses of recombinant iron metabolism genes and their application in the studies on iron metabolism

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Construction of adenoviruses and retroviruses of recombinant iron metabolism genes and their application in the studies on iron metabolism

 

Author: Ge, Xiaohu
Title: Construction of adenoviruses and retroviruses of recombinant iron metabolism genes and their application in the studies on iron metabolism
Degree: Ph.D.
Year: 2009
Subject: Hong Kong Polytechnic University -- Dissertations
Iron -- Metabolism
Adenoviruses
Retroviruses
Nervous system -- Degeneration -- Genetic aspects.
Department: Dept. of Applied Biology and Chemical Technology
Pages: 358 leaves : ill. (some col.) ; 30 cm.
InnoPac Record: http://library.polyu.edu.hk/record=b2342988
URI: http://theses.lib.polyu.edu.hk/handle/200/5706
Abstract: Human iron metabolism is the set of chemical reactions that maintains human homeostasis of iron. Iron is essential for most lives on earth, including human beings. Iron participates in a series of cellular metabolic processes in the brain, for example, as tyrosine hydroxylase, and cofactor for the enzymes. Iron is also essential for the biosynthesis of CNS lipids and cholesterol. In oligodendroglia, it plays an important role in action of metabolic enzymes as a co-factor. But excessive iron is damaging to the brain and may lead to many neurodegenerative diseases. The existence of excessive total brain iron, a common feature of some neurodegenerative diseases, is thought to be a cause of many such diseases. A significant increased concentration of brain iron is found in the neuronal systems or some specific brain regions in some neurodegenerative diseases. In iron metabolism, Divalent metal transporter 1 (DMT1), Transferrin receptors 1 (TfR1), Ferroportin1 (FPN1), Hephaestin (Heph), hepcidin (Hepc) are important iron-related protein and regulative peptide. In order to investigate the effects of these iron-related genes on neurodegenerative diseases, we constructed a series of recombinant adenoviruses and retroviruses, including rAd-DMT1 (+), rAd-DMT1 (-), rAd-FPN1, rAd-Heph, rAd-Hepc, Retro-DMT1, Retro-FPN1, Retro-Heph, and Retro-Hepc through molecular biological technology. All these recombinant virus products were applied to primary culture neurons or some cell lines. Our results proved that there are high biological expression activities of these recombinant adenoviruses and retroviruses in cells. In this study, we also provided solid evidence for the first time for the association of DMT1-IRE with neurotoxicity induced by L-DOPA. We believe that inhibition of DMT1-IRE expression or neuronal iron uptake might be an effective approach to prevent or delay the development of neurotoxicity induced by L-DOPA in PD patients through the retrovirus gene knockout system. Furthermore, we investigated the regulating effects of hepcidin, an iron regulatory peptide, in neurons through rAd-hepc and retro-hepc. Our results suggested that hepcidin has the ability to regulate the expression of some iron related genes as an upstream regulatory factor, such as FPN1, DMT1 (+), DMT1 (-) etc. This thesis consists of 9 chapters, beginning with a general introduction, followed by the methodology section, and 6 chapters on results, and ends with suggestions on future work.

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