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Title: Mechanism of miglustat-induced infertility in male mice
Author: Chuang, Chia-Chen Celeste
Awarding Body: Oxford University
Current Institution: University of Oxford
Date of Award: 2010
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Miglustat IS an inhibitor of multiple enzymes involved in glycosphingolipid (GSL) metabolism, and is used as substrate reduction therapy to treat type 1 Gaucher disease. It has also been shown to disrupt spermatogenesis and induce infertility in male mice. The reversible drug effect, oral administration and established safety profile of miglustat suggest this drug or a derivative has the potential to be a male contraceptive. However, the mechanism of its anti-spermatogenic action was not clear. In this thesis, research has been dedicated to study the drug's mechanism of action using multiple approaches. A specific type of GSLs, fucosylated very long chain poly-unsaturated fatty acid GSLs, were identified to be essential for the completion of meiosis in spermatogenesis. Also, studies of a recently identified GlcCer transport protein, FAPP2, indicate that there may be cell and tissue type-specific complexity to the GSL biosynthesis pathway. These findings suggest that GSL modulation may induce infertility. Testicular proteins that can bind miglustat were isolated using a miglustat- affinity-column chromatography. Interestingly, several proteins identified are involved in spermatogenesis, and some in the specific steps where miglustat treated germ cells display defects. Interaction between miglustat and novel protein candidates may be relevant to the contraceptive potential of this compound. These studies have established the basis of infertility-induction through GSL modulation and also point to novel potential miglustat targets outside of the GSL metabolic pathway. These advances may lead to new avenues in male contraceptive development and shed new light on the biochemical regulation of male germ cell development.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available