Zinc is emerging as a vital component of both normal functioning mammalian cells as well as the infectious agents that invade these host cells. Although zinc plays many important roles in sustaining life, elevated levels of the ion can be detrimental to cell survival and biological success. Therefore, intracellular zinc concentrations and transport are tightly controlled via proteins involved in homeostasis, trafficking, and transcriptional regulation.
The Plasmodium parasite, the infectious agent that causes the malarial disease, concentrates zinc to levels that exceed normal concentrations within the host red blood cell by up to four times. Although very little is known about the role of zinc in this pathogen, this work begins to uncover the interesting requirement for freely available ion stores. These bioavailable pools are located within subcellular compartments outside of both the nucleus and the food vacuole of the parasite. Accumulation of the essential ion is shown here to occur during later developmental stages including those involved in cellular division and multiplication within the host red blood cell.
Although it is apparent that the parasite accumulates extraordinary quantities of zinc, the cell's requirement for the ion is not fully understood. Chelator treatments using tight-binding, highly zinc-specific compounds are shown to inhibit the growth of the parasite while causing an arrest in development at the trophozoite stage. We further show that the efficacy of these chelators is directly correlated to their zinc binding affinity, which suggests that the compounds' zinc binding actions are causing death. These chelator treatments result in a depolarization of Plasmodium mitochondria, which suggests a mechanism of chelator-induced cell death via mitochondrial disruption. Treatment with current antimalarial drugs results in a decrease in bioavailable zinc pools, which may prove to play an important role in antimalarial activity.
Zinc is not only important for the survival of infectious agents such as parasites, but also for the normal function of many cells within our body. Insulin releasing cells within pancreatic islets require zinc for several functions, particularly in synthesis, storage and secretion of insulin, which is necessary for adequate glucose metabolism. Our work, in collaboration with an islet transplant surgeon, is aimed at improving a treatment technique for Type I diabetes, namely islet transplantation, by focusing on the importance of zinc in cell survival and insulin production. Data presented here reveals the need for zinc supplementation in culturing solutions used during these treatments. We show that zinc supplementation enhances cell viability and improves islet morphology suggesting that zinc is an important component for improved islet transplantation success rates.
|Advisor:||O'Halloran, Thomas V.|
|Commitee:||Lewis, Frederick D., Meade, Thomas J.|
|School Location:||United States -- Illinois|
|Source:||DAI-B 70/12, Dissertation Abstracts International|
|Subjects:||Biochemistry, Inorganic chemistry, Parasitology|
|Keywords:||Diabetes, Islet cells, Malaria, Mitochondria, Plasmodium falciparum, Zinc|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be