Dissertation/Thesis Abstract

Physiological chemistry of zinc in malaria and diabetes
by Marvin, Rebecca Grace, Ph.D., Northwestern University, 2009, 252; 3386519
Abstract (Summary)

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.

Indexing (document details)
Advisor: O'Halloran, Thomas V.
Commitee: Lewis, Frederick D., Meade, Thomas J.
School: Northwestern University
Department: Chemistry
School Location: United States -- Illinois
Source: DAI-B 70/12, Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Biochemistry, Inorganic chemistry, Parasitology
Keywords: Diabetes, Islet cells, Malaria, Mitochondria, Plasmodium falciparum, Zinc
Publication Number: 3386519
ISBN: 9781109518665
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