Zinc ion homeostasis in cellular physiology and experimental models of traumatic brain injury

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dc.contributor.advisorJonathan B. Warden_US
dc.contributor.committeeMemberWolfgang Mareten_US
dc.contributor.committeeMemberRobert A. Colvinen_US
dc.contributor.committeeMemberPing Wuen_US
dc.contributor.committeeMemberKarl E. Andersonen_US
dc.contributor.committeeMemberDouglas S. DeWitten_US
dc.creatorYuan Lien_US
dc.date.accessioned2011-12-20T16:04:22Z
dc.date.available2010-09-28en_US
dc.date.available2011-12-20T16:04:22Z
dc.date.created2009-03-18en_US
dc.date.issued2009-03-06en_US
dc.description.abstractA major yet unsolved quest in treating traumatic brain injury (TBI) is the understanding of the secondary cellular injury that contributes to cell death. Whether zinc ions are toxic or protective in TBI is controversial. As an essential human micronutrient, zinc is needed for the structure and function of at least 3,000 proteins, and thus affects almost any aspect of cellular function. Although extremely low, intracellular zinc ion concentrations, [Zn2+]i, are tightly controlled to ensure optimal physiology and to avoid toxicity. Furthermore, zinc ions are now believed to be signaling ions, especially in neuronal systems. This dissertation addresses the dynamics of [Zn2+]i and quantitatively defines its safe range in particular cell types. [Zn2+]i was measured to be pico- to nanomolar in undifferentiated and differentiated rat pheochromocytoma (PC12) cells and in rat glioma (C6) cells. When PC12 cells proliferate, [Zn2+]i undergoes precisely controlled fluctuations with two peaks within one cell cycle. These results demonstrate that the already established requirement for zinc in the cell cycle and in differentiation relates to the availability of zinc ions. In a mechanical model of cellular injury, namely rapid stretch injury (RSI), nitric oxide induces an increase in [Zn2+]i that subsequently may protect cells by repressing the generation of ROS. A peak at one hour was followed by decreased [Zn2+]i. In PC12 cells, [Zn2+]i dropped below its normal level, indicating that these cells were in a state of ¡°zinc ion deficiency¡± hours after RSI. In an in vivo model of neural injury, namely fluid percussion TBI of rats, changes of [Zn2+]i were indirectly demonstrated by measuring the levels and states of the zinc-binding protein, metallothionein/thionein, in the hippocampus and the cortex. These results demonstrate that [Zn2+]i as well as zinc buffering dynamically fluctuate to adapt to the requirements of cellular functions, even when [Zn2+]i is extremely low inside the cell. They suggest that toxicity occurs when [Zn2+]i falls outside the safety thresholds. Therefore, when, where, how much and in which form zinc is present determine whether chelation or supplementation is an option for treatment. These new concepts provide new leads for developing strategies to treat TBI.en_US
dc.format.mediumelectronicen_US
dc.identifier.otheretd-03182009-113244en_US
dc.identifier.urihttp://hdl.handle.net/2152.3/52
dc.language.isoengen_US
dc.rightsCopyright © is held by the author. Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works.en_US
dc.subjectzincen_US
dc.subjecttraumatic brain injuryen_US
dc.subjectoxidative stressen_US
dc.subjectmetallothioneinen_US
dc.subjectmechanical cell injuryen_US
dc.subjectcell cycleen_US
dc.titleZinc ion homeostasis in cellular physiology and experimental models of traumatic brain injuryen_US
dc.type.genredissertationen_US
dc.type.materialtexten_US
thesis.degree.departmentPreventive Medicine and Community Healthen_US
thesis.degree.grantorThe University of Texas Medical Branchen_US
thesis.degree.levelDoctoralen_US
thesis.degree.namePhDen_US

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