CapZ is an actin capping protein that locates at cardiac Z-discs and anchors sarcomeric actin [1]. Transgenic (TG) mice overexpressing CapZ in cardiac myocytes develop a lethal cardiac hypertrophy [2], while a large reduction in CapZ protein causes severe myofibrillar disarray and death [2]. However, a TG model that contains a modest reduction in cardiac CapZ protein levels is viable and is associated with decreased PKC-dependent regulation of myofilament function [3]. Given the well known role of PKC in myocardial pathogenesis, the general aim of this thesis was to investigate how the modest reduction in CapZ protein affects cardiac function in models of cardiac stress. I found that PKC-translocation to cardiac myofilaments during cold cardioplegic arrest impairs myofilament activation, and that decreased cardiac CapZ protein disrupts this pathway and provides cardioprotective benefit. Using an in vivo model of ischemia-reperfusion (IR), I made the novel discovery that myofilament-associated PKC is altered during prolonged global ischemia, and found that a CapZ deficiency affects the translocation of PKC to myofilaments in a time-dependent manner. Furthermore, I found that TG mice deficient in CapZ demonstrate significant reductions in IR injury, while providing enhanced cardioprotection following ischemic preconditioning. The cardioprotected phenotype of CapZ-deficient TG mice is associated with altered translocation of several PKC-isoforms to cardiac myofilaments. Finally, having uncovered new information about the activation of protein phosphatase type 2A (PP2A) in IR, I investigated the role of CapZ in PP2A-dependent myofilament regulation. I found that reductions in CapZ may affect cardiac contractility by interrupting the association of PP2A with myofilaments. Together these findings expand the role of CapZ as a regulator of intracellular signaling molecules and demonstrate the novel ability of reduced CapZ to protect the heart against significant pathological threats. / Canadian Institutes of Health Research (CIHR), Heart and Stroke Foundation of Ontario (HSFO), Heart and Stroke Foundation of Canada (HSFC), The Premier's Research Excellence Award (PREA), Ontario Graduate Scholarship Program (OGS).

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Glutamate AMPA receptors (AMPARs) are major excitatory receptors in the vertebrate CNS. In many biological systems there are changes in the properties of AMPARs during development that are essential for providing an increase in efficiency of information transfer between neurons and a refinement of motor co-ordination and sensory perception and cognition. It is not surprising that improper development or loss of function of AMPARs can lead to many neurological disorders such as epilepsy and amyotrophic lateral sclerosis. Thus, determining the mechanisms by which AMPARs mature is of particular importance. The objectives of my thesis were to characterize the developmental changes in AMPAR-mediated currents in zebrafish Mauthner cells and to determine the mechanisms underlying any changes. The major findings reported in this thesis are that (1) there are developmental changes in the properties of AMPAR-currents as the Mauthner cell matures; (2) the mechanism underlying these changes is a switch in the composition of AMPA receptor subtypes; and (3) PKC is necessary for the developmental switch in AMPAR subtypes from slow receptors to fast receptors. These findings provide valuable insights into the mechanism underlying the development of AMPARs. In addition, they provide the first instance of a signalling link (PKC) required for the developmental subunit switch and the developmental speeding of AMPAR kinetics. / Physiology, Cell Biology and Developmental Biology

Diss. (sammanfattning) Linköping : Univ., 2003. / Härtill 4 uppsatser.

Diss. (sammanfattning) Umeå : Umeå universitet, 2006. / Härtill 4 uppsatser.

Thesis (Ph. D.)--Northeastern University, 2008. / Title from title page (viewed March 3, 2009). Graduate School of Arts and Sciences, Dept. of Psychology. Includes bibliographical references (p. 148-156).

Thesis (Ph. D. in Biological Sciences)--Vanderbilt University, Aug. 2009. / Title from title screen. Includes bibliographical references.

Thesis (Ph. D.)--Marshall University, 2004. / Title from document title page. Document formatted into pages; contains p. xvi, 173 p. Includes abstract. Includes bibliographical references (p. 153-173).

Thesis (Ph. D.)--University of Missouri--Columbia, 2000. / "May 2000." Typescript. Vita. Includes bibliographical references (leaves 90-104). Also available on the Internet.

Thesis (Ph.D. in Cell and Developmental Biology) -- University of Colorado, 2005. / Typescript. Includes bibliographical references (leaves 155-180). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;