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Calcineurin-mediated signaling in ischemic preconditioning and neuronal cell death

Shah, Niyati (2014) Calcineurin-mediated signaling in ischemic preconditioning and neuronal cell death. Doctoral Dissertation, University of Pittsburgh.

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Abstract

Stroke is a leading cause of morbidity and mortality in the United States and worldwide. However, few effective therapeutic interventions exist to treat this devastating disease. A detailed understanding of endogenous cell-adaptive mechanisms in ischemia, as well as signaling pathways leading to ischemic neurodegeneration, will critically aid in developing better treatments for stroke. In this dissertation, I investigated calcineurin-mediated signaling pathways in ischemic preconditioning and neuronal cell death. Calcineurin is a calcium/calmodulin-dependent phosphatase that regulates important neuronal functions. An ischemic preconditioning stimulus triggers calcineurin-dependent changes in the localization, phosphorylation status, and voltage-gated activation of Kv2.1 channels, which are involved in promoting neuronal tolerance in the context of otherwise lethal excitotoxic injury. Recent studies suggest that the signaling pathways mediating Kv2.1 channel regulation are complex, and may not be calcineurin activity-dependent in all cases. Additionally, how these processes contribute to neuroprotection is not well defined. In this thesis, I tested the hypothesis that Kv2.1 channel declustering may be sufficient to promote neuronal tolerance. I discovered that preconditioning leads to calcineurin-dependent increases in cyclin E1 protein levels in cortical neurons, which induces Kv2.1 dephosphorylation and dispersal of channel clusters without a concomitant shift in voltage-gated activation. Importantly, cyclin E1 over-expression reduces excitotoxic cell death in neurons. Although calcineurin is required for normal neuronal function, dysregulated calcineurin activation may be neurotoxic. In the second part of my studies, I explored the isoform-specific effects of over-expressing Regulator of calcineurin 1 (RCAN1) in neurons. I found that RCAN1 mediates isoform-dependent, distinct neuroprotective and neurotoxic cell signaling pathways through calcineurin-dependent and independent mechanisms. Thus, the studies in this dissertation provide insight into calcineurin-mediated neuronal cell survival and neurotoxic signaling pathways that may be important in the pathology of stroke and other neurodegenerative disorders.


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Details

Item Type: University of Pittsburgh ETD
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Shah, Niyatingh7@pitt.eduNGH7
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorAizenman, Eliasredox@pitt.eduREDOX
Committee ChairDeFranco, Donalddod1@pitt.eduDOD1
Committee MemberKathryn, Alberskaa2@pitt.eduKAA2
Committee MemberRoss, Sarahsaross@pitt.eduSAROSS
Committee MemberSun, Dandansund@upmc.eduDDS30
Committee MemberWills, Zacharyzpwills@pitt.eduZPWILLS
Committee MemberMohapatra, Durgadp-mohapatra@uiowa.edu
Date: 29 July 2014
Date Type: Publication
Defense Date: 11 July 2014
Approval Date: 29 July 2014
Submission Date: 24 July 2014
Release Date: 29 July 2014
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 156
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurobiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: calcineurin, Kv2.1, stroke, excitotoxicity, cyclin E1, ischemic preconditioning
Date Deposited: 29 Jul 2014 14:01
Last Modified: 19 Dec 2016 14:42
URI: http://d-scholarship.pitt.edu/id/eprint/22508

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