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SENSORY NEURON SUBPOPULATION-SPECIFIC REGULATION OF INTRACELLULAR CALCIUM IN A RAT MODEL OF CHEMOTHERAPY- INDUCED PERIPHERAL NEUROPATHY

Yilmaz, Eser (2016) SENSORY NEURON SUBPOPULATION-SPECIFIC REGULATION OF INTRACELLULAR CALCIUM IN A RAT MODEL OF CHEMOTHERAPY- INDUCED PERIPHERAL NEUROPATHY. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Chemotherapeutic-induced peripheral neuropathy (CIPN) is associated with a unique stocking-glove distribution of signs and symptoms. CIPN starts with numbness and tingling and proceeds to ongoing pain. The potential impact of target of innervation on CIPN has been largely ignored despite the tremendous heterogeneity among sensory neurons regarding their resting and injury-induced properties. Moreover, there is compelling evidence from other neuropathy models indicating that dysregulation of intracellular Ca2+ in sensory neurons contributes to the signs and symptoms of the neuropathy. Therefore, the central hypothesis I pursued in this thesis was that both the positive and negative signs of CIPN are due to subpopulation-specific changes in Ca2+ regulation, which I tested in a paclitaxel-induced peripheral neuropathy model. Paclitaxel was associated with a persistent decrease in mechanical nociceptive threshold in response to stimuli applied to the glabrous hindpaw skin, but not the other areas that were tested. While paclitaxel had no detectable influence on either resting or depolarization-evoked Ca2+ transients in putative non-nociceptive neurons, there was a significant paclitaxel-induced decrease in the evoked Ca2+ transient duration in putative nociceptive glabrous neurons, which correlated with the paclitaxel-induced nociceptive behavior. This paclitaxel-induced change in Ca2+ regulation was not due to increased activity of Na+-Ca2+-exchanger (NCX), which contributes to the regulation of evoked Ca2+ transient durations in this subpopulation of neurons. However, the paclitaxel-induced decrease in the duration of the evoked Ca2+ transient did appear to be due to both direct and indirect influences of mitochondria. The direct influence reflected an increase in mitochondria volume, enabling an increase in total Ca2+ uptake, while the indirect influence reflected an increase in the activity of ATP-dependent Ca2+ regulatory mechanisms, such as the sarco-endoplasmic-reticulum-ATPase (SERCA). The results generated in this dissertation expand the current view of CIPN mechanisms and constitute an important step towards understanding the roles of intracellular Ca2+ as well as mitochondrial changes to the pain associated with CIPN, paving the road for novel therapeutic strategies to limit the side effects of chemotherapy.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Yilmaz, Eseresy4@pitt.eduESY4
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairGebhart, Geraldgebhartgf@upmc.edu
Thesis AdvisorGold, Michaelmsg22@pitt.edu
Committee MemberHastings, Theresahastingst@upmc.edu
Committee MemberMeriney, Stephenmeriney@pitt.edu
Committee MemberAizenman, Eliasredox@pitt.edu
Committee MemberIbinson, Jamesibinsonjw@upmc.edu
Committee MemberDougherty, Patrickpdougherty@mdanderson.org
Date: 7 September 2016
Date Type: Publication
Defense Date: 8 June 2016
Approval Date: 7 September 2016
Submission Date: 23 June 2016
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 160
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurobiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: paclitaxel, dorsal root ganglia, pain, mitochondria, NCX
Date Deposited: 07 Sep 2016 15:07
Last Modified: 07 Sep 2017 05:15
URI: http://d-scholarship.pitt.edu/id/eprint/28554

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