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Investigating the Pattern of Coordination between the Sarcoplasmic Reticulum Ca2+ Handling Channels and Calcineurin/NFAT Signalling Pathway in Distinct Mouse Models and Approaches of Muscular Dystrophy Studies

Title:

Investigating the Pattern of Coordination between the Sarcoplasmic Reticulum Ca2+ Handling Channels and Calcineurin/NFAT Signalling Pathway in Distinct Mouse Models and Approaches of Muscular Dystrophy Studies

Salah, Mohammadhadi (2015) Investigating the Pattern of Coordination between the Sarcoplasmic Reticulum Ca2+ Handling Channels and Calcineurin/NFAT Signalling Pathway in Distinct Mouse Models and Approaches of Muscular Dystrophy Studies. Masters thesis, Concordia University.

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Abstract

Duchenne muscular dystrophy is a progressive neurodegenerative muscle disease that makes the patients wheelchair-dependent around the age of 12 and eventually causes death in the late twenties due to lung and/or heart failure. A functional dystrophin is absent in DMD patients which makes their muscle cells prone to physical damage by every single movement. A homolog of this fundamental protein is utrophin which is known to be able to partially compensate for the lack of dystrophin. Hence, up-regulation of this protein has been promising for years as a strategy to improve this disorder. It has been repetitively proved that this approach could be achievable via stimulation of calcineurin/NFAT signalling pathway which in turn promotes the oxidative capacity of the muscle. Also, pharmacological induction of the Adenosine monophosphate - activated protein kinase pathway can provoke the slow oxidative myogenic program. Nevertheless, recent evidence shows the capability of the Heat Shock Protein 70 to ameliorate the dystrophic phenotype by preserving the function of sarco/endoplasmic reticulum Ca2+ ATPase channels independent of utrophin. Thus in this study, we sought to shed light on the underlying mechanisms by which intracellular Ca2+ oscillations coordinate with calcineurin/NFAT signalling in these adaptive responses. Our data suggest an inhibitory effect of AMPK activators on calcineurin activity and further prove the independence of HSP70 regulation from the calcineurin /NFAT pathway. Moreover, we were able to represent a more detailed understanding of the way Ca2+ handling proteins determine the activity rate of calcineurin in response to altered cytosolic Ca2+ oscillations. Collectively, our results may bring the scientific community one step closer to finding a comprehensive approach to cure or improve the dystophic disorders in general and duchenne muscular dystrophy in particular.

Divisions:Concordia University > Faculty of Arts and Science > Biology
Item Type:Thesis (Masters)
Authors:Salah, Mohammadhadi
Institution:Concordia University
Degree Name:M. Sc.
Program:Biology
Date:15 April 2015
Thesis Supervisor(s):Michel, Robin N and Zerges, William
Keywords:Cn, Ca2+, [Ca2+]i, Cn/NFAT signalling pathway, mdx, DMD
ID Code:979893
Deposited By: MOHAMMAD HADI SALAH
Deposited On:13 Jul 2015 15:53
Last Modified:18 Jan 2018 17:50
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