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|Title:||INVESTIGATION OF THE CYTOPROTECTIVE EFFECTS OF SONIC HEDGEHOG IN CELLULAR AND ANIMAL MODELS OF AMYOTROPHIC LATERAL SCLEROSIS|
|Department:||Medical Sciences (Neurosciences)|
|Keywords:||Amyotrophic Lateral Sclerosis;Sonic hedgehog;excitotoxicity;Spinal motor neuron;neuroprotection;Life Sciences;Medicine and Health Sciences;Molecular and Cellular Neuroscience;Molecular Biology;Neuroscience and Neurobiology;Life Sciences|
|Abstract:||<p>Amyotrophic Lateral Sclerosis (ALS) is a fatal progressive neurodegenerative disease with no known cause. Despite the efforts of investigators over the past 150 years, there remains no effective cure which substantially prolongs life. Therapeutic strategies have explored all of the proposed underlying pathological pathways of the disease from increased oxidative damage to impaired axonal transport, with little to no success. In the following pages, a novel perspective will be presented outlining the preliminary investigations of a new line of research demonstrating that Sonic hedgehog (Shh) protein and its agonists have cytoprotective effects on motor neurons. To begin these investigations, initial experiments were conducted <em>in vitro</em> utilizing a mouse hippocampal cell-line (HT-22) which served as a model for transient transfection and oxidative challenge assays. The results are reported in Chapter 2. Building upon these introductory findings, further investigations were conducted exploiting the SOD1<sup>G93A</sup> mouse model of ALS. Chapter 3 summarizes key observations pertaining to the abundance of a key cellular organelle in the sensing of Shh signalling, the primary cilium, in the spinal cord of SOD1<sup>G93A</sup> mice. In Chapter 4, a semi-quantitative analysis of the effects of Shh and Shh agonists pre-treatment <em>in vitro </em>on primary mixed spinal cord cultures are described. Subsequent challenge with an excitotoxic NMDA treatment was also conducted, as well as an <em>in vivo</em> survival study exploring the potential therapeutic effects of chronic Shh administration on SOD1<sup>G93A</sup> mice. The cumulative research presented here represents the very first investigation into the unique application of Shh and its agonists as potential therapeutic agents for the treatment of ALS, and our findings indicate that Shh has the potential of becoming a novel therapeutic agent for the treatment of ALS.</p>|
|Appears in Collections:||Open Access Dissertations and Theses|
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