Browsing by Author "Zochodne, Douglas"

Now showing 1 - 12 of 12
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    Impact and Mechanisms of Extracellular Electrical Stimulation on Peripheral Nerve Regeneration
    (2013-07-15) Singh, Bhagat; Zochodne, Douglas
    Peripheral nerve injuries are unfortunately very common and debilitating. Peripheral nerve regeneration is slow and regenerative outcomes following severe transection injuries remain limited. Intrinsic inhibitors of neurotrophin signalling diminish the regenerative ability of axotomized neurons and regulate regenerative responses. The overall theme of this thesis is to evaluate whether extracellular electrical stimulation (ES) enhances peripheral nerve regeneration after severe and challenging nerve injuries such as transection and superimposed diabetes, and to understand and exploit its molecular correlates. First, I describe the impact of ES in a severe transection injury model and demonstrate that ES enhances early axon outgrowth that later translates into earlier skin target reinnervation and recovery of sensory and motor function. Utilizing an in-house designed microelectrode array (MEA), I illustrate that ES enhances neurite outgrowth of adult sensory neurons in vitro (Chapter 3). Next, I describe the potential cellular and molecular mechanisms of ES-enhanced regeneration in cultured sensory neurons in vitro and in animal models. Specifically, I observed activation of the PI3-K pathway through downregulation of PTEN expression in response to ES. Other contributing mechanisms involve upregulation of regeneration-associated genes, and enhanced support from perineuronal satellite cells in DRGs (Chapter 4). Finally, in Chapter 5, I show that an ES paradigm has the potential to regenerate axons in a diabetic animal model known for its inherent neuroregenerative deficits (Chapter 5). The results suggest that ES modulates the intrinsic mechanisms of axon regeneration and has a remarkable impact on peripheral neuron plasticity. Overall, the findings support the concept that ES can be utilized as a therapeutic option for severe peripheral nerve injuries.
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    Impact of insulin or incretin hormones in reversing diabetic neuropathy in type 1 and type 2 diabetes mellitus
    (2011) Kan, Michelle; Zochodne, Douglas
    Diabetes mellitus is a metabolic disorder where long-term complications including neuropathy, or nerve damage may arise. Peripheral neuropathy affects approximately 50% of total diabetic patients. Diabetic peripheral neuropathy (DPN) is a length-dependent sensorimotor nerve disorder that can lead to pain, loss of feeling and motor ability. In this work we sought to determine whether insulin or exendin-4 will serve as neurotrophic and neuroprotective factors in both type 1 and type 2 diabetes and reverse DPN pathology. Our results showed that insulin or exendin-4 treatment improved some features of neuropathy in type 1 but not type 2 diabetes. Furthermore, a full reversal of DPN was not observed showing that current clinical dosing of insulin or exendin-4 therapy does not benefit neuropathy.
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    Ndel1 promotes axon regeneration via intermediate filaments
    (Public Library of Science, 2008-04-23) Toth, Cory; Shim, Su Yeon; Wang, Jian; Jiang, Yulan; Neumayer, Gernot; Belzil, Camille; Liu, Wei-Qiao; Martinez, Jose; Zochodne, Douglas; Nguyen, Minh Dang
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    The motor unit in long-term experimental diabetes
    (2005) Ramji, Noor; Zochodne, Douglas
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    The pi3-k pathway and pten inhibition in peripheral nerve injury
    (2010) Christie, Kimberly Joy; Zochodne, Douglas
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    The Role of AlphaB-crystallin During Peripheral Nerve Regeneration
    (2016) Lim, Erin-Mai; Ousman, Shalina; Zochodne, Douglas; Biernaskie, Jeff; Midha, Rajiv; Lacroix, Steve
    This dissertation characterizes the role of a small heat shock protein called alphaB-crystallin (αBC) in peripheral nerve regeneration. Peripheral nerve injuries are fairly common and often result in patient disability due to the partial and incomplete regeneration of nerves. The expression of αBC in the peripheral nervous system (PNS) has been known, but its role has not been determined. Because many protective and beneficial functions of the heat shock protein has been reported in a variety of cells and models, I explored whether αBC also has a beneficial role in the PNS particularly after sustaining an injury. Using 129S6 wild-type (WT) and αBC null (αBC-/-) mice, I discovered that αBC positively influenced PNS regeneration. Following sciatic nerve crush, I found that αBC-/- mice had decreased functional recovery, slower motor nerve conduction velocities, and thinner myelin sheaths 28 days post-injury. I additionally observed higher numbers of macrophages (mΦ) in the distal sciatic nerves of αBC-/- mice during the late time points post-injury that may explain the heightened sensitivity towards mechanical and thermal stimulation observed in these animals. I further elucidated that the injury deficits observed in the αBC-/- mice were due to aberrant neuregulin-1/ErbB2 and pAkt signaling. Cumulatively, these findings indicate that αBC positively modulates peripheral nerve regeneration by promoting remyelination and mediating clearance of macrophages in the distal nerve. Lastly, because of reduced expression of αBC with increasing age, I investigated whether αBC plays a role in deficits associated with the aging PNS. I found that αBC-/- mice displayed thinner myelin sheaths before and after injury at different ages. Moreover, 12-month-old αBC-/- mice displayed higher numbers of macrophages before and after injury and, lower numbers of squalene monooxygenase (SQLE), an important enzyme in cholesterol synthesis. These findings are consistent with previous reports that revealed in the aging PNS there is upregulation of genes associated with inflammation and downregulation of genes associated with lipid metabolism. Further exploration is needed to identify the mechanisms involved. Collectively, the work presented in this dissertation provides novel evidence of the significant roles of αBC following peripheral nerve injury.
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    The roles of rgd-integrin interactions in peripheral nerve regeneration
    (2008) Liu, Wei-Qiao; Zochodne, Douglas; Wildering, Willem C.
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    Tumour-Suppressor Knockdown as a Strategy for Peripheral Nerve Regeneration: The Effects of PTEN and Rb
    (2016) Eaton, Shane; Zochodne, Douglas; Ousman, Shalina; Whelan, Patrick; Schuurmans, Carol
    Tumour-suppressors, such as PTEN and Rb, function to limit growth and proliferation. In post-mitotic peripheral sensory neurons, their knockdown may be utilized to promote regenerative growth. The goal of this thesis was to evaluate the effects of PTEN and Rb knockdown on peripheral nerve regeneration. Towards this goal I first addressed technical challenges, improving on a neuronal culture and immunostaining protocol. In assessing Rb knockdown I found increases in neuritic branching, but use of the PTEN inhibitor bpV(pic) was ineffective on neurite outgrowth, and therefore my results with combined Rb knockdown and PTEN inhibition were inconclusive. I also evaluated the phenotype of a PTEN conditional knockout mouse where PTEN is deleted from peripheral sensory neurons and found that they exhibited enlarged nerves with supernumerary myelinated axon profiles and a corresponding increase in SNAP amplitudes. Loss of phenotype was observed in a subsequent generation, pointing to complications in the Cre-lox conditional knockout system.