Diabetic neuropathies are the Cinderella of neurological diseases. The WHO informs us that by 2025 there will be 300 million sufferers from diabetes worldwide - a figure approximately equal to the population of the USA. Currently close to 50% diabetic patients develop some form of peripheral nerve disease, which can lead to loss of protective sensation and limb amputation. The incidence is expected to rise 10-fold in the next 10 years in First Nations peoples of Canada. There is no treatment. My group is, therefore studying pathogenetic mechanisms and potential drug targets. Key approaches involve identification of the cellular transduction of damage signals (neurotrophic deficits, oxidative stress, glucose stress, mitochondrial dysfunction) and failure of cellular protective mechanisms.
Techniques: cell culture, confocal microscopy, fluorescence imaging, neuronal plasmid transfection, general biochemistry and pharmacology.
*Fernyhough, P., Roy Chowdhury, S.K. and R.E. Schmidt (2010). Mitochondrial stress and the pathogenesis of diabetic neuropathy. Expert Review of Endocrinology and Metabolism. 5, 39-49
Jackson, A.C., Kammouni, W., Zherebitskaya, E. and P. Fernyhough (2010). Role of oxidative stress in rabies virus infection of adult mouse dorsal root ganglia neurons. Journal of Virology. 84, 4697-4705. (if, 5.31)
*Roy Chowdhury, S. K., Zherebitskaya, E., Smith, D.R., Akude, E., Chattopadhyay, S., Jolivalt, C.G., Calcutt, N.A. and P. Fernyhough (2010). Mitochondrial respiratory chain dysfunction in lumbar dorsal root ganglia of streptozotocin-induced diabetic rats and its correction by insulin treatment. Diabetes. 59, 1082-1091. (if, 8.26)
*Fernyhough, P. and N.A. Calcutt (2010). Abnormalities in calcium homeostasis in peripheral neuropathies. Cell Calcium. 47, 130-139. (if, 4.12)
*Akude, E., Zherebitskaya, E., Roy Chowdhury, S.K., Girling, K. and P. Fernyhough (2010). 4-hydroxy-2-nonenal impairs mitochondrial function and induces aberrant axonal outgrowth in adult sensory neurons that mimics features of diabetic sensory neuropathy. Neurotoxicity Research. 17, 28-38. (if, 5.23)
*Zherebitskaya, E., Akude, E., Smith, D.R. and P. Fernyhough (2009). Development of selective axonopathy in adult sensory neurons isolated from diabetic rats: role of glucose
Malisza, K.L., Jones, C., Gruwel, M.L.H., Summers, R., Smith, D.R., P. Fernyhough and N.A. Calcutt (2009). Functional magnetic resonance imaging of the spinal cord during sensory stimulation in diabetic rats. Journal of Magnetic Resonance Imaging. 30, 271-276. (if, 2.21)
Smith, D., Tweed, C., Fernyhough, P. and G.W. Glazner (2009). Activation of NF-kB in axons and Schwann cells at site of sciatic nerve crush and role in modulating axon regeneration: studies with etanercept. Journal of Neuropathology and Experimental Neurology. 68, 691-700. (if, 4.72)
*Calcutt, N.A., Jolivalt, C.G. and P. Fernyhough (2008). Growth factors and therapeutics for diabetic neuropathy. Current Drug Targets. 9, 47-59. (if, 4.27)
*Verkhratsky, A. and P. Fernyhough (2008). Mitochondrial malfunction and Ca2+ dyshomeostasis drive neuronal pathology in diabetes. Cell Calcium. 44, 112-122. (if, 4.12)
*Wang, Z., Gardiner, N.J. and P. Fernyhough (2008). Blockadeof hexokinase activity and binding to mitochondria inhibitsneurite outgrowth in cultured adult rat sensory neurons. Neuroscience Letters. 434, 6-11. (if, 2.1)
Brussee, V., Guo, G.F., Dong, Y.Y., Cheng, C., Martinez, J.A., Smith, D., Glazner, G.W., Fernyhough, P. and D.W. Zochodne (2008). Distal degenerative sensory neuropathy in a long term type 2 diabetes rat model. Diabetes. 57, 1664-1673. (if, 8.26)
Gardiner NJ, Moffatt S, Fernyhough P, Humphries MJ, Streuli CH, Tomlinson DR.Preconditioning injury-induced neurite outgrowth of adult rat sensory neurons on fibronectin is mediated by mobilisation of axonal alpha5 integrin. Mol Cell Neurosci. 2007 Jun;35(2):249-60. Epub 2007 Mar 6.
Arboleda G, Huang TJ, Waters C, Verkhratsky A, Fernyhough P, Gibson RM. Insulin-like growth factor-1-dependent maintenance of neuronal metabolism through the phosphatidylinositol 3-kinase-Akt pathway is inhibited by C2-ceramide in CAD cells. Eur J Neurosci. 2007 May;25(10):3030-8.
Fernyhough, P, Smith, D., Schapansky, J., Van Der Ploeg, R., Gardiner, N., Tweed, C., Kontos, A., Freeman, L., Purves-Tyson, T., and G. W. Glazner. (2005). Activation of NF-kB via endogenous TNF-alpha regulates survival of axotomized adult sensory neurons. J. Neuroscience 25(7) 1682-1690.
Gardiner, N.J., Fernyhough, P., Tomlinson, D.R., Mayer, U., von der Mark, H., and C.H. Streuli (2005) α7 integrin mediates axon regeneration of distinct populations of adult sensory neurons. Molecular and Cellular Neuroscience. Mol Cell Neurosci. 28(2):229-40.
Huang, T-J, Verkhatsky, A, and P. Fernyhough. (2005) Insulin enhances mitochondrial inner membrane potential and increases ATP levels through phosphoinositide 3-kinase in adult sensoryneurons. Molecular and Cellular Neuroscience. 28;42-54.
Middlemas, A., Delcroix, J.-D., Sayers, N.M., Tomlinson, D.R. and P. Fernyhough (2003). Enhanced activation of axonally transported stress-actived protein kinases in peripheral nerve in diabetic neuropathy is prevented by neurotrophin-3. Brain 126, 1671-1682.
Fernyhough, P., Huang, T.Z. and A. Verkhratsky (2003). Mechanism of mitochondrial dysfunction in diabetic sensory neuropathy. Journal of the Peripheral Nervous System 8, 227-235.
Huang, T.-Z., Price, S., Chilton, L., Calcutt, N.A., Tomlinson, D.R., Verkhratsky, A. and P. Fernyhough (2003). Insulin prevents depolarization of the mitochondrial inner membrane in sensory neurons of Type I diabetic rats in the presence of sustained hyperglycemia. Diabetes 52, 2129-2136.
Sayers, N.M., Beswick, L.J., Middlemas, A., Calcutt, N.A., Mizisin, A.P., Tomlinson, D.R. and P. Fernyhough (2003). Neurotrophin-3 prevents the proximal accumulation of neurofilament proteins in sensory neurons of streptozocin diabetic rats. Diabetes 52, 2372-2380.
Huang, T.-Z., Sayers, N.M., Fernyhough, P. and A. Verkhratsky (2002). Diabetes-induced alterations in calcium homeostasis in sensory neurones of streptozotocin-diabetic rats are restricted to lumbar ganglia and are prevented by neurotrophin-3. Diabetologia 45, 560-570.
Fernyhough, P. and R. Schmidt (2002). Neurofilaments in diabetic neuropathy. Int. Rev. Neurobiol. 50, 115-144.
Glazner, G.W. and P. Fernyhough (2002). Neuronal survival in the balance: Are endoplasmic reticulum membrane proteins the fulcrum? Cell Calcium 32, 421-433.
Averill, S., Delcroix, J.-D., Michael, G.J., Tomlinson, D.R., Fernyhough, P. and J.V. Priestley (2001). Nerve growth factor modulates the activation status and fast axonal transport of ERK 1/2 in adult nociceptive neurones. Molecular and Cellular Neuroscience 18, 183-196.
Purves, T., Middlemass, A., Agthong, S., Jude, E., Boulton, A., Fernyhough, P. and D.R. Tomlinson (2001). A role for mitogen-activated protein kinases in the aetiology of diabetic neuropathy. FASEB Journal 15, 2508-2514.
Fernyhough, P., Gallagher, A., Averill, S., Priestley, J.V., Hounsom, L., Patel, J., and D.R. Tomlinson (1999). Aberrant neurofilament phosphorylation in sensory neurons of rats with diabetic neuropathy. Diabetes 48, 881-889.
Delcroix, J.-D., Averill, S., Fernandes, K., Tomlinson, D.R., Priestley, J.V. and P. Fernyhough (1999). Nerve growth factor modulates axonal transport of the transcription factor ATF2 in sensory neurones. Journal of Neuroscience 19, RC24 (1-7).
Current Research group:
Dr. Ali Saleh – research associate (SBRC)
Dr. Savitha Balakrishnan – postdoctoral fellow (CIHR)
Dr. Subir Chowdhury – research associate (JDRF)
Dr. Elena Zherebitskaya – research associate (JDRF)
Mr. Randy Van Der Ploeg – technician (CIHR)
Mr. Eli Kwaku Akude – PhD student (NSERC)
Dr. Darrell Smith – PhD student (MHRC)
Mr. Jason Schapansky – technician (CIHR)
Miss. Emily Mutch – research assistant (JDRF)
Neurodiab meeting in Toronto, October 2009
In the news.....
Drs. Paul Fernyhough & Peter Zahradka receive CFI funding...
Fernyhough receives JDRF Grants
Drs. Paul Fernyhough & Alan Jackson receive CIHR Operating Award
Dr. Paul Fernyhough receives Presidential Outreach Award
SBHRC receives $1.2 million in funding from JDRF for diabetes research
The Health Report: "Neurodegenerative Disorders: The Search for Answers and Cures"
New faculty earn CFI support