Strathclyde Institute for Pharmacy and Biomedical Sciences
Ph.D.
Research Project Descriptor
Project Title: Investigating the role of the NF-kB modulators, IkBa/b & IKKa/b, in themodulation of neuronal death associated with CNS disease.
Primary Supervisor: Dr Trevor Bushell
Email:
Webpage: http://spider.science.strath.ac.uk/sipbs/staff/staffDetails.php?u=TBushell
Secondary Supervisor: Dr Andy Paul
Email:
Webpage: http://spider.science.strath.ac.uk/sipbs/staff/staffDetails.php?u=andypaul
Project Area: (insert key words and/or research group(s)/sub-theme(s) or cross theme(s)
Neuroinflammation, Neuroscience, Cell signalling.
Project Description:
An increasing amount of evidence suggests that the family of nuclear factor kappaB (NF-kB) transcription factors plays an important role in synaptic transmission, plasticity and long-term memory formation1. Furthermore, it has recently been proposed that the inhibition of NF-kB is beneficial in certain chronic CNS diseases including Parkinson’s 2. NF-kB activity is regulated by IB and IKK kinase proteins in a variety of preparations 3, however, whether NF-kB activity is modulated by IB and IB kinase in central neurones and how this contributes to neuronal function under physiological and pathophysiological conditions is unknown.
Hence, the aims of this study are to use a multidisciplinary approach in order to elucidate 1) whether these regulatory kinases modulate NF-kB activity in central neurones, 2) determine the effect of upregulation /downregulation of these kinases on neuronal activity and 3) elucidate whether their activation is neuroprotective or degenerative in models of neurological disorders.
Answers to these questions will lead to a better understanding of inhibitory kappaB kinase modulation of NF-kB under physiological and pathophysiological conditions which could have implications for the treatment of inflammation-related CNS disorders.
Techniques to be used:
1. Quantitative immunohistochemistry to identify the effect of a variety of physiological and
pathophysiological conditions on these pathways.
2. Extracellular and patch-clamp electrophysiology to determine the effect of kinase regulation on
synaptic transmission and plasticity.
3. Tissue-culture to prepare primary and organotypic neuronal cultures.
4.
References:
1. Meffert et al., (2003) NFkappa B functions in synaptic signaling and behavior. Nat Neurosci 6, 1072–1078.
2. Ghosh et al., (2007). Selective inhibition of NF-{kappa}B activation prevents dopaminergic neuronal loss in a mouse model of Parkinson's disease. Proc Natl Acad Sci U S A. 104, 18574-18759.
3. MacKenzie et al., (2007). IKKalpha and IKKbeta function in TNFalpha-stimulated adhesion molecule expression in human aortic smooth muscle cells. Cell Signal. 19, 75-80.
Strathclyde Institute for Pharmacy and Biomedical Sciences
Ph.D.
Research Project Descriptor
Project Title: Do T cells modulate neuronal activity and plasticity in the CNS during chronicinflammatory disease?
Primary Supervisor: Dr Trevor Bushell
Email:
Webpage: http://spider.science.strath.ac.uk/sipbs/staff/staffDetails.php?u=TBushell
Secondary Supervisor: Professor Paul Garside
Email:
Webpage: http://www.biophotonics.strath.ac.uk/showPage.php?page=garside
Project Area: (insert key words and/or research group(s)/sub-theme(s) or cross theme(s)
Neuroinflammation, Neuroscience, Immunology. Cross theme between Cell Biology & IIM
Project Description:
Despite the CNS and the immune system formerly being thought of as separate entities, it is now well recognised that the communication between these two systems is a bidirectional process 1. With the increased understanding of this interaction, it has now become clear that one of the fundamental defence mechanisms of the immune system, namely inflammation, is implicated to play a major role in the certain CNS disorders. Indeed, the upregulation of certain inflammatory cytokines are observed in acute CNS conditions such as brain trauma, as well as in chronic CNS diseases states, including Alzheimer’s disease, Parkinson’s disease and Multiple Sclerosis 3. This increased expression of inflammatory cytokines in CNS disorders mirrors their well-documented role in peripheral inflammatory diseases, such as rheumatoid arthritis 4. In addition to elevated cytokine levels, it has been reported that lymphocytes including T cells invade the brain in certain CNS disorders linked to inflammation 5. However, their effect on neuronal function remains unclear.
The aims of this project are to use a multidisciplinary approach in order to 1) determine how T cells modulate neuronal excitability, synaptic transmission and plasticity and 2) elucidate how different inflammatory conditions affect T cell movement within the CNS. Answers to these questions will lead to a better understanding of the physiological and pathophysiological role of T cell infiltration of the brain which could have implications for the treatment of inflammation-related CNS disorders.
Techniques to be used:
1. Extracellular and patch-clamp electrophysiology to determine the effect of T cells on synaptic transmission and
plasticity
2. State-of-the-art real time imaging techniques to monitor the movement of T cells within the brain.
3. Immunohistochemistry to identify the location of T cell swith the brain in chronic inflammatory diseases
4. Tissue-culture to prepare fluorescently labelled T cells etc utilised in this study.
References:
1. Exton, M.S. et al., (2001). Conditioning in the rat: an in vivo model to investigate the molecular mechanisms and clinical implications of brain-immune communication. Immunological Reviews 184, 226-35.
2. Campbell, A. (2004). Inflammation, neurodegenerative diseases, and environmental exposures. Annals of the New York Academy of Science 1035, 117-32.
3. Lucas, S.M. et al., (2006). The role of inflammation in CNS injury and disease. British Journal of Pharmacology 147, Suppl 1:S232-40.
4. McInnes, I.B. & Gracie, J.A. (2004). Targeting cytokines beyond tumor necrosis factor-alpha and interleukin-1 in rheumatoid arthritis. Current Rheumatology Reports 6, 36-42.
5. Nitsch et al., (2005). Direct impact of T cells on neurons revealed by two-photon microscopy in living brain tissue. Journal of Neuroscience 24, 2458-64.
Strathclyde Institute for Pharmacy and Biomedical Sciences
Ph.D.
Research Project Descriptor
Project Title: Characterisation of a novel mechanism for modulating the activity ofpain-sensing nerves.
Primary Supervisor: Dr Trevor Bushell
Email:
Webpage: http://spider.science.strath.ac.uk/sipbs/staff/staffDetails.php?u=TBushell
Secondary Supervisor: Dr Charles Kennedy
Email:
Webpage: http://spider.science.strath.ac.uk/sipbs/staff/staffDetails.php?u=ckennedy
Project Area: (insert key words and/or research group(s)/sub-theme(s) or cross theme(s)
Neuroscience, Pharmacology, Cell Biology
Project Description:
At present the therapeutic options for treating chronic pain are limited. However, a number of new targets have recently been identified, including P2Y receptors and 2-pore potassium ion (K2P) channels. Both are expressed in the pain-sensing C and Ad sensory nerve fibres, which have their cell bodies in the dorsal root ganglia (DRG) and so are potentially important targets for controlling the activity of pain-sensing nerves.
P2Y receptors are a family of G protein-coupled receptors that are activated by nucleotides, such as adenosine 5'-triphosphate (ATP) (Abbrachio et al., 2006). K2P channels are highly selective for K+ ions and make a substantial contribution to the neuronal resting membrane potential in many regions of the CNS (Kim, 2005). We have shown that native, ATP-sensitive P2Y receptors inhibit the K2P background current normally present in rat cerebellar granule neurones and that recombinant human P2Y1 and P2Y2 receptors inhibit currents carried by K2P channels co-expressed in a cell line. As both P2Y receptors (Kennedy et al., 2003) and K2P channels (Alloui et al., 2006; Linden et al., 2006) are expressed in sensory neurones, the aim of this project is to characterise how they interact to modulate sensory nerve activity in rat DRG. The student will use the patch clamp technique to record ion currents carried by K2P channels and characterise their modulation by P2Y receptor activation. This will be supported by the use of recombinant channels and receptors. They will also learn tissue-culture and will use immunohistochemical techniques to study native protein expression.
Together, these experiments will help advance the search for new, effective analgesics that could be beneficial in the treatment of certain pain disorders for which current treatments are ineffective.
Techniques to be used:
1. Patch-clamp electrophysiology in both expression systems and neuronal preparations.
2. Molecular biology.
3. Immunohistochemistry.
4. Tissue-culture (expression of recombinant receptors & ion channels in expression systems, preparation of DRG cultures).
References:
1. Abbracchio, MP et al., (2006). Update of the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy. Pharmacol. Rev., 58, 281-341
2. Kennedy, C. et al., (2003). Crossing the pain barrier: P2 receptors as targets for novel analgesics. J. Physiol., 553, 683-694.
3. Kim, D. (2005). Physiology pharmacology of two-pore domain potassium channels. Curr Pharm Des. 11, 2717-36.
4. Alloui A et al., (2006). TREK-1, a K+ channel involved in polymodal pain perception. EMBO J., 25, 2368-76.
5. Linden, AM et al., (2006). The in vivo contributions of TASK-1-containing channels to the actions of inhalation
anesthetics, the alpha(2) adrenergic sedative dexmedetomidine, and cannabinoid agonists. J Pharmacol Exp Ther. 317,
615-26.