Age-Related Diseases (Wolfson Centre for)

As the age of the population increases, dementia is becoming increasingly frequent in western countries. Already there are more than 700,000 people with dementia in the UK and the number is likely to double in the next 30 years. Our group is adopting a variety of scientific approaches to understand the basis of key symptoms in people with dementia, to determine the mechanisms underlying dementia and to develop new treatments, with a particular emphasis on non-Alzheimer’s dementia such as those related to stroke, Parkinson’s Disease and Downs Syndrome.

020 7848 8054

020 7848 6145

(Head of group) Age-related degenerations of the eye: interaction of light and lasers with ocular tissues.

020 7188 4296

Our studies have concentrated on identifying the specific retinoic acid receptor (RAR) signalling pathways in neurite outgrowth, neuronal survival and stem/progenitor cell differentiation. The identification of these pathways allows the design of retinoids, these are small molecules which can cross the blood brain barrier. These retinoids are either agonists or antagonists and may have therapeutic potential in CNS disorders, such as Alzheimer’s disease, stroke and spinal cord injury.

020 7848 6156

020 7848 6816

Neurochemistry of Alzheimer’s disease

Alzheimer’s disease (AD) affects over 500,000 people in the UK and the annual cost of care is estimated at £11 billion. The disease is characterised by regionally selective gross cerebral atrophy, senile plaques, neurofibrillary tangles together with selective neurone and synapse loss. The principal neuronal types affected used glutamate or acetylcholine as transmitter. These changes produce a characteristic clinical syndrome of progressive cognitive dysfunction and behavioural abnormalities with declining activities of daily living. Current treatments are based reducing the breakdown of acetylcholine in the synaptic cleft and they provide symptomatic benefit for a majority of patients.

The research of this group focuses on the relationship between neurochemical changes in the brains of patients with AD and their particular symptoms. Thus we have shown that, in addition to the well-known relationship between acetylcholine and cognitive decline , there is a relationship between this system and non-cognitive, behavioural changes seen in patients with AD. This then provides a scientific rationale for the clinical improvement in this domain following treatment with acetylcholinesterase inhibitors (AChEI).

We are also interested in the mechanism of action of AChEIs and a newly approved drug in the AD field, memantine (Ebixa, Lundbeck). We have argued that AChEIs work by increasing the release of glutamate that is reduced in AD as a consequence of glutamatergic cell and synapse loss . Memantine appears to have a glutamatergic mechanism of action, but one that is possibly at odds with our working hypothesis. We are keen to resolve this possible conflict.

Another area of great interest is second messenger/signalling systems that may be altered as a consequence of disturbed neurotransmission or as a primary pathological event. In collaboration with Dr Robert Williams we are investigating the status of signalling pathways involved in cell death and cell survival and using model systems to test whether any changes are a cause or consequence of AD neurochemical pathology.

020 7848 6269

020 7848 6145

Intracellular trafficking and the membrance micro-environment of prion protein and their effects on normal physiological function and in transmissible spongiform encephalopathies.

020 7848 6801

The main focus of work in my research group is in identifying new targets for reducing abnormally overactive glutamate and GABA signalling in the basal ganglia in Parkinson's disease. Targets of interest include the Gi/Go coupled receptors purported to negatively regulate transmitter release. Such targets may offer an alternative route to symptom relief and neuroprotection in this debilitating disease. We are also interested in finding ways to provide protection against cell loss or to permit neuroregeneration in Parkinson's disease. We use a range of molecular, cellular and whole system approaches to address these issues.

020 7848 6013

020 7848 6145

For many years, the concept of the non-regenerating adult brain was a universally acknowledged dogma. Over 40 years ago, a few pioneer studies showed the existence of proliferating cells in the brain, but it was the last two decades where the use of new techniques verified that. Today, the existence of neural stem cells located at very specific neurogenic niches in the adult nervous system has been documented in all organisms, from fish to humans. These cells have been shown to give rise to new, functional neurons in the brain, opening a new whole area for therapeutic applications.

020 7848 6910

020 7848 6816

Peripheral neuropathy is common and is associated with significant disability as a result of weakness, sensory loss and chronic pain. My research is concerned with the response to peripheral nerve injury, and in particular factors which may promote successful nerve regeneration. I am also investigating mechanisms of and novel treatments for neuropathic pain. My laboratory employs a wide variety of techniques including transgenic animal models, neurophysiology, animal behaviour and psychophysical testing in patients. I am also a Neurologist and see patients weekly in a Neuropathy clinic. This facilitates an excellent understanding both of the basic neurobiology of nerve injury and of its clinical correlates.

020 7848 8168

020 7848 6165

Control of nerve growth; regeneration and synapse formation; developmental neurobiology.

020 7848 6257

Work carried out in my laboratory first demonstrated an involvement of EphB receptor tyrosine kinases and their ephrinB ligands in the onset of inflammatory pain. My main interests are in exploring further the involvement of this signalling system in the onset and maintenance of different types of chronic pain (inflammatory and neuropatjic), acting both at central and peripheral level, and mediating communication between glial and neuronal cells, as well as between neurons.

020 7848 6739

020 7848 6165

Major research interests include the role of transcriptional control in the processes of axonal regeneration and neuronal differentiation. We are particularly interested in the delivery of potential axon growth-promoting genes into neurons of the peripheral and central nervous systems. Gene transfer techniques include both viral and non-viral delivery systems while the experimental approaches involve in vitro systems using both primary neurons and cell lines.
Subsidiary research interests include the role of the GATA transcription factor family in cardiogenesis and their role in the epicardium in terms of both development of the coronary vasculature and the potential for cardiomyocyte diffrentiation.

020 7848 6461

020 7848 6569

http://www.kcl.ac.uk/schools/biohealth/research/wolfson/jpizzey

Cerebral ischemia (stroke) and spinal cord injury (SCI) cause disability due to axonal damage and loss of neurons and glia. Axons regenerate following injury to the peripheral nervous system but there is only limited axon sprouting after stroke or SCI. Factors within and surrounding CNS neurons limit regrowth of their axons. Extrinsic factors include a paucity of positive influences in the environment (e.g. growth factors) and the presence of cavities and inhibitory cues (e.g. myelin inhibitors, proteoglycans).

Intrinsically, mammalian CNS neurons downregulate many growth-promoting genes on maturation and consequently extend axons poorly after injury. CNS axon regeneration remains extremely limited in most experimental paradigms and effective restorative therapies remain to be developed.

My research has two main threads. First, my work (and that of others) shows that CNS axon growth can be promoted by degrading growth-inhibitory molecules within CNS injury sites using an enzyme known as chondroitinase ABC. Ongoing studies aim to determine whether this treatment has benefits in clinically relevant models of stroke and SCI.

Second, I have recently identified a set of growth-associated genes that are regulated during regeneration of injured spinal cord axons into a growth permissive transplant in the spinal cord. To do this, I combined several cutting-edge technologies including laser microdissection, amplification of mRNA, microarray analysis and real time RT PCR. Ongoing work aims to determine which of these growth-associated genes are necessary or sufficient to promote growth of injured axons. We use medium throughput screening using primary neurons and a 96 well electroporator to identify genes that promote CNS axon growth. We also use viral vectors to overexpress and knock down candidate genes in vitro and in vivo.

In conclusion, my long-term research goal is to identify and test novel strategies for promoting CNS axon growth and recovery after CNS injury.

020 7848 8141

020 7848 6154

Spinal cord injury repair strategies.

020 7848 6183

020 7848 6165

Positive and negative modulation of nociceptive fibre synaptic activity in the spinal cord.

020 7848 6092

020 7848 6165

We are interested in how the excitability of sensory neurones can change depending on conditions in their environment. Signals that are generated in the environment can excite the neurones directly e.g. bradykinin, or they may change the nature of the neurones and how they respond e.g. prostaglandin E2. Changes in excitability may also result from dysfunction of the nerves themselves without obvious associated tissue damage. Over the last 20 years or so it has become very clear that ion channels that are expressed in the plasma membranes of sensory neurones are key regulators of sensory neuronal excitability. As such, these ion channels and the mechanisms that control them offer potential targets for the development of new drugs that could be used to control sensory neurone excitability and associated pain and paresthesia.

Voltage-gated sodium channels:

We have had a long-standing interest in one particular group of ion channels in sensory neurones - the voltage-gated sodium channels (VGSCs). Many years ago (1996) we demonstrated the importance of a particular type of VGSC, now called NaV1.8, in the mechanism by which inflammation 'sensitises' sensory neurones making them more excitable and we described the cellular processes that cause this to occur. We have since found that another VGSC type expressed in sensory neurones is involved in this mechanism and responds to the same stimuli as NaV1.8. We know that this is one of the tetrodotoxin-sensitive group of VGSCs (unlike NaV1.8 which is not tetrodotoxin sensitive) but have not yet identified the precise subtype. We are very interested in determining what the precise subtype is and also whether the increased excitability is because more VGSCs become available or whether the existing population of VGSCs are working in a different way to normal.

TRPV1, the capsaicin receptor:

TRPV1, formerly known as the capsaicin receptor, is an ion channel that is found in the plasma membrane of nociceptive sensory neurones. Chilli peppers contain capsaicin which binds to and opens the channel, exciting the neurones and giving rise to the perception of hot, burning pain. A few years ago we put forward the idea, now widely substantiated, that capsaicin receptors are dephosphorylated by the calcium-dependent enzyme calcineurin and this is associated with desensitization of the channel. As well as contributing to our understanding of sensory mechanisms this idea has special importance because it gives us a basis for explaining the paradoxical phenomenon of capsaicin-induced analgesia whereby capsaicin - a pain provoking chemical - can produce profound and broad spectrum analgesic effects. We have proposed that the mechanism of capsaicin induced analgesia is a calcineurin-mediated cross-desensitization that occurs between TRPV1 and other receptors and ion channels in sensory neurones and are trying to learn more about the mechanisms by which this cross-desensitization occurs.

Non-neuronal nociceptors:

Sensory neuronal somata are ensheathed by a layer of 'satellite' cells. It has recently been shown that the satellite cells interact with sensory neurones and participate in complex responses to tissue injury. We have shown that the cells play a critical role in provoking the response of sensory neurones to bradykinin - an important inflammatory mediator - so the satellite cells may act as nociceptors in their own right. Further, bradykinin provides us with a chemical probe that we can use to investigate the satellite-cell neurone signalling mechanism. Satellite cells may prove to be critical for neurone-neurone cross talk in the sensory ganglia with all that this implies including specification of the size of sensory receptive fields and even 'modality switching' such as occurs in neuropathic pain where sensory receptors that are not normally associated with the sensation of pain acquire pain provoking properties.

020 7848 6193

020 7848 6193

Chronic pain is a debilitating disorder that affects millions of people world-wide and has a considerable detrimental impact on quality of life. There are multiple events which can lead to chronic pain including trauma, diabetes, surgical procedures, cancer and HIV. Effective analgesic therapies are inadequate in the majority of chronic pain patients and are often associated with unpleasant side-effects. Consequently at present there is a substantial, unmet, clinical need for better pain control in these patient populations.

020 7848 8141

020 7848 6165

Behavioural, electrophysiological and anatomical studies of somatosensory systems, particularly pain; actions of trophic factors on adult sensory neurones.

020 7848 6270

020 7848 6165

Stem cells are self-renewing and expandable cells capable of generating every cell type in a tissue or organism. The work in our lab is focused on the derivation, propagation, characterisation and assessment of the therapeutic potential of a wide range of stem cell population, including those from early embryos, as well as those obtained from foetal and adult tissues.

020 7848 6169

020 7848 6169

Since the discovery of the ion channel Transient Receptor Potential Vanilloid 4 (TRPV4) in 2000 it has been implicated in a wide variety of physiological and pathophysiological processes. These range from control of body fluid homeostasis to sensation of noxious pressure. The identification of TRPV4 as a molecular sensor of mechanical pain is particularly exciting, as there is still controversy over the molecules involved in this process. It is hoped that a deeper understanding of TRPV4 will validate it as a novel therapeutic target in pain and inflammatory conditions.

020 7848 6187

020 7848 6165

Neural stem cells; neuroimmune networks; brain repair. I have studied the effects of the endocannabinoid sytem on neuroinflammation for over ten years, focusing on the neuroimmune interactions of cytokines and cannabinoids (CBs) in CNS (central nervous system) development, neuroprotection and brain repair. The beneficial actions of CB1 and CB2 cannabinoid receptor agonists in experimental neurodegeneration have long been recognised and it is believed that CBs may slow the neurodegenerative processes that ultimately lead to chronic disability in patients. In our research, we have provided extensive evidence that activation of the endocannabinoid signalling system is both neuroprotective and anti-inflammatory in the brain via different signalling cascades. Specifically, we discovered that interleukin-1 receptor antagonist (IL-1ra, a natural occurring antagonist for the inflammatory actions of IL-1 in the CNS) is the critical mediator for the neuroprotective actions of CBs in the CNS Moreover, our team was the first to demonstrate the presence of CB1 and CB2 cannabinoid receptors in oligodendrocytes and their involvement in progenitor survival, proliferation and differentiation via PKB/Akt signalling. Preliminary tests to measure whether the anti-inflammatory actions of CBs could assist the process of proliferation and differentiation on neural stem cells in rodents have proved extremely positive. Neurospheres are clonal cellular aggregates of neural stem/precursor cells that grow in culture as free-floating clusters. Activation of CB1 cannabinoid receptors, which are expressed by these cells, promotes proliferation. We investigated the expression of CB2 cannabinoid receptors and the effect of exogenous cannabinoids on neural stem/precursor cell proliferation. Neurospheres containing nestin-positive and sn-1 diacylglycerol lipase alpha-positive cells expressed both CB1 and CB2 receptors, which were maintained through several passages. Application of the non-selective cannabinoid agonist HU-210, stimulated neural stem cell proliferation. This action involved both CB1 and CB2 cannabinoid receptors. In addition, cannabinoid agonist-stimulated proliferation was reduced by the Akt translocation inhibitor BML-257, suggesting a role for phosphoinositide-3 kinase signalling. Together, our results suggest that cannabinoids stimulate proliferation of neural stem/precursor cells acting on both CB1 and CB2 cannabinoid receptors through a phosphoinositide-3 kinase/Akt pathway Selected Publications: Rubio-Araiz A, Arevalo-Martin A, Gomez-Torres O, Navarro-Galve B, Garcia-Ovejero D, Suetterlin P, Sanchez-Heras E, Molina-Holgado E, Molina-Holgado F. The Endocannabinoid System Modulates a Transient TNF Pathway that Induces Neural Proliferation. Mol Cell Neurosci 2008. Doi:10.1016/j.mcn.2008.03.010 Arevalo-Martin A, Garcia-Ovejero D, Gomez O, Rubio-Araiz A, Navarro-Galve B, Guaza C, Molina-Holgado E, Molina-Holgado F. CB2 cannabinoid receptors as an emerging target for demyelinating diseases: from neuroimmune interactions to cell replacement. British Journal of Pharmacology 2008, 153(2):216-225. Arevalo A, Garcia-Ovejero D, Rubio-Araiz A, Molina-Holgado F, Molina-Holgado E. Cannabinoids modulate OLIG2 and PSA-NCAM expression in the subventricular zone of postnatal rats through CB1 and CB2 receptors. Eur J Neurosci 2007, Eur J Neurosci. 2007 Sep;26(6):1548-59. Molina-Holgado F, Rubio-Araiz A, Garcia-Ovejero D, Williams RJ, Moore JD, Arevalo-Martin A, Gomez-Torres O, Molina-Holgado E. CB2 cannabinoid receptors promote mouse neural stem cell proliferation. Eur J Neurosci. 2007, 25(3): 629-634. Molina-Holgado F, Pinteaux E, Heenan L, Moore JD, Rothwell NJ, Gibson RM. Neuroprotective effects of the synthetic cannabinoid HU-210 in primary cortical neurons are mediated by phosphatidylinositol 3-kinase-AKT signaling. Mol. Cell Neurosci. 2005, 28(1): 1891-94. Molina-Holgado F, Pinteaux E, Moore JD, Molina-Holgado E, Guaza C, Gibson RM, Rothwell NJ. Endogenous interleukin-1 receptor antagonist mediates anti-inflammatory and neuroprotective actions of cannabinoids in neurons and glia. J Neurosci. 2003, 23: 6470-6474

020 7848 6806

02078486145

Research touching on most aspects of bioinformaticsmostly applied to neurobiology: Predicting protein intearction hot spots; Developing protein interaction modulators; Novel sequence analysis tools.

+44 (0)20 7848 6806

+44 (0)20 7848 6816

Signalling and trafficking mechanisms determining neuronal shape The establishment of a correct cellular morphology is at the basis of proper neuronal function. This event involves the creation of a highly polarized cell usually characterised by multiple dendrites and a single axon. Such cellular processes form a highly branched network ensuring functional neurotransmission. Neurite branching is essential for the establishment of appropriate neuronal connections during development and regeneration. Axons can branch as they navigate toward target cells and then again upon arrival at their destination. Dendrites also branch extensively, giving rise to characteristic dendritic trees able to influence the propagation of electric signals. Neurite sprouting and branching are also observed in cases of regeneration after lesion-induced traumas. A central challenge in neurobiology is therefore to define the molecular mechanisms by which neurite branching is achieved. Formation of new branches depends on the ability of the cell cortex and cytoplasm of elongating neurites to undergo dynamic reorganization in response to extrinsic cues. The sprouting of new motile structures, such as filopodia, is thought to be an early step in this process. A variety of extracellular cues such as neurotrophic factors, slits, ephrins, netrins, semaphorins, integrins and cell adhesion molecules can affect neurite branching. The signals establishing a branch point and the molecular machinery involved, however, are still poorly understood. It is likely that neurite branching requires the coordination of multiple events, including actin polymerization, formation of new adhesive sites, changes to the microtubule cytoskeleton and membrane delivery. I have recently identified the Ral (Ras-like) small GTPase as a new mediator of neurite branching in distinct neuronal cell types. The two Ral isoforms, RalA and RalB, are found at the plasma membrane as well as on endocytic and exocytic vesicles, and they have been implicated in a variety of cellular processes such as oncogenic transformation, transcriptional regulation, cell proliferation, vesicle trafficking, and cytoskeletal reorganization. Ral activation specifically promotes neurite branching, while Ral inhibition decreases laminin-induced branching. In addition, depletion of endogenous Ral by RNA interference (RNAi) decreases branching in cortical neurons. RalA and RalB promote branching through distinct pathways, involving the exocyst complex and phospholipase D (PLD), respectively. Finally, Ral-dependent branching is mediated by PKC-dependent phosphorylation of 43 kD growth-associated protein (GAP-43), a molecule playing a crucial role in pathfinding, plasticity and regeneration. These findings highlight an important role for Ral in the regulation of neuronal morphology and provide a cellular context for dissecting different signalling pathways leading to neurite branching. As a principal investigator I plan to study how these pathways are activated and coordinated in order to achieve a correct neuronal shape. Using a combination of cell biology and biochemical techniques I am investigating a role for Ral in signalling cascades leading to branching, characterising the function of Ral effectors and identifying specific Ral guanine nucleotide exchange factors (GEFs) involved in branching and, more generally, in the control of neuronal morphology. Since Ral signalling involves GAP-43, a molecule reinduced in injured and regenerating neural tissues and able to potentiate nerve-sprouting responses, it will also be important to analyse the expression and function of this GTPase and its effectors in lesion-induced sprouting models currently available at the Wolfson CARD. My long-term goal is to clarify how cytoskeletal rearrangements and membrane trafficking are coupled to initiate and maintain neurite growth. The knowledge acquired from these studies could therefore have the potential for therapeutic applications aiming at functional recovery after trauma in the nervous system. Recent publications: Lalli, G and Hall, A. (2005) Ral GTPases regulate neurite branching through GAP-43 and the exocyst complex. J Cell Biol 171: 857-869 G?rtner, A, Collin, L and Lalli, G Nucleofection of primary neurons. (2006) In Regulators and Effectors of Small GTPases, Part E : Rho Family, Methods in Enzymology, A. Hall, editor. Elsevier press, 406: 374-388

020 7848 8154

020 7848 6816

The enteric nervous system and neuroendocrine systems and their roles in co-ordinating intestinal functions in health and disease. We utilise physiological, pharmacological and molecular strategies to elucidate peptide-receptor actions in complex (isolated human tissue) and simple models (epithelial cells in culture).

020 7848 6182

020 7848 6182

Regulation of ion channels by receptors and second messenger systems. Proton activated ion channels. Interfacing neurons with semiconductors. Novel membrane targeted peptides. Cell culture, electrophysiology, intracellular calcium mesurements, multichannel recording, patch clamping. Retina, retinal ganglion cells, NG108-15 cells, superior cervical ganglion cells.

020 7848 6191

020 7848 6569

Regulation of growth and neuronal differentiation in Drosophila.

020 7848 8144

020 7848 6145

Our recent work has focussed on the identification and cloning of the diacylglycerol lipases (DAGLs). Our interest in this enzymatic activity stems directly from our work on cell adhesion molecules (CAMs). We have established that a numbers of CAMs can promote axonal growth by activating FGF receptors in neurons. Importantly, DAGL activity couples the CAM/FGFR pathway to an axonal growth response upstream from calcium influx into the growth cone . DAGL hydrolyses diacylglycerol (DAG) to 2-arachidonylglycerol (2-AG) and 2-AG is the most abundant endocannabinoid in the nervous system. This led us to test the hypothesis that FGF receptors can “cross-talk” with the endocannabinoid system; interestingly, we found that activation of the CB1 cannabinoid receptor in neurons is both necessary and sufficient for CAM and FGF stimulated neurite outgrowth. For complete picture of our interests please visit the following site to review our groups publications

http://www.researcherid.com/rid/A-8752-2008

020-7848 6811

020 7848 6816

Protein kinase signalling and oxidative stress in neurodegeneration; neuroprotection by dietary flavonoids.

020 7848 6170

020 7848 6145

Sensory transduction; nociception; analgesia; ion channels; TRP channels; cell signalling.

020 7848 6141

020 7848 6145