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Our research aims to understand the mechanisms responsible for the disease, in order to arrest them and thereby avoid the production of symptoms even before they have started. Our recent research has focused on the reduction in blood flow through inflamed tissue which reduces the supply of the oxygen needed to maintain function and avoid tissue damage. We have shown that appropriately timed treatments to maintain tissue oxygenation can provide remarkable protection from symptoms and damage. Indeed, we have advanced studies from the earliest laboratory observations of previously unsuspected mechanisms, to devise at least one novel treatment strategy that has been proven effective in neuroprotection in clinical trial.Ìý

A second major line of research concerns cerebral small vessel disease, which becomes common with ageing, and is a major cause of strokes and dementia. The disease affects arterioles, capillaries and venules and causes a reduction in blood flow, and impaired regulation of blood flow. Our research explores the importance of inadequate tissue oxygenation in causing symptoms and damage, and also the therapeutic value of drugs that promote blood flow and oxygenation in achieving protection of cognitive function and tissue integrity.Ìý

Research

Hypoxia

Particular current interests derive from our discovery that neuroinflammatory lesions can be hypoxic, and sufficiently hypoxic to impair mitochondrial metabolism.Ìý This impairment is especially likely in an inflammatory environment containing nitric oxide and superoxide. The hypoxia and energy deficit directly contribute to three of the cardinal features of MS, namely loss of function (symptoms), demyelination and degeneration.Ìý Based on this realisation, our research explores novel protective treatment strategies that we are developing for clinical trial. One approach is to reduce energy demand by partial blockade of sodium channels. This therapy is also effective in dampening the activation of microglial cells (these cells can damage brain tissue), and we have recently shown the efficacy of one clinically relevant drug in this respect.Ìý Therapies based on this new understanding have been examined in recent and ongoing clinical trials in MS and related diseases.Ìý Encouragingly, such therapies can be very effective in neuroprotection, and they are also inexpensive and safe for long term administration.

Image: Inflamed spinal cord showing strong labelling for hypoxia in the grey matter.

Blood flow

Impaired blood flow or hypoperfusion is becoming an increasing focus of our research, as it is likely to be the primary cause of the tissue hypoxia observed in neuroinflammation. Hypoperfusion is well established in MS with reports of reduced flow affecting both grey and white matter. The white matter (composed of myelinated nerve fibres)Ìýis particularly vulnerable to disturbances in blood flow, explaining why MS lesions have a predilection to form at sites known to have a vulnerable blood supply. Our evidence is that therapies aimed at maintaining or restoring blood flow improve neurological function and reduce structural damage, with major implications for the way MS is treated.

Image:ÌýBlood flow in vessels indicated by fluorescent streaks.Ìý Long streaks (upper image) show fast flow through normal tissue, and short streaks (lower) show slow flow through inflamed tissue.

Mitochondria

Mitochondria are of particular interest inÌýour research.Ìý In the normal nervous system we have found that mitochondrial trafficking along axons is highly influenced by the level of impulse activity along the axons, which has implications for neurodegenerative disease.Ìý In the inflamed nervous system we have discovered that many axonal mitochondria become non-functional, which starves the axons of energy.Ìý In fact our evidence is that the energy insufficiency can cause conduction failure (and hence symptoms) and ultimately degeneration.Ìý We have also investigatedÌýhow mitochondria become damaged in diabetic axons, and how this damage contributes to diabetic neuropathy.

Image: Retinal vasculature revealed as a shadow over green fluorescence due to ongoing retinal mitochondrial respiration.

Image:ÌýExcessive superoxide production in inflamed tissue on the left of the spinal cord.

Model of the early MS lesion

We have developed and characterised a model of the Pattern III (hypoxic) type of demyelination found in early MS lesions.Ìý The model lesion demonstrates the prominent role of innate immune mechanisms in lesion formation. The lesion provides an excellent opportunity to test the efficacy of putative therapeutic agents.

Image: Pattern III demyelination (circled), as occurs in early MS lesions.

Model of ‘slow-burning’ neurodegeneration

Among our experimental models is a new focal lesion of ‘slow burning’ degeneration of the grey matter, consequent to a neuroinflammatory event.Ìý The lesion commences after a short delay following induction andÌýit causes slowly progressive disability that advances hand in hand with progressive neurodegeneration and atrophy of the grey matter.Ìý The lesion shares many features with progressive MS, and we are exploring the underlying mechanisms in the belief that this will indicate rational neuroprotective strategies.

Image:ÌýGrey matter atrophy (left) and mitochondrial failure (asterisk) in a lesion of slowly progressive neurodegeneration.

Research projects

Blood flow, oxygenation and neurological dysfunction

Neurological deficits in multiple sclerosis (MS) have traditionally been attributed to abnormalities in axonal conduction as a result of demyelination. However, increasing evidence suggests that inflammation alone is sufficient to impair function. Research from the laboratory has revealed that the inflamed CNS suffers from a significant reduction in blood flow, resulting in tissue hypoxia, which in turn leads to mitochondrial dysfunction and the expression of symptoms. We can monitor oxygen gradients across vessels and tissue using different techniques, including, but not limited to, in vivo confocal microscopy and hyperspectral imaging, allowing us to understand oxygen delivery in the inflamed CNS. We aim to examine different models of MS to determine the downstream effects of impaired blood flow and tissue hypoxia, in order to develop rational therapeutic strategies aimed at restoring function by improving tissue perfusion and oxygenation.Ìý

Dr. Zhiyuan (Helen)ÌýYang, PhDÌý
Dr. Ayse Yenicelik, MDÌý
Prof. Kenneth Smith, PhD

Pattern III demyelination

Different demyelinating lesion subtypes have been described in MS, based on the mechanism of tissue damage. One particular subtype, Pattern III, has been described as ‘hypoxia-like’ due to the similarities to acute white matter stroke, and has been attributed to nitric oxide-mediated mitochondrial inhibition. We have developed an experimental model of the human Pattern III lesion, and have shown an important role for tissue hypoxia in lesion development. Thus, the model can be used to evaluate the efficacy of novel therapeutic agents, aimed at increasing oxygenation, on the formation of Pattern III demyelination and axonal degeneration.

Dr. Zhiyuan (Helen)ÌýYang, PhDÌý
Prof. Kenneth Smith, PhD

Slowly progressive disease

MS is a central, neuroinflammatory demyelinating disease that causes neurological deficits due primarily to impaired neuro/axonal function in the short term, and primarily due to slowly progressive neuro/axonal degeneration in the longer term. Current evidence suggests that the acute neurological deficit can arise from inflammation, even in the absence of demyelination, although the mechanism(s) remain uncertain. Equally uncertainÌýis the cause of the slowly progressive degeneration. We are exploring the mechanisms responsible for both acute and chronic deficit by studying a new model of MS that expresses a period of acute inflammation, and then a slowly progressive degeneration of the grey matter, which resembles the slow and progressive grey matter degeneration in MS. We also study potential therapies to protect against the acute and chronic deficits.

Dr. Zhiyuan (Helen)ÌýYang, PhDÌý
Prof. Kenneth Smith, PhDÌý

Overcoming tissue hypoxia for therapy to restore function and prevent damage

The earliest symptoms of MS are often in the visual system and due to optic neuritis. The optic nerve lesions are typically demyelinating, and associated with neuro/axonal degeneration. ÌýIf degeneration is substantial, the visual disturbances will be permanent. Our research aims to study whether improved oxygenation of the lesion by increasing oxygen or blood supply can reduce the retinal and optic nerve pathology, as assessed by electrophysiological and histological examination. We plan clinical trials to examine our novel therapies, guided by our new finding that an energy insufficiency is an important and hitherto unappreciated cause of damage.

Dr. Ayse Yenicelik, MDÌý
Dr. Zhiyuan (Helen)ÌýYang, PhDÌý
Prof. Kenneth Smith, PhDÌý

Cerebral small vessel disease

Cerebral small vessel disease (cSVD) encompasses a range of pathological conditions affecting the cerebral vasculature, with various causes. About half of patients with a diagnosis of cSVD go on to develop stroke and/or dementia. Risk factors for cSVD include ageing, hypertension and diabetes. ÌýOur lab is a part of an international consortium supported by the Fondation Leducq focusing on the role of perivascular space in the pathogenesis of cSVD. We use a laboratory model to study the development of changes in blood-brain barrier, microglial activation and tissue oxygenation.ÌýÌýWe use in vivo confocal imaging combined with oxygen-sensitive microspheres and near-infrared spectroscopy to examine cerebral perfusion, vascular dysfunction and histological techniques to assess tissue pathology.ÌýWe also explore the value of agents to improve vascular perfusion in protecting cognitive function and tissue integrity.

Dr. Zhiyuan (Helen)ÌýYang, PhD
Prof. Kenneth Smith, PhD

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