Targeting a common pathway in neurodegeneration
Our studies on the CNS show that gap junctions regulate the neuroinflammatory response
and disrupt the positive feedback driven by activation of the inflammatory mediators
- astrocytes and microglia. This chronic neuroinflammation follows regardless
of the initial disease trigger. Connexin43 is upregulated in CNS injury and
plays a significant role in the spread of damage, the neuroinflammatory response
and accompanying oedema.
We are investigating the cell-specific expression of gap junction proteins in PD
human brains, since we believe that regulation of gap junction protein expression
and function may offer a potential treatment for the chronic inflammation characteristic
of neurodegenerative diseases of the brain.
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Identifying potential targets to halt the progression of Parkinson's disease
Oxidative stress, inflammation, glial cell activation and formation of neuronal
cell inclusion bodies (Lewy body) are implicated in the progressive cell loss in
PD but the mechanisms remain unknown. Oxidative stress accelerates the interaction
between carbohydrates and proteins, called glycation, resulting in the accumulation
of glycation products known as Advanced Glycation End products (AGEs). AGEs
can activate glial cells and exert harmful effects via the receptor for Advanced
Glycation End products, RAGE. RAGE is expressed on a number of cell types, including
glial cells and neurons. The AGE-RAGE interaction can lead to a number of
cytotoxic effects including inflammation. Inflammatory signals spread via
cell-to-cell connections called gap junctions.
We are investigating the complex interaction between neurons and glial cells involving
'cross talk' amongst AGE, RAGE, and connexin as critical pathway in progressive
cell death in Parkinson's disease.
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Regulation of cell to cell communication for spinal cord injury –
taking the next
step
Spinal cord injury results in a devastating loss of mobility for the victim. After
the initial injury, damage spreads, leading to a significant increase in the size
of the area affected. This damage spread is caused by transfer of neurotoxins from
the damage site to otherwise healthy tissue via intercellular channels called gap
junctions.
We aim to 'block' these channels at the time of injury, using small protein molecules,
in order to significantly reduce the damage spread. We believe this powerful new
approach will lead to significantly improved outcomes for spinal injury victims.
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Connexins as key players in neuronal differentiation
A major feature of many neurological disorders is the death of populations of neurons.
Replacing lost cells with new neurons - cell transplantation therapy - offers great
promise. We need to better understand the 'factors' that control neuronal
differentiation - how precursor cells transform into neurons.
The cells of the developing brain exhibit a whole array of different connexins as
they mature and changes in connexins are increasingly being seen as fundamental
to cellular processes.
We are investigating ways of controlling gap junction proteins expressed during
development to see if we can drive neuronal differentiation, with the goal of using
this technology as an approach to assist brain repair.
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The role of connexins in adult neurogenesis
The adult central nervous system contains
stem cells that differentiate into neurons throughout adult life. These cells migrate
to areas of the brain and spinal cord where cells are lost under normal conditions
or as a result of disease or injury. Connexins are involved in the generation and
migration of new neurons in the developing brain. We are investigating whether connexins
also play a similar role during neurogenesis in the normal or injured adult brain
and spinal cord.
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AGERs (AGE-receptors) in the activation of microglia by AGEs
Microglial activation is one of the main pathological hallmarks of Parkinson's disease
(PD) and contributes to neuronal dysfunction and cell loss seen in PD brains.
Microglia respond to several stimuli found in disease conditions, including accumulation
of Advanced Glycation End Products (AGEs). AGEs have been shown to activate microglia
via the receptor RAGE. Recently additional AGE-binding proteins (AGERs) have been
identified. We are investigating their presence on microglia in human glial
cells, and their contribution to microglia activation.
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The role of RAGE in neuronal differentiation
We have a long time interest in the role of RAGE and its ligands in disease processes,
including neurodegeneration. Differentiation of precursor cells into neurons
is critical for repair in neurodegenerative diseases. We are investigating
the role of RAGE and its ligand Amphoterin in the differentiation of precursor cells
into neurons as a potential regulator of differentiation.
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