At the interface of translational research for glucose-regulation in children

Congenital hyperinsulinism is the single most common cause of hypoglycaemia in the newborn. Although relatively uncommon, this disease has serious and lifelong morbidities for affected children, and causes neurological problems in a significant proportion of patients. The genetic basis of this condition is not known in more than 50% of patients. In those patients where genotyping has been successful, many of the identified genes cause or are associated with the mirror condition– diabetes, see figure. The Royal Manchester Children's Hospital is one of two national treatment centres for congenital hyperinsulinism and research within this the Faculty of Life Sciences is making important advances in this area.

Hypoglycaemia as a consequence of hyperinsulinsm is a troublesome medical condition to treat since not only is the brain deprived of both its primary and secondary energy sources (glucose and ketone bodies), but the normal physiological mechanisms responsible for preserving blood glucose levels through glucagon counter-regulatory hormone responses to hypoglycaemia are lost. The cornerstone of medical therapy is diazoxide which normally inhibits insulin release through the activation of ATP-sensitive potassium channels. However, diazoxide is ineffective in patients with severe disease as these channels are defective; it is poorly tolerated by a significant proportion of patients and causes adverse effects such as hypertrichosis and fluid retention, and may lead to cardiac failure. Somatostatin analogues are widely used “off-label”, but they also have adverse effects such as feeding intolerance and necrotising enterocolitis, and are commonly associated with tachyphylaxis. Thus, for patients intolerant or poorly tolerant to medical therapy, without an advanced understanding of the mechanisms of disease, the only option to prevent hypoglycaemia-induced brain injury is a curative pancreatectomy. For many patients this involves a 95% to near total pancreatectomy. Not only is this a complicated and expensive procedure, but it will also cause iatrogenic diabetes mellitus in up to 90% of cases.

The Cosgrove and Dunne research groups are working with colleagues in the Royal Manchester Children's Hospital to better understanding of the causes and pathogenesis of CHI which will lead to improved, earlier detection of disease, personalized treatment options in order to limit adverse neurological developmental consequences, and provide opportunities to develop new or adjunct therapeutics to control unregulated insulin release and alleviate hypoglycaemia. Examples of our translational research have been the staging of an NHS-funded pilot clinical trial to examine the potential of highly purified fish-oil as an adjunct therapy (due to end in December 2012) and to establish how measurements of serum peptide levels can be used to diagnose non-typical forms of CHI for which there is no genetic basis of disease.

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Physiological Systems and Disease research group.

Oxidative stress promotes prion formation

Prions are novel protein-only infectious agents associated with a group of transmissible neurodegenerative diseases typified by human Creutzfeldt Jakob Disease (CJD). Although CJD is a rare disease, it shares many pathological features with other more common, non-infectious diseases of the brain such as Alzheimer’s Disease. In spite of its infectious nature, the majority of cases of human CJD (~80%) are sporadic i.e. they are not caused by any detectable underlying genetic change. The molecular basis of how prions form spontaneously into infectious amyloid-like structures is poorly understood at present. Chris Grant in the Gene Regulation and Cellular Biotechnology group at The University of Manchester in collaboration with Professor Mick Tuite at the University of Kent are using the baker's yeast Saccharomyces cerevisiae as a model organism to study how prions form spontaneously.

Their studies have focussed on one yeast prion called [PSI+], the prion form of a normal cellular protein called Sup35, as a model to identify what triggers the spontaneous formation of a prion in the cell. Their studies have shown that the formation of [PSI+] is increased when cells lack the peroxiredoxin proteins Tsa1 and Tsa2. Peroxiredoxins play multiple roles in protecting against stress, including acting as antioxidants and suppressing potential harmful oxidative damage to proteins following oxidative stress. These important new findings strongly implicate oxidative damage of Sup35 as an important trigger for the formation of the heritable [PSI+] prion in yeast. Interestingly, oxidative damage has also been implicated in the de novo formation of mammalian prions and as a trigger for other protein misfolding diseases of man. More recent studies have established that direct oxidation of the Sup35 protein by hydrogen peroxide leads to structural transitions favouring conversion to the transmissible [PSI+] form and hence plays a role in the mechanism of induction of de novo prion formation. These studies using a simple model organism are likely to have wider implications for our understanding of the de novo formation of infectious amyloids in mammalian diseases such as CJD.

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Gene Regulation and Cellular Biotechnology research group.

Mosaic brain evolution: the whole story

The mammalian brain consists of many distinct parts such as the neocortex, cerebellum and olfactory bulb that fulfil different functions. The size of these parts varies across and within species and also in relation to body size. This leads to fundamental questions on how the evolution of the brain takes place: first, can different brain parts evolve independently from each other and overall brain size in a mosaic, adaptive fashion or is brain evolution developmentally constrained and occuring in a concerted way as argued by Finlay and Darlington in their highly influential research published in Science in 1995? Second, can overall brain size evolve independently of body size, suggesting that the relatively large brain found in vertebrates is due to an increase in brain size rather than a change in body size? To date only comparative studies have addressed these questions from a macro-evolutionary perspective with support for both mosaic and concerted scenarios. These questions, however, remain untested at a micro-evolutionary level even though fundamentally macro-evolutionary patterns arise through micro-evolutionary changes.

Reinmar Hager in the Computational and Evolutionary Biology group at The University of Manchester with collaborators in the USA have recently provided new insights in this area of research. Their study of over 10,000 mice from the largest genetic model system (BXD mice) has found for the first time evidence in mammals in support of a mosaic mechanism of brain evolution. Importantly, they find independent genetic loci for size variation in seven functionally different brain parts and low to absent phenotypic correlation among brain parts. Further, their results demonstrate that overall brain size is independently regulated from overall body size, despite intermediate phenotypic correlation between the two. These results show that selection on the size of functionally different brain parts can result in size changes in each of the brain parts, independent of apparent constraints on other parts or overall brain size, despite the allometric relations shown by Finlay and Darlington. Strikingly, Reinmar and collaborators find no evidence for genetic constraints that may impede a mosaic response to selection in the different brain parts or between body and overall brain size.

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Nature Communications paper: Genetic architecture supports mosaic brain evolution and independent brain-body size regulation. Hager R, Lu L, Rosen GD, Williams RW. Nat Commun. 2012 Sep 25;3:1079. doi: 10.1038/ncomms2086.

Computational and Evolutionary Biology research group.

Connecting the brain using microRNAs

The brain is made up fundamentally by neurons, and for the brain to function neurons need to connect with each other forming neuronal circuits. In our lifetime, the ability to think, move or sense depends on the correct formation and subtle changes of such neuronal circuits and their billions of connections. This connectivity depends on the extension of long, thin, cable-like processes called axons, which are essentially the “wiring” of the neuronal circuits.

Although the pattern of neuronal circuits in our brain looks very complex, connections between neurons follow a stereotypical and reproducible master plan. In fact, neurons, or rather their axons, can travel great distances in order to connect with the right partner or target. Once they do so, they stop growing and branch out to form connections or synapses. To get an idea of how long an axon may have to grow before it finds its target, one can scale a neuron to the size of a human body and then imagine the complexities of growing an arm a kilometer long! The way axons grow longer is from their free end, or “distal tip” and they do so by locally assembling new material from cellular skeletal components.

While the axons are such amazing self-assembling structures, they are also quite delicate and a number of neurodegenerative diseases are due to the break down of the connective circuits they form. In addition, nerve regeneration relies on the ability of neurons to re-grow axons towards their normal targets. Hence, scientists are very interested in understanding how the growth and branching of axons is regulated.

Investigators at The University of Manchester have now identified a novel way to regulate both the lengthening of axons and their branching. The work recently published in Nature Neuroscience describes how a small regulatory molecule (a microRNA) is able to control the synthesis of a protein that stabilizes the microtubule scaffold of the axon. Like a cane supporting the growth of a plant, this protein can sustain and foster the growth of axons in the nervous system. As a result, controlling the levels of microRNAs can make the axonal cables that connect brain neurons grow, or stop. Neurons regulate these processes according to their environment; however, being able to control these events by adding or taking away this microRNA opens up huge possibilities for manipulating axonal development. Due to their small size and comparatively easier delivery methods, microRNAs are being considered as potentially successful strategies for clinical trials. Although we are still far from applying this knowledge to human disease, one can see how being able to support axonal growth can have potentially beneficial effects in helping neuronal regeneration or halting the progression of some neurodegenerative diseases. Who knows, but manipulating the levels of these microRNAs could allow us to finely tune the way we make, trim or strengthen our neuronal circuits.

Read more about related research:

Nature paper: microRNA-9 regulates axon extension and branching by targeting Map1b in mouse cortical neurons
Developmental Biology research group.