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Marsden grants to advance novel medical research

4 November 2014

Marsden grants to advance novel medical research

Novel medical research projects for personalised cancer, treating skin inflammation, diabetes’ impact on the heart, and creating neural bridges in pharmacology were the recipients of Marsden Grants worth $2.16 million this week.

The result was about the same as last year in a tough funding round, says the Associate Dean for Research, Associate Professor Andrew Shelling at the University of Auckland’s Faculty of Medical and Health Sciences.
Overall the University had 28 research projects funded from Marsden grants, totalling $15,215,000 with a funded success rate, of 8.80 percent and 27.3 percent of the total funding available this round.

The four grants are;

Professor Bill Wilson
Auckland Cancer Society Research Centre, FMHS
An insect jumping gene to guide personalised cancer medicine
$805,000

Senior Research Fellow, Dr Chris Hall
Molecular Medicine and Pathology, FMHS
Treating cutaneous inflammation by putting skin on a fat-free diet
$755,000

Lecturer, Dr Kim Mellor
Department of Physiology, FMHS
Diabetic heart pathology: is it all about the glycogen?
$300,000

Lecturer, Dr Darren Svirskis
School of Pharmacy, FMHS
Creating neural bridges: a conducting polymer neurotransmitter releasing system
$300,000

Professor Bill Wilson says the $805,000 Marsden Grant is for three years. The team of researchers that will be working on this at the Faculty includes Associate Professor Cris Print, Professor Stefan Bohlander, Dr Francis Hunter and PhD student Naveen Joshi. The project also includes Professor Richard Lock at the Lowy Cancer Research Centre at the University of New South Wales.

“The research addresses the urgent need for biomarkers that will help us to match specific drugs to specific cancers for personalised cancer medicine,” says Professor Wilson.

He says the approach dates back to work on ‘jumping genes’ (transposons) by Barbara McClintock in maize in the 1940s and 1950s, which was eventually recognised through a Nobel prize in 1983.

“We are using a transposon that was first discovered in an insect virus and has recently been shown to work efficiently in human cells,” he says. “It can be used to change expression of genes in cancer cells that control sensitivity to anticancer drugs.”

“Our specific objective is to identify genes that make leukaemia cells sensitive to the experimental drug PR-104, which was discovered at the Auckland Cancer Society Research Centre.”

Although the title of the grant refers to transposons only, they intend also to make use of a complementary technology for gene discovery called CRISPR/Cas. The essential genetic elements are derived from a bacterial adaptive immunity system, and can be used to make targeted disrupting mutations in human cancer cells.

“We will use CRISPR/Cas to make ‘libraries’ in which each individual cancer cell carries a mutation inactivating one of the approximately 20,000 known human genes,” says Professor Wilson. “The genes that confer drug resistance when knocked out will then be identified by determining which CRISPR sequences are over-represented in the population of surviving cancer cells.”

*********************

“I’m thrilled to have received what is my first major grant,” says Senior Research Fellow, Dr Chris Hall who has gained a Marsden grant for $755,000 over the next three years. He works with Professors Phil and Cathy Crosier in Molecular Medicine and says other researchers involved in the project include honorary senior researcher, Dr Kevin Sun and senior research technician, Lisa Lawrence.

“There will also be a contribution from Associate Professor Marius Rademaker who will provide a clinical advisory role,” says Chris. “Dr Rademaker is an honorary professor at the Waikato Clinical School and the clinical director of the dermatology unit for the Waikato DHB. He is an expert in inflammatory dermatoses and will provide valuable clinical insights throughout all aspects of this project.”

The research project investigates the persistent, damaging and inappropriate accumulation of immune cells within the skin that contributes to increasingly prevalent inflammatory dermatoses like atopic dermatitis and psoriasis.

“Understanding what regulates this immune response is fundamental to designing new therapies to
treat inflammatory dermatoses,” says Chris. “It is now well-recognised that immune cell function is partly controlled through intrinsic metabolic processes (metabolic reprogramming).”

By live imaging epidermal cell metabolism during cutaneous inflammation, in transparent zebrafish embryos, the researchers have shown epidermal cells utilise fatty acid metabolism to ‘fuel’ immune cell accumulation.

“We propose inhibiting uptake and metabolism of fatty acids within epidermal cells, during skin inflammation, represents a new strategy to block/suppress the persistent immune response that underlies cutaneous inflammation,” he says.

“The objective of this research is to exploit these novel findings and identify drugs that suppress skin
inflammation by targeting this new pathway,” says Chris. “Importantly, understanding the mechanisms of action of identified drugs will provide an entry point to explore new pathways that modulate the metabolic-immunological interface within skin cells during inflammation.”

********************

Dr Kim Mellor, from the Department of Physiology has Marsden funding of $300,000 for a project that investigates why heart failure is common in diabetes.

As part of a worldwide diabetes epidemic, more than 200,000 New Zealanders are now diagnosed with the disease and Māori and Pacific Island populations are affected nearly twice as much as Pākehā.

“Diabetics have a greater (2.5-fold) risk of heart failure, but the reasons for this are poorly understood,” says Kim. “We know that people with diabetes have disturbed carbohydrate processing in heart muscle cells, which is associated with increased cell death.”

“The loss of functional cells makes the heart walls stiffer as the heart muscle is replaced by scar tissue. This may make it harder for the heart to pump blood around the body,” she says.

Previous studies of diabetic heart disease by Dr Mellor have demonstrated a role for excess ‘recycling’ of cell components in diabetes, and consequent cell death through a pathway called autophagy (‘self-eating’).

More recently, Dr Mellor and her colleagues have found a direct link between carbohydrate mishandling and autophagy activity.

Using a Marsden Fast-Start grant, Dr Mellor’s team will use gene manipulation techniques to target the mishandling of carbohydrate in a cardiac muscle cell culture system. They aim to find out whether disturbances in cellular processing of carbohydrate are an underlying reason for heart muscle cell death and heart dysfunction.

“Results of this research will increase understanding of how cell death contributes to diabetic heart failure. Ultimately, this project has the potential to identify new targets for therapies to prevent patients going into diabetic heart failure,” she says.

********************

“This grant validates our research ideas - we’ve convinced people it’s worth a go”, says Dr Darren Svirskis of the Marsden Grant awarded for work on creating neural bridges. “This will help reinforce interdisciplinary collaborations between the School of Pharmacy, the Centre for Brain Research and the School of Chemical Sciences.”

The $300,000 funding will support research costs for two PhD students, Zaid Aqrawe and Saiful Azmi, to work on parallel arms of the project.

Until now, conducting polymers (CPs) have been used to release bioactive molecules in response to non-biologically derived electrical triggers, says Dr Svirskis.

“We hypothesise that neurotransmitter loaded CPs can function as neural bridges, modifying neuronal action potential firing patterns and facilitating neuronal communication,” he says. “We propose to develop a glutamate releasing conducting polymer responsive to the intrinsic electrical activity of neurons.”

“The researchers will culture neurons together with CPs in vitro, forming neural bridges,” he says. “For the first time, we will study how action potentials in living neurons alter the properties of stimuli-responsive CPs.”

Using these neural bridges, they will determine if the firing of one neuron can trigger a CP to release a neurotransmitter and subsequently influence the firing rate of a second neuron. The data from this research will provide a platform to develop new treatment strategies for conditions of abnormal neuronal signalling, such as autism, epilepsy, nerve injuries and hereditary sensory impairments.

The methods developed in this research could be used to study and manipulate other electrically active cells such as those found in the heart and gastro-intestinal tract, says Dr Svirskis.

ENDS

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