CHBRI Wound Healing Laboratory

Group Leader
Dr Rachael Z Murray,
Head CHBRI Wound Healing Laboratory/NH&MRC RD Wright Fellow
Phone: +61 02 98453101
Email: rachaelm@chw.edu.au

Dr Murray's laboratory was established in November 2006 as a laboratory research arm of CHBRI.

Current Research Program of the Wound Healing Laboratory

Four million patients acquire burn scars each year in the developed world, of these 70 % occur in young children. At the Children's Hospital at Westmead alone 1000 children are seen each year with burns. Burns often leave patients with scars covering much of their body. Scarring may be aesthetically disfiguring, is frequently painful and may be functionally disabling such as scar contractures. Burn treatment is often a long process and unfortunately as children are still growing and developing multiple painful surgeries may be required to release contractures until they reach adulthood. There are no licensed therapeutics in clinical use proven to reduce scars. Current clinical practice to reduce scarring in burns patients involves mainly painful mechanical intervention for these patients such as pressure bandages, or surgical intervention using skin grafts. New healing therapies need to be developed to reduce these painful scars and ensure a happy normal childhood for these children.

The aim of our research is to cut down the time it takes for a burn to heal and therefore reduce the subsequent scarring; minimising the length of hospitalisation, surgeries, costs, disfigurement, functional disabilities and emotional burden of the burns patients. Wounds that heal more rapidly tend to have an improved outcome in terms of scaring, contracture and overall cosmetic result. The healing of skin is a complex process and is generally accompanied by a robust inflammatory response. The selective influx of macrophages into and their persistence in the wound dictate the extent of inflammation during wound healing where excess and ongoing inflammation lengthens healing time resulting in increased scarring, contracture and reduced overall cosmetic results. Mice that lack macrophages have been shown to heal faster with reduced scarring. We are identifying how, if and when would be a good time to decrease the number of macrophages in a wound to reduce scaring without affecting the over healing process..

Key Wound Healing Laboratory research questions

• Which integrins are responsible for macrophage migration and adherence in a burn wound?
• How are integrins delivered to the leading edge of a macrophage to regulate migration/adhesion in a wound?
• Where does the extra membrane required for migration come from?
• Can we dampened down inflammation in the wound by reducing the number of macrophages and will this reduce scarring?

We are uniquely positioned in this clinical environment to answer these questions with access debrided skin samples from burns patient through the Burns Unit. We purify primary macrophages from these samples and use cell lines for our research.

Major achievements of the Wound Healing Laboratory

The CHBRI Wound Healing Laboratory was established in November 2006 and after equipping the laboratory research has focused on macrophage migration and adhesion. We have established a method to separate macrophages from blood and skin debrided from burn patients and have identified the specific integrins upregulated in macrophages purified from debrided skin by comparing these macrophages to those found in the same patients' blood. We have also looked at how these integrins are transported to the cell surface to allow the macrophages to adhere and migrate around the wound.

Key publications with comments on their significance

Stow JL, Manderson, A, Murray RZ. 2006 SNAREing immunity. Nat. Rev. Imm. 12, 919-20. IF = 30.458, citations = 14. This publication is an invited review on the mapping of important trafficking/secretory pathways in immune cells using SNARE proteins.

Kay JG, Murray RZ, Pagan JK, Stow JL. 2006 Cytokine secretion via cholesterol-rich lipid raft-associated SNAREs at the phagocytic cup. J. Biol. Chem. 281, 11949-54. IF = 6.482, citations = 14. This publication shows that the relocation of syntaxin 4 into lipid rafts in the phagocytic cup in macrophages is a critical and rate-limiting step in initiating an effective immune response.

Murray RZ, Kay JG, Sangermani DG, Stow JL. 2005 A role for the phagosome in cytokine secretion. Science, 310, 1492-5. IF = 31.853, citations = 33. This paper identified a joint trafficking pathway in macrophages that links cytokine secretion and phagocytosis. It showed that TNF is trafficked via the recycling endosome, where the SNARE protein VAMP3 mediates its delivery to the cell surface at the site of phagocytic cup formation. Fusion of the RE at the cup simultaneously allows rapid release of TNF and provides the excess membrane required for phagocytosis, economizing on membrane transport and augment the immune response. This paper was deemed important in the field and was one of three papers published in advance on line in Science Express and was highlighted in the December issue of Nature Reviews Immunology.

Murray RZ, Wylie FG, Khromykh T, Hume DA, and Stow JL. 2005. Syntaxin 6 and Vti1b form a novel SNARE complex, which is upregulated in activated macrophages to facilitate exocytosis of TNFa. J. Biol. Chem. 280, 10478-83 IF = 6.482, citations = 18. This paper identified a novel SNARE complex, upregulated in LPS-activated macrophages, that mediates and is rate-limiting for the initial post-Golgi step in TNF trafficking and its subsequent secretion.

Research Staff

Staff Position Qualifications Ruby Estrella Research Officer PhD, BSc (Hons) Kelly Veale Research Assistant BSc Hons Shane Whittaker Research Assistant BSc Hons

Research Support

In the 18 months that laboratory has been established we have received:

Granting Agency Grant Type Total NH&MRC Project grant 2008-2010 $416,625 NM&MRC RD Wright Biomedical Career Development Award, 2007-2011 $445,000 University of Sydney Research Fellow Establishment Grant 2008 $20,000 Burns Trust Fund/ Children's Hospital Burns Research Institute Start up funding 2006-2010 $500,000

Opportunities for Students

Postgraduate Research available at the University of Sydney