Celebrating 20 years ANNUAL REPORT 2010 - SCIENTIFIC SUPPLEMENT PRINCIPAL PARTNER Contents Cell Biology ............................................................................2 Children’s Leukaemia and Cancer Research .........................8 Drug Discovery ..................................................................... 18 Genetics and Health ............................................................. 21 Inflammation ........................................................................ 27 Lung Growth and Respiratory Environmental Health .......... 30 Molecular Biotechnology ...................................................... 35 Paediatric Respiratory Physiology ....................................... 37 Population Sciences ............................................................. 40 Vaccine Trials Group ............................................................. 96 Publications ........................................................................ 107 2 • TELETHON INSTITUTE FOR CHILD HEALTH RESEARCH 2010 TELETHON INSTITUTE FOR CHILD HEALTH RESEARCH 2010 • 1 Throughout the past year, the Telethon Institute for Child Health Research has celebrated 20 years of service to improve and promote the health and wellbeing of all children through the unique application of multidisciplinary research. From humble beginnings in the renovated nursing school at Princess Margaret Hospital, it is now the largest medical research facility in Western Australia, and one of the most significant in the nation. Independent and not-for-profit, the Institute is home to more than 500 staff and postgraduate students and in the past year generated more than $30 million in research funding. This report not only outlines the highlights from the past year, but achievements over the 20 year period. It shows how Institute researchers have made significant discoveries and influenced policy to bring about substantial improvements in health and wellbeing for children in Australia and around the world. Our Mission To improve and to promote the health and wellbeing of all children through the unique application of multidisciplinary research. Our Aims • to conduct high quality research • to apply research findings to improve the health of children, adolescents and families • to teach the next generation of health researchers • to be an advocate for research and for children TELETHON INSTITUTE FOR CHILD HEALTH RESEARCH 2010 • 1 Cell Biology Overview Aetiology and pathogenesis of atopy and are collecting similar prospective data on atopy, infections and asthma risk in children, with the long-term aim of developing Our research continues to focus upon the mechanisms asthma an internationally applicable diagnostic tool for use in this underlying susceptibility versus resistance to respiratory context. Assessing risk for asthma development amongst infections and allergic diseases during childhood, and in INFANTS particular how these mechanisms interact to drive asthma P.G. Holt, J. Rowe, M. kusel, F. Parsons, E.M. Hollams, A. pathogenesis. Our long-term goal is to utilize this information TH2-associated immunity to mucosal dwelling Bosco, k.L. Mckenna, L. Subrata, N.H. de klerk, M. Serralha, to guide the development and testing of preventative bacteria in children B.J. Holt, G. Zhang, R. Loh(2), S. Ahlstedt(1), P.D. Sly treatments for asthma in early childhood, before the disease E.M. Hollams, B. Hales, C. Bachert(1), W. Huvenne(1), F. (1)karolinska Institute, Sweden, (2)Princess Margaret consolidates into its persistent form. In addition, we are Parsons, N.H. de klerk, M. Serralha, B.J. Holt, S. Ahlstedt(2), Hospital, West Perth expanding our research into the mechanisms underlying acute W.R. Thomas, P.D. Sly, P.G. Holt. severe asthma attacks in children with established asthma, in A series of studies from our group have established the (1)Ghent University Hospital, Belgium; (2)karolinska Institute, particular how virus infections harness allergic responses to important principle that asthma is potentially a preventable Sweden. aid them in escaping attack by antimicrobial defences. We are disease, if appropriate treatments can be instituted in its Recent indirect evidence has linked bacterial colonization continuing our research in areas related to pediatric vaccines, early stages during which long-term patterns of asthma- of the airways with increased risk for childhood asthma. particularly those which protect against respiratory infections. associated lung funtion(s) are “programmed” irreversibly in Possibly related to this, IgE against bacterial antigens has A unifying theme in this research stems from our earlier young children. A crucial requirement for such intervention been reported in some asthmatics, suggesting a role for findings that risk for development of allergy, respiratory treatments is development of robust methods for early bacterial-specific Th2 immunity in disease pathogenesis. infections and asthma is determined primarily by factors identification of “at risk” infants and preschoolers who are We have recently investigated the relationship between which control the functional maturation of the immune system on the trajectory towards asthma development . Our recent IgE against S. aureus-specific antigens versus IgE against during early childhood. In particular we have shown that a studies have identified two major risk factors for asthma antigens from H. influenzae and S. pneumoniae and asthma variety of the cellular immune effector mechanisms which development: expression of the atopic phenotype during susceptibility amongst 14-year-olds from the W.A. Pregnancy are suppressed in utero in order to protect the placenta from the first two years of life as evidenced by production of IgE Cohort. Our findings demonstrate that IgE titres against S. inflammatory damage are vital for protection against both against aeroallergens, and concomitant lower respiratory aureus-derived superantigens are highest amongst atopics infections and allergy during infancy, and the speed of their tract infections associated with fever or wheeze. Importantly, and are associated with risk for asthma, rhinoconjunctivitis functional maturation during the preschool years is retarded these risk factors interact quantitatively, and we have devised and eczema. In contrast, IgE against cell-surface antigens in children from families with a history of allergic diseases. An objective methodology for assessing these interactions. A from H. influenzae and S. pneumoniae is associated with important complementary stream of research in our Division key finding in this regard is that levels of aeroallergen- diminished risk, particularly for asthma. We hypothesise that involves animal model studies on immunoregulation of the cell specific IgE below the conventional sensitization threshold these “protective” IgE responses are a surrogate marker of populations responsible for triggering T-lymphocyte activation (0.35kU/L) are associated with asthma risk, if they are present underlying Th2 immunity in which the key elements are IL-4 in the airway mucosa during the “late phase response” in at the time these early infections occur. In principle, armed and IL-13, which function to suppress activation of phagocytic asthma. The main focus of this aspect of our research is on with information on the number of lower respiratory tract cells in airway tissues in response to exposure to membrane interactions between T-regulatory cells and the network infections accounted during the first two years of life, and associated TLR ligands present on the organisms during viral of airway mucosal Dendritic Cells which are responsible aeroallergen-specific serum IgE titres at age two, it is possible induced asthma exacerbations, resulting from a breakdown for immune surveillance in the respiratory tract. We are to objectively categorise individual children as low versus of local mucosal barrier functions. Ongoing research is additionally expanding this experimental area to encompass high asthma risk which in turn determines their suitability as investigating in more detail the relationship between the viral infections and how these interact with and exploit allergic subjects for potential enrolment in asthma prevention trials. presence of these different clans of organisms in the upper inflammatory mechanisms. We are exending these studies with colleagues in the US who 2 • TELETHON INSTITUTE FOR CHILD HEALTH RESEARCH 2010 TELETHON INSTITUTE FOR CHILD HEALTH RESEARCH 2010 • 3 airways during early childhood and risk for subsequent at the Ramaciotti Centre at UNSW, using a high-throughput measured at both ages for 693 participants. Low vitamin D asthma development. Roche 454 GS FLX Titanium genome sequencer system. Our at age 6 was again associated with increased risk of current ultimate aim is to track the changes in bacterial colonisation BHR and allergy. Further regression analyses showed that This work is funded by the National Health and Medical throughout childhood within the cohort, to examine how this is low vitamin D at age 6 increased risk of current asthma, Research Council of Australia. affected by recurrent respiratory infection, and to determine rhinoconjunctivitis, BHR and allergic sensitization at age 14. the relationships between the composition of upper airways We are in the process of extending these studies into younger bacterial flora and risk for asthma development in childhood. age groups, with the particular aim of assessing the impact of Characterisation of