Head

Professor Angel Lopez

Address	Division of Human Immunology Institute of Medical and Veterinary Science Frome Road, Adelaide SA 5000, Australia
Phone	+61 8 8222 3483
Fax	+61 8 8232 4092
Email	Angel.Lopez@imvs.sa.gov.au

Lab Members

Research Interests

The elucidation of the molecular mechanisms involved may permit the specific targeting of this pathway in conditions such as leukaemia where inappropriate survival of leukaemic cells frustrates current forms of therapy.

CURRENT RESEARCH PROJECTS  (July 2008)

• Solving the structure of cytokine : cytokine receptor complexes

In collaboration with the laboratory of Professor Michael Parker (St Vincent's Institute of Medical Research, Melbourne), we are seeking to determine the 3-D structure of the GM-CSF complexed to its receptor. This information will be utilized to understand how the GM-CSF signals and for the rational design of novel receptor agonists and antagonists.

• Characterizing the "survival-only pathway" triggered by GM-CSF

We are currently mapping the molecular events involved in GM-CSF-mediated stimulation of cell survival. We are following on from our discovery that nM concentrations of cytokine leads to serine phosphorylation of the receptor, 14-3-3 recruitment and activation of "cell survival-only" to map in detail this novel signaling pathway (in collaboration with Paul Ekert, Royal Children's Hospital, Melbourne). The Cytokine Receptor Laboratory investigates the mechanisms by which cytokines such as GM-CSF, IL-3 and IL-5 engage their receptors leading to the activation of multiple biological functions. The overall aim is to discover novel paradigms in cytokine signaling and use these insight in the development of novel therapeutics.

• Determining the composition and the spatial and temporal organization of cytokine receptor signosomes

Cytokine receptor signaling resulting in multiple biological activities is a complex process that involves the recruitment of distinct signaling molecules and their assembly into a functional signosome. We are studying the molecular determinants of these interactions and their regulation by cytokine concentrations and duration of stimulation. Defining how cytokine receptor signaling is organized should help understand the molecular basis of pleiotropy and specificity.

• Targeting leukaemic stem cells

Low cycling self-renewing leukaemic stem cells represent a major impediment to long lasting therapies for many types of leukaemia. We have developed a unique antibody that targets the IL-3 receptor a chain which is over-expressed in leukaemic progenitor cells, and we are assessing its activity on stem cell function. In parallel, we are investigating the role of the
IL-3Ra chain itself on stem cell biological activities and the underlying mechanisms that control its expression.

• Role of 14-3-3 proteins in cell signaling

We have previously shown that 14-3-3 proteins directly couple cytokine receptors to distinct signaling complex that regulate key biological functions such as cell survival. In an effort to understand the global role of the 14-3-3 family of proteins, we have now knocked out 14-3-3 zeta in mice and we are studying the role of this protein in vitro and in vivo.

• Mast cells as negative regulators of immunity and inflammation

Mast cells have long been recognized as active participants of the allergic response at specific sites. Whether in the skin or the lung, the binding and cross-linking of IgE on the surface of mast cells stimulate the release of inflammatory mediators that exacerbate the allergic response. However, our recent data (Grimbaldeston et al, 2007) indicates that mast cells can also dampen the allergic response. This unexpected new role of mast cells is mediated by IL-10. Current experiments are exploring the underlying regulation of IL-10 production in mast cells and stimuli other than IgE cross-linking that lead to IL-10 production.

Recent Publications