Leukocyte Signalling Laboratory - Hibbs
Bottom L-R: Ms Cassandra Castelino, Associate Professor Margaret Hibbs, Ms Lakshanie Wickramasinghe, Dr Jess Borger
The Leukocyte Signalling Laboratory studies signalling pathways that play a role in immune system development, function and disease. The lab is particularly interested in the pathways and processes that become dysregulated in autoimmune and chronic inflammatory diseases. The chronic inflammatory diseases that are studied in our lab include lupus, inflammatory bowel disease, asthma and chronic obstructive pulmonary disease (COPD). These diseases are prevalent in Australia and are major contributors to morbidity and mortality amongst Australians. To aid our studies, we have developed unique experimental models and research analysis techniques, we have ready access to patient samples through established clinical links, and we utilise advanced research methodologies. We aim to identify key pathways or targets for therapeutic intervention, with an overarching goal to develop new ways to control inflammation and restrain chronic inflammatory disease progression.
Research Projects for Students
Identifying pathogenic signatures in inflammatory lung disease
We have recently developed novel immunophenotyping methods and have identified pathogenic signatures in the lungs of humans and mice with COPD. To expand on these new findings, we will perform transcriptome profiling on highly purified subsets of immune cells from mice with chronic lung disease and from mice with lung inflammation induced in response to cigarette smoke, virus, bacteria or hyperoxia. The student will utilise advanced flow cytometry and cell sorting procedures, next generation sequencing, and bioinformatics analyses.
Immune mechanism driving granulomatous inflammation in Crohn’s disease (with B Cell Differentiation Lab)
Crohn’s disease is a debilitating chronic auto-inflammatory disorder that affects the intestinal tract, with a peak onset in young adults. The aim of this project is to study processes in the immune system that become dysregulated during Crohn’s disease development, utilizing both clinical samples and tissues from genetically susceptible disease-bearing mice, which are uniquely available in our labs. The student will be exposed to basic and clinical research, and will apply state-of-the-art conventional and imaging flow cytometry with cell biology and histopathology.
Do lymphatic growth factors play an important role in the immune system?
Recent studies show that immune cells can produce vascular endothelial growth factors (VEGFs) and participate in inflammatory angiogenesis and lymphangiogenesis. Mice deficient in the lymphatic growth factor VEGF-D are protected from developing pulmonary oedema associated with hyperoxic acute lung injury but nothing is known about the function of VEGF-D in the immune system. The student will phenotype VEGF-D-deficient mice, applying sophisticated flow cytometry with in vivo challenge studies and histopathology to examine a possible role for VEGF-D in immune responses.
Defining mechanisms underlying pathogenic inflammation in lupus
The Lyn tyrosine kinase is a regulator of autoimmunity, and Lyn-deficient mice develop a lupus-like autoimmune disease with autoantibodies and immune complex-mediated glomerulonephritis. Mice harbouring a kinase-dead form of Lyn are autoimmune-prone but are largely protected from developing autoimmune disease due to reduced inflammation. The student will aim to define the mechanism underlying the important difference between these two highly related strains, using advanced biochemical approaches, in vivo challenge studies and gene profiling work.
Can diet limit the development of chronic inflammatory disease?
It is now appreciated that diet, a known a source of inflammation, can influence the development of autoimmune and inflammatory diseases. The aim of this project is to define how diet influences the development of chronic diseases such as lupus or COPD using genetically susceptible animal models. Mice will be fed different types of diet from either weaning or from time of disease diagnosis and the student will use advanced flow cytometry procedures, histopathological techniques, gene profiling approaches, and microbiome analyses to assess the efficacy of diet therapy.
Is G-CSF a pathogenic factor in lupus?
G-CSF is a growth factor that stimulates the production and function of neutrophils, and the release of stem cells from the bone marrow. Recent studies have shown that elevated levels of G-CSF are associated with certain chronic inflammatory diseases. The aim of this project will be to determine if G-CSF has a pathogenic role in the autoimmune disease lupus, which is characterised by chronic systemic inflammation. The student will fully characterise the phenotype of the Lyn-deficient lupus-prone strain where G-CSF has been knocked out using advanced flow cytometry, immunophenotyping and histopathology.
Are immunometabolic processes perturbed in chronic inflammatory disease?
It has become increasingly clear that immune cells can change their metabolic state in response to activation in order to meet their energy requirements, however much less is known about the metabolic condition of immune cells in disease settings. The aim of this project will be to investigate immunometabolic processes in immune cells from mice harbouring chronic inflammatory diseases. The student will be involved in immune cell purification, advanced biochemical methods and imaging flow cytometry.
Defining the factors underpinning steroid-insensitive asthma
Severe asthma is difficult to manage clinically since it is often insensitive to high dose corticosteroid treatment, with patients typically displaying neutrophil-rich inflammation. The aim of this project is to investigate how the immune system becomes dysregulated during disease development, utilizing experimental asthma models and genetically susceptible mice together with clinical samples. The student will be exposed to basic and clinical research, and will apply advanced flow cytometry, immunophenotyping and cytokine profiling with histopathology and lung function testing.
Are SHIP-1 deficient mice are model of Alzheimer’s disease? (In collaboration with Dr Bridgette Semple, Department of Neuroscience, CCS)
Recent genome-wide association studies have revealed that the gene encoding immune cell specific SHIP-1 phosphatase is a risk locus for Alzheimer’s disease. The aim of this project will be to examine the role of SHIP-1 in brain-resident immune cells. The student will examine whether SHIP-1 functions to antagonize microglial activation and determine whether SHIP-1-deficient mice represent a model of neuroinflammation. This will be an interdisciplinary project involving animal model studies, histological methods, immune cell purification, signalling work and advanced flow cytometry.
See Pubmed search, Hibbs ML [author]
- CASS Foundation Science/Medicine Award A strategy to treat the common deadly lung disease COPD (2017-2018)
- NHRMC Project Grant 1100099 Characterisation of emerging new signalling networks that underlie COPD (2016-2019)
- NHRMC Project Grant 1141208 G-CSF: a pathogenic effector in COPD and its comorbidities (2018-2021)
- NHRMC Project Grant 1147267 Dissecting the contribution of IL-17-producing γδ T cells in the pathogenesis of airway diseases (2018-2020)