Cole Lab research
About Associate Professor Tim Cole
Bachelor of Science (Hons), University of Melbourne, 1982; Doctor of Philosophy (PhD), University of Melbourne, 1987. Associate Professor Cole has a tenured academic position at the Department of Biochemistry & Molecular Biology, Monash University (Melbourne). He is currently the Deputy Head of Department and he leads a medical research group investigating cell signalling pathways important for mammalian respiratory development and function. He is currently on the Council of the Endocrine Society of Australia as the President of the Society, a member of the US Endocrine Society and was on the editorial board of the journal Endocrinology, 2008-2012.
- Glucocorticoid-regulated pathways in the preterm infant and the development of Selective Glucocorticoid Receptor (GR) Modulators (SGRMs) to treat prematurity.
- Steroid metabolising enzymes: Hydroxysteroid dehydrogenases, PPARg, DHRS7 and human cancer.
- Analysis of genomic versus non-genomic effects of Mineralocorticoid Receptor-mediated cell signalling in vivo using mouse mutant models.
Visit Associate Professor Cole’s Monash research profile to see a full listing of current projects.
The endocrine system controls cell-cell communication and coordinates almost all our daily activities. Abnormalities in hormones, receptors and cell signalling pathways underpin many common diseases such as diabetes, high blood pressure and obesity. We are studying the actions of two important steroid hormones, cortisol (a glucocorticoid) and aldosterone (a mineralocorticoid) that are secreted by the adrenal gland and regulate important aspects of systemic physiology and homeostasis, in humans and other mammals. Cortisol has many homeostatic roles in a wide range of tissues both during embryogenesis, particularly the developing lung. Premature babies have underdeveloped lungs and require treatment with synthetic glucocorticoids. Glucocorticoids exert their effects by binding to the intracellular glucocorticoid and mineralocorticoid receptors, GR and MR respectively. Both are members of the nuclear receptor super-family of ligand dependent nuclear transcriptional regulators. We utilize a range of molecular, biochemical and genetic techniques in both cell-based and animal systems to investigate these cell signalling pathways and their specific roles.
Cortisol has many homeostatic roles in a wide range of tissues both during embryogenesis, particularly the developing lung. Premature babies have underdeveloped lungs and require treatment with synthetic glucocorticoids. Glucocorticoids exert their effects by binding to the intracellular glucocorticoid and mineralocorticoid receptors, GR and MR respectively. Both are members of the nuclear receptor super-family of ligand dependent nuclear transcriptional regulators. Research projects below will utilize a range of molecular, biochemical and genetic techniques in both cell-based and animal systems to investigate these cell signalling pathways and their specific roles.
Basic research area
Steroids and other endocrine hormones help to maintain the normal operation of the organs and tissue systems of the human body. Their inappropriate action can lead to common adult human diseases such as hypertension, heart failure, metabolic syndromes and even cancer. Steroid hormones exert their effects through intracellular protein receptors that specifically bind the steroid ligand and are members of the nuclear receptor superfamily of ligand-dependent gene regulators or transcription factors. We are studying their signalling pathways in the developing lung (this organ is underdeveloped in very preterm babies), the liver, the immune system (leukaemia) and the brain (depression), utilising a range of molecular, cellular and animal-based approaches. We are also studying their potential use in stem-cell based respiratory therapeutics for treatment of a range of lung-related diseases. The development of lung-like cells would be a major advance for the treatment of injured lungs both in preterm babies and in adults with respiratory diseases. Specific projects are outlined below and the lab will take research students at the Honours, Masters and PhD level.
Specific Research Project Areas
1. Dissecting steroid and growth factor cell signalling pathways in the developing lung in vivo; mouse models of respiratory dysfunction:
We are investigating the role of steroid and growth factor signalling pathways using mouse models that lack various genetic components of these pathways. These gene-targeted mice lack functional receptors or enzymes and exhibit a range of phenotypes. We are studying mouse lacking the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), the Creb1 transcription factor and the enzyme 11bHSD1. We have shown that mice lacking GR die during the perinatal period due to retarded lung development. To dissect the cell types responsible we have targeted mice for deletion of the GR gene using the Cre recombinase/LoxP system in mice and have compared respiratory phenotypes for mice lacking GR in epithelial cells, the mesenchyme and endothelial cells (see Figures 1 & 2).
Projects continue to study these lines of mice to describe the specific phenotypes. This is also continuing for mice specifically lacking the Creb1 transcription factor in the lung and for mice with a targeted mutation in the 11bHSD1 gene. This enzyme is strongly expressed in specific cells in the fetal lung (Figure 3).
Figure 3: E18.5 fetal mouse lung. Left: 11b-HSD1 expressed in conducting airway epithelium. Right: 11b-HSD1 expressed in a cell layer surrounding specific large blood vessels
2. Dissecting cell-specific steroid actions in the developing mouse lung:
With the use of primary cell cultures of rat lung fibroblasts and lung epithelial cells we are investigating the cell signalling pathway of different steroids in the lung. We are comparing effects of endogenous steroids versus synthetic steroids to try to understand how the clinically important steroids betamethasone and dexamethasone work on the developing human lung near birth. We will also trial various new selective steroid agonists when they become available.
3. Stem cell repair of lung injury from hyperoxia:
Very preterm babies are given various levels of oxygen therapy at birth to help provide appropriate gas exchange. High levels of oxygen (40%-100%) can promote long-term lung damage due to the effects of hyperoxia. To study the specific effects of high oxygen or hyperoxia in the developing lung we are using a mouse model of hyperoxia (90% oxygen for four days) to study the damage caused to the lung and follow pups to 7 weeks of age. We are trialling a number of specific stem cell populations to see if injection of these stem cells after hyperoxia is able to restore normal lung structure and function to new-born mice.
4. Dissecting Mineralocorticoid Receptor (MR) actions in vivo:
The mineralocorticoid receptor mediates the action of both aldosterone and glucocorticoids depending on the cell type and also the intracellular presence of the pre-receptor steroid modification enzymes 11bHSD1 (activating glucocorticoids) or 11bHSD2 (inactivating glucocorticoids and thereby conferring aldosterone specificity). We are studying the MR in vivo with a number of gene-targeted mutations in the mouse MR gene. This is a collaboration with the research groups of Prof Peter Fuller and Dr Morag Young at the Hudson Institute, Monash Medical Centre, Clayton.
5. The 11bHydroxysteroid Dehydrogenase (11bHSD) family of steroid modification enzymes and the SDRs in Cancer:
The two steroid modification enzymes 11bHSD1 and 11bHSD2 are members of the superfamily of short-chain alcohol dehydrogenases, which has 14 members. We are investigating the role 11bHSD1 plays in the mouse lung via the use of a conditional gene-targeted allele for the mouse HSD1 gene. We are also studying a new HSD enzyme, tentatively termed ‘HSD3' that may play a role in very specific organs such as the brain, and may be a useful marker in cancer cells where it is up-regulated.
We use an array of molecular, cellular and in vivo animal models to investigate basic cellular mechanism and their relation to the cause of human disease.
We use cell based models in culture and in vivo mouse models that contain specific mutations in the mouse genome.
We collaborate with many scientists and research organisations around the world. Click on the map to see the details for each of these collaborators (dive into specific publications and outputs by clicking on the dots).
Student research projects
The Cole Lab offers a variety of Honours, Masters and PhD projects for students interested in joining our group. There are also a number of short term research opportunities available.
Please visit Supervisor Connect to explore the projects currently available in our Lab.