The Therapeutic Technologies Research Initiative (TTRI) is focused on new applications of mechanopharmacology and organ-on-a-chip technology to transform drug-screening processes.
The Initiative has selected three Research Themes as initial areas of focus:
- Cell/Tissue/Organ-on-a-chip drug screening technology - Drug Evaluation.
- Cellular biomechanics - Mechanopharmacology.
- Stem cells and disease modelling.
2D --> 3D.
Plastic --> (patho)physiologically stiff matrix.
Static --> Dynamic mechanical input (shear/stress/strain/compression).
Seconds --> Minutes --> Days (chronicity).
Square wave concentration escalation --> Realistic pharmacokinetic profiling.
Mechanopharmacology is a discipline at the interface of biology and engineering examining the effects of physical forces on the response of cells, tissues and organs to drugs. Cellular mechanics strongly influences development, physiology and disease. New screening processes are needed to examine therapeutic candidates that target mechanosensing and/or cellular mechanical performance. The TTRI will bring together the expertise needed to achieve drug screening in microfluidic environments that are mechanically appropriate, with a focus on use of human cell culture.
TTRI Interdisciplinary Journal Club
The journal club runs every fourth Thursday of a month 12 pm – 1 pm in the meeting room N203, ground floor Medical Building. We discuss interdisciplinary reviews and high-impact papers in the area of TTRI research focus.
- 2017 TTRI Journal Club schedule:
Thursday 23 February, 12 – 1 pm. Daniel Heath, Department of Chemical and Biomolecular Engineering. Paper for discussion: Zhao et al. Engineered Tissue–Stent Biocomposites as Tracheal Replacements.
Thursday 23 March, 12 – 1 pm. Fred Hollande, Department of Pathology. Paper for discussion: Mohme et al. Optical Barcoding for Single-Clone Tracking to Study Tumor Heterogeneity.
Thursday 25 May, 12 – 1 pm. Cristiana Mattei, Centre for Neural Engineering. Paper for discussion: Birey et al. Assembly of functionally integrated human forebrain spheroids.
- 2016 TTRI Journal Club:
Thursday 25 August 12 – 1 pm. Alastair Stewart presenting Benam et al. Small airway-on-a-chip enables analysis of human lung inflammation and drug responses in vitro. Nature Methods, 2016.
Thursday 15 September 12 – 1 pm. Note, this is the third week of a month - the journal club is shifted due to room availability. Graham Mackay (Dept of Pharmacology and Therapeutics) presenting Dellinger et al. Inhibition of Inflammatory Arthritis Using Fullerene Nanomaterials. PLOS One, 2015.
Thursday 27 October 12 – 1 pm. Vijay Rajagopal (Dept of Mechanical Engineering) presenting Aufderheide et al. A new computer-controlled air–liquid interface cultivation system for the generation of differentiated cell cultures of the airway epithelium. J of Experimental and Toxicologic Pathology, 2016.
Thursday 24 November 12 – 1 pm. David Simpson (School of Physics) presenting Fabry et al. Signal Transduction in Smooth Muscle Selected Contribution: Time course and heterogeneity of contractile responses in cultured human airway smooth muscle cells. J of Applied Physiology, 2001.
Thursday 22 December 12 – 1 pm. General discussion about hot topics in the area of Therapeutic Technologies research.
TTRI Steering Committee
The Therapeutic Technologies Research Initiative Steering Committee helps to facilitate collaborative and interdisciplinary research by involving research staff from across University faculties, departments, and schools, and by facilitating connections and introductions with external researchers. It provides leadership and strategic advice regarding the Initiative's activities and projects.
- Prof Alastair Stewart, Initiative Chair (Pharmacology and Therapeutics)
- Dr Tatiana Kameneva, Academic Convenor (Electrical and Electronic Engineering)
- Dr Susan Northfield, Acting Academic Convenor, Feb-Apr 2016 (Pharmacology and Therapeutics)
- Prof Greg Dusting (CERA)
- A/Prof Fred Hollande (School of Biomedical Sciences, Pathology)
- Prof Danny Hoyer (Pharmacology and Therapeutics)
- Dr Helene Jousset (Chemical Biology Division, WEHI)
- Prof Peter Lee (Mechanical Engineering)
- A/Prof Megan Munsie (Anatomy and Neuroscience / Stem Cells Australia)
- A/Prof Andrea O’Connor (Chemical and Biomolecular Engineering)
- A/Prof Alice Pebay (Centre for Eye Research Australia)
- A/Prof Peter Pivonka (Australian Institute of Musculoskeletal Science)
- Dr David Simpson (School of Physics)
- A/Prof Spencer Williams (School of Chemistry, Associate Director BIO21 Institute)
Seed Funding Awardees for 2017
Congratulations to the following researchers on their successful TTRI Seed Funding Applications:
Characterising pluripotent stem cell reprogramming using fluorescent barcoding
Lead Investigator: Frédéric Hollande (Pathology, SBS)
Induced pluripotent stem cells (iPSCs) represent an ideal model to investigate the mechanisms of self-renewal and differentiation during human embryonic development. However, a key limitation towards optimal translational usage of iPSC technology is the very low efficiency of the reprogramming process. Reprogramming is a multi-step and heterogeneous event, reflected by the presence of partially and fully reprogrammed clones with different epigenetic signatures in mouse and human iPSCs. iPSC induction likely occurs through a combination of stochastic and deterministicevents, but there is still no general consensus on the precise molecular events in this process. This project aims to combine an innovative fluorescent barcoding technology with systems biology and mathematical modelling to monitor, identify and analyse the molecular characteristics of cells that fail or complete the reprogramming process. Findings from this project will bolster our understanding of reprogramming events and drive improvements in reprogramming, maintenance and differentiation technology for translational purposes.
Design of an air-liquid-interface microfluidic chip with an array of electrode
Lead Investigator: Mirella Dottori (Centre for Neural Engineering)
Transepithelial electrical resistance (TEER) is a commonly accepted non-invasive technique to measure electrical resistance across a cellular layer. We propose to incorporate TEER measurement into an on-a-chip microfluidic platform for continuous monitoring of cell mechanical properties and cell integrity in response to drugs. The innovation of our design is an air-liquid-interface microfluidic chip, incorporating a conductive polymer semi-permeable membrane to separate air- and liquid-filled chambers and an array of electrodes located at the bottom of the liquid chamber. The proposed technology will allow the behaviour of mechanically active cells (including epithelial cells, neurons, stem cells) to be quantitatively measured in response to drug application in a physiologically-plausible environment. The project will generate new insights into benchmarking for the evaluation of drug effects.
Using stem cell models to investigate mitochondrial protein transport in disease
Lead Investigator: Diana Stojanovski (Biochemistry and Molecular Biology)
Mitochondria are “power stations” that provide our cells with energy in the form of ATP, but also play important roles in metabolism, oxidative stress, calcium homeostasis, cell signalling and death. But, mitochondria are not self-sufficient structures. They rely on ~1500 nuclear-encoded proteins being imported into the organelle via large machines known as the Protein Import Machinery. Mitochondrial protein import dysfunction has been linked to numerous pathologies in humans, for instance (i) an X-linked neurological disorder, Mohr-Tranebjaerg Syndrome (MTS) is caused by mutations in deafness dystonia peptide 1 (DDP1), an intermembrane space chaperone that functions in protein import; and (ii) missense mutations in TIMM50, an import component of the mitochondrial inner membrane manifest in severe intellectual disability and epilepsy accompanied by 3‐methylglutaconic aciduria and variable mitochondrial complex V deficiency. Mitochondrial diseases are clinically and genetically heterogeneous. These diseases can affect any organ/tissue, particularly those with high energy requirements such as the heart and brain. Accessible patient samples, such as muscle or skin biopsies, do not always represent affected tissues so there is a need to develop model systems to enable a better understanding of the disease mechanisms. Co-investigators Stojanovski, Frazier, Elliott and Thorburn will generate human stem cell (hESC) knock out lines for a panel of mitochondrial disease genes associated with mitochondrial protein import. These stem cells will be differentiated to disease relevant cell types, such as cardiomyocytes or neuronal cell types, for further investigation. This will provide us with a powerful opportunity to dissect the pathomechanisms of specific mitochondrial diseases in a tissue specific manner.
Figure shows mitochondria from a human. Contrary to the classical text-book description that show mitochondria as tiny-bean shaped organelles, the mitochondrion is in fact highly dynamic and reticular in human cells. Mitochondrial shape and function are dependent on the organelles proteome which is why failure dysfunction in protein import leads to disease.
A role for C. elegans in high-throughput drug discovery: Bridging the innovation gap
Lead Investigator: Raymond Dagastane (Chemical and Biomolecular Engineering)
Without treatments that prevent or slow progression of Alzheimer’s disease (AD), the ageing of global populations carries undesirable socio-economic costs. The stubborn resistance of AD to effective therapeutic intervention coupled with the increasing costs of drug development demand new, cost-effective technologies better able to identify which of the “hits” emerging from discovery pipelines will show efficacy in the clinic. Development of next generation in vivo high-throughput screens (HTS) utilising small animal models such as Caenorhabditis elegans for hit identification and lead optimization promise an inexpensive avenue to improving the clinical success rate for drug discovery and development. Such in vivo systems recapitulate disease complexity more accurately by facilitating analysis of drug absorption, distribution, metabolism, excretion, and toxicity within one experimental paradigm. This proposal seeks funds to scope the eventual development of an automated microfluidic platform able to undertake both high-throughput and high-resolution imaging of C. elegans for the purposes of assaying the uptake, distribution and efficacy of ~1,000 compounds across hundreds of thousands of individual animals.
TTRI Seed Funding 2017
The main objective of the Seed Funding is to scope opportunities for funding research with a new collaborator to jointly develop a research proposal for a third party funder (e.g. ARC Linkage Project Grants, NHMRC Partnership Projects, or major industry player) in the corresponding 2017-2018 rounds.
Applications have now closed for this round of funding. Future seed funding opportunities will be advertised on the TTRI website - please check for updates. Documents for funding provided for 2017 can be download here: Funding Rules and Application Form.
If you require any further information please contact email@example.com with the subject line: “SF-query”.
TTRI - IRRTF Funding 2016
Therapeutic Technologies Research Initiative (TTRI) in collaboration with International Research and Research Training Fund (IRRTF) - Mechanobiology Research Consortium invited applications from outstanding Undergraduate and Postgraduate students from top-ranking Universities in China, Singapore, Japan and New Zealand to work on research projects aligned with one of the three focused areas of the TTRI at the University of Melbourne, Australia.
Applications have now closed for this round of funding. Future seed funding opportunities will be advertised on the TTRI website - please check for updates. Documents for funding provided for 2016 can be found below.
For applicants from China.
For applicants from Singapore.
For applicants from Japan.
For applicants from New Zealand.
The funding scheme application form can be found here.
If you require any further information please contact firstname.lastname@example.org with the subject line: “TTRI-IRRTF query”.
Congratulations to the following researchers on their successful TTRI-IRRTF Funding Applications 2016:
Xumei Gao, National University of Singapore
Kai Huang, Institute of Mechanobiology and Medical Engineering, Shanghai Jiao Tong University
Shihao Li, National University of Singapore
Image: Visiting Fellow Kai Huang is investigating the effect of TGF-beta on human umbilical vein endothelial cells.
Seed Funding Awardees for 2016
Congratulations to the following researchers on their successful TTRI Seed Funding Applications:
Microfluidics device for automated preparation and maintenance of air-liquid interface epithelial cell culture
Lead Investigator: Dr Christine Keenan (Pharmacology & Therapeutics)
The cells that line our lungs (epithelial cells) sit at the interface between the air we breathe and our blood supply carrying vital nutrients for cellular health. Recapitulating this environment in the laboratory means we can grow cells that physically resemble the airway surface. In this project, we propose to develop a microfluidics device to automate air-liquid interface culture of epithelial cells. This device will allow live measurements of cellular function and will comprise a transformative addition to the field of organ-on-a-chip technology.
A diagnostic device for studying rare cell types in patient samples for laboratory and clinical use
Lead Investigator: Dr Daniel Heath (Chemical & Biomechanical Engineering)
Rare cells such as stem cells or metastatic tumour cells are critically important to human health. However, the rarity of these cells makes them difficult to isolate and study. This project aims to develop a new cell culture platform that will enable these rare cells to be isolated and cultured individually in order to assess their true prevalence in patient samples as well as determining the heterogeneity within the cell population. This cell culture platform will enable unprecedented insight into the biology of these cells and has the potential to be used in disease diagnostics.
Controlling the ‘Master’: Generating more relevant models to facilitate discovery of novel mast cell regulators
Lead Investigator: Dr Graham Mackay (Pharmacology & Therapeutics)
Mast cells are found everywhere in the body and whilst their pariah status in allergic disease is well known, there is increasing evidence that these cells can play both deleterious and protective roles in many other diseases and are thus truly ‘master’ cells. Whilst mast cells are found embedded within a 3-dimensional tissue environment, to date all cultured human mast cell lines grow and are examined in suspension. This is clearly not representative of the in vivo interactions and biomechanical forces the cells experience and may consequently distort the phenotype of the mast cell with potential to provide misleading information on drug sensitivity. In this project we will identify extracellular matrix compositions that permits optimal adherence of human mast cells and examine the effects of these matrices on mast cell phenotype and activation. Moreover, the effects of cyclical ‘stretch’, as the mast cell would experience in the lungs, will also be examined. Combined, this project will generate new and more physiologically/pathophysiologically appropriate models to identify novel, more clinically-relevant mast cell modulators.
Identifying novel inhibitors using an FDA-approved drug screening library on a drosophila brain tumor model
Lead Investigator: Dr Rodney Luwor (Surgery, Melbourne Medical School)
Fig 1: Image of drosophila with brain over-growth (green). We will test our panel of inhibitors on these drosophila and determine which are capable of reducing brain cell growth.
Approximately 2000 Australians will be diagnosed with brain cancer (called gliomas) and of these 1500 will die within the next year. The most severe form, glioblastoma is extremely lethal, with the average survival time of 15 months. Surgery to remove the majority of the tumour is often performed. Unfortunately, in almost all cases, the residual tumour cells continue to divide uncontrollably, leading to tumour recurrence and patient mortality. Current treatment after surgery includes the use of radiotherapy and chemotherapy. However, these therapies and additional anti-cancer agents have thus far proven unsuccessful in substantially extending patient survival. Therefore, there is an urgent need to discover novel therapeutic agents that will prolong the survival times of patients with glioblastoma. Evaluating potential agents through large scale drug testing on cell lines is limited as this methodology does not adequately represent the complex conditions observed in a biological system. However, such studies would be prohibitively expensive using mouse models. Thus we proposed to screen a large number of potential FDA-approved agents for their efficacy in our recently developed Drosophila brain tumour models (Fig 1). Importantly, we will identify novel agents that can inhibit brain tumour proliferation and invasion to reveal drugs with excellent potential as effective agents for the treatment of glioblastoma patients.
Modelling retinoblastoma using human induced pluripotent stem cells (iPSCs)
Lead Investigator: Dr Raymond Wong (Ophthalmology, Department of Surgery)
Retinoblastoma (RB) is the most common malignant tumour of the eye in children caused by mutations in the RB1 gene. Familial RB is transmitted in an autosomal dominant fashion with a 50% risk to future offspring if a parent has a germline mutation. Current RB models include tumour-derived cell lines which are often the result of endpoint transformation which may not necessarily reflect what is happening in patients. RB mouse models have been shown to have different disease mechanisms compared to humans. Thus there is pressing need for a human model of RB to allow for better understanding of the disease mechanisms to improve and maximise treatment options whilst minimising ocular and systemic morbidity.
Disease modelling using patient specific iPSCs offers the unique ability to interrogate pathological processes in specific cell types, which cannot be easily obtained pre-mortem, such as retinal cells. We propose to use RB patient-derived iPSCs with known RB1 mutations, to model this disease. RB iPSCs will be differentiated into retinal progenitor cells and used to establish in vitro phenotypes associated with RB1. In particular, the funding provided my TTRI will be used to develop CRISPR gene-editing technology to induce knockout of RB1 as a positive control as well as to induce a “second RB1 hit” in RB patient derived cells. Studies from this project will build a better understanding for RB disease with the ultimate aim to drive advancements in better treatment for patients.
TTRI Seed Funding 2016
The main objective of the Seed Funding is to scope opportunities for funding research with a new collaborator to jointly develop a research proposal for a third party funder (e.g. ARC Linkage Project Grants, NHMRC Partnership Projects, or major industry player) in the corresponding 2016-2017 rounds.
Applications have now closed for this round of funding. Future seed funding opportunities will be advertised on the TTRI website - please check for updates. Documents for funding provided for 2016 can be download here: Funding Rules and Application Form
If you require any further information please contact email@example.com with the subject line: “SF-query”.
Learn more about the graduate pathways, research degrees and currently available PhD topics leading to exciting careers.
The PhD is designed for graduates to demonstrate academic leadership, independence, creativity and innovation in their research work. Doctoral studies provide advanced training which enhances professional knowledge in a specialised area and develops a range of advanced transferable skills.
Currently available PhD topics
Our research domains align closely with the University of Melbourne’s three Grand Challenges of research, with a particular focus on fostering health and wellbeing.
Bio-Metrology and Modelling of a Complex System: The Malaria Parasite
Two PhD Research Awards will be available through the Professor Leann Tilley’s Laureate Fellowship Program. The vision of the Laureate Program is to develop sophisticated and integrated bio-metrology (measurement) methods to study a complex cellular process – sexual differentiation of the malaria parasite. The Program's team of experts will undertake quantitative microscopy, biochemical and biophysical techniques that will enable, for the first time, whole organism modelling of the malaria parasite, leading to testable predictions.
Laureate Fellowship Post-Graduate Research Award (4 year appointment). An outstanding PhD candidate will be sought to undertake a project in theoretical modelling studies of the physical organisation of biomembranes. The mathematical model of the red blood cell cytoskeleton will be used to predict environment-dependent changes in physical properties, such as deformability. The successful candidate will use the latest techniques in computational modelling of biomolecules.
Laureate Fellowship Post-Graduate Research Award (4 year appointment). An outstanding PhD candidate will be sought to undertake a project examining the mechanisms that control sexual commitment in the malaria parasite, and the mechanisms by which gametocytes adhere within the vasculature and then re-enter the circulation. The work will employ electron tomography and Super-Resolution microscopy to generate 3D views of cells at very high resolution, coupled to molecular analyses, including transfection experiments.
Contact: Professor Leann Tilley
Department of Biochemistry and Molecular Biology
Bio21 Molecular Science and Biotechnology Institute
30 Flemington Road
The University of Melbourne
Melbourne, Victoria 3010, Australia
Immunopharmacology laboratory RHD opportunities
Glucocorticoids are the most effective anti-inflammatory drugs in a wide range of conditions. However, viral infection, fibrosis and certain types of inflammatory response restrict the effectiveness of glucocorticoids. Our group offers several projects related to understanding the determinants of glucocorticoid sensitivity and the discovery of therapeutics that complement or synergise with glucocorticoids. Respiratory disorders including asthma, COPD, infections and pulmonary fibrosis are the main areas of interest. Projects use systems biology approaches including transcriptomics and proteomics as well as cellular and in vivo bioassay.
We also offer projects of a collaborative and inter-disciplinary nature encompassing the development of novel cellular mechanics measurements and the use of microfluidics-based bioassay of multicellular 3D structures to achieve biomechanical environments representative of the disease for which the drugs are being developed.
Scholarships providing a stipend and fee remission are available to scholars with an outstanding level of academic achievement.
Contact lab head
Prof Alastair Stewart
Graduate Research Hub page: http://gradresearch.unimelb.edu.au/
Thomson Reuters Cortellis Competitive Intelligence
Thomson Reuters Cortellis Competitive Intelligence provides drug pipeline analysis for over 61K drugs (including preclinical), 6 million patents, 6K deals, clinical trials, competitive and disease intelligence reports, sales forecasts, the latest news from conferences and more. From one source you can create a full picture of the competitive and intellectual properly landscape in your chosen area. All content is manually curated and indexed by our scientific editors enabling you to identify and track the competition by disease, mechanism of action or by chemical structure.
Cortellis Competitive Intelligence can help you to answer questions such as:
- How are my competitors doing?
- What clinical milestones have they achieved?
- What biomarkers are in clinical investigation for breast cancer?
- What patenting activity has there been around my target/chemical structure in the last few months?
- Can I interrogate the intellectual property landscape around similar targets?
- What is the value of my drug asset/discovery?
Postdoc opportunity at Monash:
Postdoc opportunity at Harvard:
There are a number of ways to connect with the Therapeutic Technologies Research Initiative, and we would love to hear from you!
Please direct queries to firstname.lastname@example.org.