Baker Institute Joint Scholarships Scheme for Cardiovascular Biology and Disease Research project summaries
PROJECT 1: TARGETING ANTIOXIDANT AND ANTI-INFLAMMATORY PATHWAYS TO LESSEN DIABETIC CARDIAC COMPLICATIONS.
Supervisors: A/Prof Judy De Haan (Baker) and Prof Grant Drummond (LTU)
Email: Judy.DeHaan@baker.edu.au or g.drummond@latrobe.edu.au
Synopsis: Cardiac complications associated with Type 2 diabetes (T2D), known as diabetic cardiomyopathy, leads to significant morbidity and mortality, for which standard treatment options are insufficient to halt or reduce the clinical burden. T2D affects almost 2 million Australians, and its prevalence is expected to increase with the growing obesity epidemic. Therefore, there is a strong clinical need to identify new pathways and targets for effective drug treatment. Recent evidence points to a strong interplay between antioxidant defence via the master regulator Nrf2, and the regulation of "sterile" inflammation via the NLRP3 inflammasome. This interconnectivity (the Nrf2/NLRP3 axis) and the targeting of this axis, has not been explored in the context of diabetic cardiac complications. This project specifically explores this relationship in the diabetic heart, using both pharmacological and genetic manipulations to address key components of the pathway.
PROJECT 2: UNDERSTANDING HOW OXIDATIVE STRESS AND GLUCOSE METABOLISM INTERACT IN THE DIABETIC HEART
Supervisors: A/Prof Judy De Haan (Baker), A/Prof Colleen Thomas (LTU) and Prof Grant Drummond (LTU)
Email: Judy.DeHaan@baker.edu.au or Colleen.Thomas@latrobe.edu.au
Synopsis: Recent evidence suggest that the transcription factor, Nrf2, plays an important role in preventing diabetes-associated vascular dysfunction. However, Nrf2 is known to be susceptible to a post-translational modification known as O-GlcNAcylation, which may limit its anti-oxidant and anti-inflammatory capacity. Protein O-GlcNAcylation is up-regulated in the diabetic heart and vasculature, but the interplay between Nrf2 and O-GlcNAcylation in this context has not been interrogated. This project will determine the extent to which these protective (Nrf2) and detrimental (O-GlcNAcylation) mechanisms interact in the heart and vasculature in diabetic mice in vivo (wildtype and Nrf2 knockout), and human iPSC-derived cardiac myocytes in vitro (available via A/Prof de Haan).
PROJECT 3: REPAIRING A BROKEN HEART: EXOSOMES IN CARDIAC REGENERATION
Supervisors: Dr David Greening (Baker/LTU), Dr Alin Rai (Baker) and Prof Chris Sobey (LTU)
Email: David.Greening@baker.edu.au or c.sobey@latrobe.edu.au
Synopsis: Extracellular vesicles are sophisticated signalling mediators, emerging as unique and highly specific targeting vehicles for cell-free therapy. We aim to explore novel approaches to regenerate the damaged heart (for example following myocardial ischemia) using exosomes derived from stem cells and potential design of exosome-based nanoparticles of therapeutic interest.
PROJECT 4: LIPID ANNOTATION FOR MORE INSIGHTFUL ANALYSES
Supervisors: Prof Peter Meikle (Baker), Dr Alex Smith (Baker) and Dr Agus Salim (LTU/Baker)
Email: Peter.Meikle@baker.edu.au or Agus.Salim@baker.edu.au
Synopsis: Until recently, the computational analysis of lipidomics data was restricted to investigating associations between measured lipid levels and pathological outcomes of interest, and integrating results to higher-level abstractions (such as lipid classes, metabolic pathways, dietary sources, etc.) was done manually. However, with technological improvements leading to the higher precision measurement of more numerous, structurally resolved lipids, it has become possible to computationally investigate the associations between lipid structural elements, lipid pathways, and other lipid meta-data (“annotations”), with clinically relevant outcomes. In this project, the student will: (1) investigate the biological relevance and applicability of existing efforts towards lipid annotation; (2) conceive and implement an annotation database using expert in-lab knowledge of lipids; and (3) investigate existing methodologies for enrichment analyses and their applicability to lipid annotation data.
PROJECT 5: MINING LIPIDOMICS DATA FOR BIOLOGICAL INSIGHT
Supervisors: Prof Peter Meikle (Baker), Dr Alex Smith (Baker) and Dr Agus Salim (LTU/Baker)
Email: Peter.Meikle@baker.edu.au or Agus.Salim@baker.edu.au
Synopsis: Until recently, the analysis of lipidomics data was restricted to investigating associations between measured lipid levels and pathological outcomes of interest. However, with technological improvements leading to higher precision measurement of more numerous, structurally resolved lipids, it has become possible to investigate the associations between the lipids themselves, or as groups at a higher level of abstraction.
We hypothesise that these sorts of data analyses can highlight the metabolic or disease pathways at play beneath the observed lipidomes, providing novel biological insight, more approachable data summarisations, and new ways to select biomarker lipids to prioritise for measurement in the clinical setting. Thus, for this project the student will: (1) investigate the existence and subsequent removal of technical artefacts that may bias lipid-lipid association analyses in real cohort lipidomics datasets; (2) investigate multivariate statistical procedures for detecting or summarising lipid-lipid associations, e.g. correlation analysis, clustering, principal component analysis; (3) investigate the statistical association between such summaries and biological outcomes in the lipidomics cohorts available in the lab, such as cardiovascular disease, diabetes, obesity, and Alzheimer’s Disease, and compare these to associations obtained with the individual lipids; and (4) investigate the use of such summaries for reducing or imputing lipidomics datasets.
PROJECT 6: LEVERAGING HIGH DIMENSIONALITY IN LIPIDOMICS FOR IMPUTATION, EXTRAPOLATION & DATASET REDUCTION
Supervisors: Prof Peter Meikle (Baker), Dr Alex Smith (Baker) and Dr Agus Salim (LTU/Baker)
Email: Peter.Meikle@baker.edu.au or Agus.Salim@baker.edu.au
Synopsis: The recent advent of high dimensional plasma lipidomics has proven to be a boon for lipid association analyses with clinical outcomes of interest. It also opens up previously imponderable data analysis questions, such as “How can we best impute missing values?”, “How can we best extrapolate the lipid levels from older datasets where they were not measured?” and “What is the minimal set of lipids we actually need to measure for a clinical test?”. We hypothesise that the informational richness in these datasets will enable more advanced and accurate methods of data imputation and reduction, providing greater statistical power, increased dataset comparability, and more clinically-relevant choices of lipids to measure. In this project, the student will: (1) investigate existing statistical methodologies for missing value imputation, trialling them on several datasets available in the lab (pertaining for example to cardiovascular disease, obesity, diabetes, or Alzheimer’s disease), and inscribing one or more into the lab’s current data analysis pipeline; (2) extend the previous to the extrapolation of lipid levels for lipids not measured in earlier datasets; and (3) investigate statistical methods for dataset reduction and their application to determining a minimal set of clinically-relevant lipids, and determining if these are pathology-specific, or globally applicable;
PROJECT 7: INVESTIGATION OF NOVEL FIBROTIC AND INFLAMMATORY PATHWAYS IN CARDIOVASCULAR DISEASES
Supervisors: A/Prof Bing Wang (Baker), Prof Grant Drummond (LTU) and Dr David Greening (LTU/Baker)
Email: Bing.Wang@baker.edu.au or g.drummond@latrobe.edu.au
Synopsis: This project will investigate the roles that a novel receptor tyrosine kinase (RTK) plays in regulation of cardiovascular inflammation and fibrosis, and the therapeutic potential of blocking this pathway using selective inhibitors and siRNA strategy. The project aims to elucidate the underlying mechanisms of the RTK pathway and may lead to the development of more effective therapies for the treatment of cardiovascular diseases related to inflammation and fibrosis.
PROJECT 8: TARGETING PLATELETS AS A NOVEL ANTI-INFLAMMATORY AND NEUROPROTECTIVE STRATEGY FOR MULTIPLE SCLEROSIS.
Supervisors: Dr Xiaowei Wang (Baker), Prof Karlheinz Peter (Baker) and Dr Jacquie Orian (LTU)
Email: Xiaowei.Wang@baker.edu.au or J.Orian@latrobe.edu.au
Synopsis: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), which principally targets young adults and for which there is no cure. MS affects an estimated 2.3 million individuals worldwide. In Australia there are about 25,600 sufferers at an annual cost of $1.75 billion. The disease is typified by an initial relapsing-remitting phase, which transitions to progressive disease after 15 to 25 years. It is now known that multiple destructive mechanisms operate concurrently in this disease, including inflammation observed in CNS white matter and neurodegeneration in grey matter. A collaboration between the Orian (La Trobe University) and Peter (Baker Heart and Diabetes Institute) laboratories has identified platelets as pivotal to both types of destructive mechanisms. We therefore hypothesize that in MS platelets become activated and develop a pro-inflammatory and neurotoxic phenotype and that platelet-targeting from early disease is key to prevention of MS evolution, in particular entry into the progressive stage. Currently options for medical therapy are limited and there is a strong need for drugs that are effective without causing strong side effects. The Peter laboratory has developed a novel drug, based on recombinant DNA technology, that combines anti-platelet and anti-inflammatory effects. We plan to generate proof of concept that the specific targeting of activated platelets represents a novel and innovative disease modifying approach for multiple sclerosis (MS), which can significantly delay progression. Using a mouse model for MS, newly developed in the Orian laboratory, we will evaluate the efficacy of this candidate therapeutic in preventing disease development. This will be achieved by clinical studies, immunopathological and molecular approaches.
PROJECT 9: INVESTIGATING THE ROLE OF THE INFLAMMATORY IMMUNE RESPONSE IN ATHEROSCLEROTIC PLAQUE INSTABILITY
Supervisors: Prof Karlheinz Peter (Baker), Dr Jonathon Noonan (Baker) and Prof Grant Drummond (LTU)
Email: Karlheinz.Peter@baker.edu.au or g.drummond@latrobe.edu.au
Synopsis: Cardiovascular diseases, including myocardial infarction and stroke, are the leading cause of mortality worldwide. Inflammation has been identified as an essential driving force in the pathogenesis of atherosclerosis, the underlying cause of these diseases, however many of the specific inflammatory pathways involved and their potential for therapeutic targeting has not yet been elucidated. This research will investigate the role of the immune system and inflammation in the pathogenesis of atherosclerosis and myocardial infarction using a murine model of unstable atherosclerotic plaques, and powerful investigative techniques including multiparameter flow cytometry, intra-vital microscopy, immunohistochemistry and single-cell mRNA sequencing. The project aims to produce novel insights into the pathobiology, and uncover potential therapeutic targets of cardiovascular disease.
PROJECT 10: THERAPEUTIC POTENTIAL OF HEPARANASE INHIBITORS IN UNSTABLE ATHEROSCLEROTIC PLAQUES.
Supervisors: Dr Yung Chi Cheng (Baker), Prof Karlheinz Peter (Baker) and Prof Mark Hulett (LTU)
Email: YungChih.Chen@baker.edu.au or M.Hulett@latrobe.edu.au
Synopsis: Heparanase is an enzyme that acts via degradation of extracellular matrix, which plays a significant role in PCSK9 gain-of-function and LDLR degradation in atherosclerosis. We will use specific heparinase inhibitors and double knock out mice on the traditional Apolipoprotein E knockout background to study plaque instability. We have adopted our novel tandem stenosis (double ligation) mouse model and would like to test heparanase inhibitors for their therapeutic potential towards plaque stabilisation. A student who embarks on this project will learn a wide range of technologies including animal models, molecular imaging, (immuno)histology, PCR, pharmacology and drug design.