Archives: Research groups

The Structural Biology of Inflammation and Cancer research group focuses on two complementary areas of research.

Genome maintenance in normal and cancer cells

The human genome is subjected to numerous genetic alterations throughout the lifespan of an individual as a consequence of exposure to environmental mutagens, such as UV-sun irradiation, cigarette smoke, as well as DNA damages induced by endogenous sources, eg, reactive oxygen species. These DNA damages are constantly monitored by genome surveillance mechanisms to ensure genome integrity is maintained. Malfunction of these surveillance and maintenance mechanisms predispose the genome to oncogenic changes, which ultimately led to the development of cancers. Furthermore, cancer cells have adapted specific genome maintenance mechanisms to ensure the appropriate genetic information are passed to the daughter cells during cell division, as well as the need to utilise DNA repair mechanisms in response to cancer chemotherapies. It is important to understand the molecular details on genome maintenance mechanisms to understand how normal cells maintain the heathy state, and how cancer cells develop.

Our research is focusing on protein-nucleic acid complexes that monitor and maintain the genome integrity of normal and cancer cells. Cells have sophisticated molecular machines that detect and repair these DNA alterations. We use cryo-electron microscopy (cryo-EM) and biochemical methods to characterise the mechanisms of these molecular machines to understand how genome integrity is maintained. The ultimate goal is to apply these knowledges to develop therapeutics that can offer new ways to treat disorders or cancers associated with genome instability.

Malaria parasite invasion

Our research also focuses on understanding the mechanisms by which malaria parasite invade human red blood cells. Malaria is an infectious disease of global significance causing close to 0.5 million deaths annually. We study the biology of blood stage infection because infection of red blood cells by malaria parasites is responsible for the clinical symptoms of malaria. Blood stage malaria antigens are important target for drug and vaccine development.

To invade red blood cells, the parasite utilises secretion machinery to display molecular “keys”, called invasion ligands that recognise specific receptors on the surface of red blood cells. These parasite ligand-host receptor interactions mediate signalling events in an orderly sequential manner to enable the parasite to move into red blood cells in a short space of 60 seconds. We aim to characterise these molecular ligand-receptor interactions by cryo-EM, as well as how these parasite ligands could be blocked by invasion inhibitory antibodies. This information will be fundamental for designing a potential malaria vaccine to mount effective immune responses to protect against malaria infection.

Hypertension is a leading risk factor for death and disability globally. Close to 6 million adults (34%) in Australia are affected; 4.1 million of them have uncontrolled or untreated hypertension. To improve blood pressure control and reduce morbidity/mortality, we need to address the under-diagnosis of secondary causes, in particular an eminently treatable and potentially curable cause – primary aldosteronism (PA), or Conn’s syndrome. PA is caused by excessive aldosterone production from either one or both adrenal glands.  Specific blockade of aldosterone action with mineralocorticoid receptor antagonists offers highly effective and targeted treatment, while a unilateral aldosterone-producing adrenal adenoma can be surgically removed.

Whilst previously taught as rare, PA has been found to affect 5-10% of hypertensive patients in primary care and up to 30% of patients with resistant hypertension.  However, PA is not routinely screened for.  Half a million hypertensive Australians may be missing out on targeted treatment or cure for their hypertension. A missed or delayed diagnosis is detrimental.  Simply controlling blood pressure is not enough; PA patients suffer excessive coronary artery disease, stroke, atrial fibrillation and chronic kidney disease compared to patients with essential hypertension due to the effects of aldosterone excess. These complications can be prevented with early diagnosis and targeted treatment.  But how early is early enough? Recent literature suggests that PA exists on a continuum such that only the tip of the iceberg is being detected. The age from which the continuum begins is unknown.  After screening, the diagnosis of PA and accurate subtyping remains challenging, time-consuming and costly, involving hospital stays.

We established the Endocrine Hypertension Service in July 2017 for the purpose of integrating research with clinical service.  We collaborate with clinicians in a range of specialties (general practice, cardiology, nephrology, stroke, respiratory medicine, radiology, chemical pathology, endocrine surgery, anatomical pathology) and researchers in various disciplines (molecular biology, genetics, physiology, cardiovascular endocrinology, health economics, biostatistics), to increase the scope and reach of our research.  We also collaborate nationally and internationally with dedicated hypertension research groups to collectively advance this field of work.

Research Projects

Our current projects include the evaluation of

• Prevalence of primary aldosteronism in a range of conditions that co-exist with hypertension (eg. diabetes, atrial fibrillation, stroke, chronic kidney disease, etc);
• Implementation of screening for primary aldosteronism in primary and tertiary care;
• Cost-effectiveness of screening and diagnosis, and modifiers of cost;
• Interaction between aldosterone excess and non-cardiovascular systems (eg. bone, muscle, parathyroid, brain etc)
• Development and validation of diagnostic tests/protocols, including novel biomarkers, for screening and diagnosing the full spectrum of primary aldosteronism;
• Pathogenesis and genetic basis for various subtypes of primary aldosteronism;
• Patient choices and patient-reported outcome measures in the diagnosis and management of primary aldosteronism;
• Effectiveness of different treatment options for primary aldosteronism in clinical trials.

The maintenance of male fertility is dependent on spermatogonial stem cells (SSCs) that self-renew and generate differentiating germ cells for production of spermatozoa. After puberty, this process continuously produces mature sperm to maintain lifelong fertility. SSC function is dependent on specific growth factors produced within the testis microenvironment plus distinct cellular factors that regulate gene expression within SSCs and modulate responses to growth factor stimulation. However, despite the importance of SSCs for male fertility, the molecular mechanisms that regulate their function and maintenance remain incompletely understood.

Importantly, SSC function and male fertility can be compromised by multiple factors including ageing or exposure to genotoxic drugs. Increased paternal age is associated with disruption of SSC activity and declining sperm quality, with an elevated risk of genetic diseases in offspring. Infertility can also occur prematurely in men as a consequence of genotoxic therapies eg; chemotherapy, for treatment of cancer. However, cellular pathways mediating the regenerative response of SSCs following germline damage and loss of SSC function with age are poorly studied.

Our research focuses on defining genetic controls and cellular pathways regulating SSC function and male fertility. We employ a range of in vivo and in vitro experimental systems allowing dissection of mammalian SSC function. Our previous work has defined essential roles for the developmental transcription factors PLZF and SALL4 in maintenance of SSC activity and the central importance of mTORC1 signalling in SSC fate regulation. In addition, our studies have characterised cellular heterogeneity within the SSC and progenitor cell pool using single cell approaches and demonstrated the dynamic nature of spermatogonial states with important clinical implications.

Current research projects are focused on understanding cellular machinery modulating the response of SSCs to stimuli from the niche, the impacts of ageing on SSC function and molecular mechanisms supporting the regenerative capacity of SSCs.

The Functional RNAomics Laboratory investigates gene regulation through RNA binding proteins in tissues that rely on continuous production of new cells during development or throughout life. RNA binding proteins form regulatory RNP complexes with RNA that are the functional units of all RNA. We aim to crack the RNP code of distinct cell types that share a common property of rapid turnover. We hope that one day our discoveries will help the development of new RNA-based therapies and diagnostics to improve the treatment of infertility, cancer and haematological conditions.

Research focus – RNP code of tissues relying on continuous production of new cells

During early development, cells are pluripotent able to give rise to all cells in the body. Although the potency of most cells declines during development, some cells remain capable of giving rise to multiple cell types even after birth. These stem cells are particularly important in tissues that need to produce new cells throughout life such as the male germ line, the intestinal lining and blood cell lineages. Our work has demonstrated that gene regulation through RNA binding proteins is particularly important in these rapidly renewing cell lineages. Our research focuses on RNA that is produced from the DNA template to bring the genome to life. RNA binding proteins are required to make these RNAs ready to serve their cellular functions. Mutations disrupting RNA metabolism account for ~30% of all known disease-causing mutations, alterations in splicing patterns are a hallmark of cancer and RNA binding protein expression is frequently dysregulated in cancer cells.

The Functional RNAomics Laboratory integrates comprehensive catalogues of RNA repertoires, global RNA binding protein maps, proteomics profiles and high-resolution structures with distinct cellular phenotypes to gain a mechanistic and functional understanding of RNP constituents in the cell lineages that rely on the continues production of new cells. Our goal is to reveal key mechanisms involved in male fertility, blood clotting, maintenance of healthy intestinal lining and causes of malignant transformation. RNA shows great promise as a therapeutic and biomarker but a detailed knowledge of RNA regulation in cells is a prerequisite to realise the full potential of RNA-based therapeutic and diagnostic development.

Research projects

• RNA regulation in pluripotent and adult stem cells
• RNA binding proteins in developmental defects and cancer
• RNA biology of blood cells– what makes blood cells vulnerable to RNA processing defects

If you have an interest in RNA, the other nucleic acid, and would like to join our quest for cracking the RNA code, either by working at the lab bench or at the computer, please contact the Research Group Head | e:  minni.anko@hudson.org.au.

Research in the group currently focuses on three molecules, the protein kinase R, the interferon-induced helicase 1, and the zinc-finger and BTB-domain containing 16, that together detect stress, transduce cell signals and induce gene responses that control inflammation. Through these three molecules, group head Dr Sadler investigates a progression of immune pathologies from the initial responses to infection, through the development of persistent inflammatory conditions (colitis), to established chronic autoimmune diseases (type I diabetes and lupus).

Research Projects

• Treating infection-induced immune pathogenesis
• Evaluating interferon therapy against colitis
• Determining innate immune responses that induce type I diabetes
• Targeting cytokine signalling in systemic lupus erythematosus

Endocrine-related cancers represent at least 35% of newly diagnosed cancers. These include sex steroid-responsive cancers such as breast, endometrium and prostate together with thyroid, adrenal and subsets of ovarian cancer. Treatment options for many of these cancers are limited. Our group’s research is focused on two underserved endocrine cancers for which we have identified a shared pathogenesis, with therapeutic implications.

Epithelial thyroid cancer (ETC) is the most common endocrine malignancy and usually affects younger adults. The recently released cancer statistics for Victoria (Cancer in Victoria Statistics and Trends) show a continuing rise in the incidence of ETC with a 3-fold increase over the last 30 years.

Granulosa cell tumours (GCT) arise from ovarian granulosa cells (GC) and represent a specific subset of malignant ovarian tumours. GCT are unusual in that they have an unexplained propensity for late recurrence. ~80% of patients with aggressive or recurrent tumours die from their disease. At present, there are no reliable methods for predicting relapse and, aside from surgery, no therapies have proven effective. It is critically important to understand molecular mechanisms which contribute to the pathogenesis of GCT and may present novel therapeutic targets.

Our research has identified potential therapeutic targets that are associated with both ETC and GCT. Our research aims to understand the roles of these proteins in the pathogenesis of these diseases, and the efficacy of a combination therapy as a novel strategy for both cancers.

Current Research

• Molecular pathogenesis of granulosa cell tumours
• Novel combination therapies for granulosa cell tumours
• Novel combination therapies for epithelial thyroid cancers
• Efficacy of Smac mimetics to treat epithelial ovarian cancer

The Cell Death and Inflammatory Signalling group aims to identify new molecules that regulate cell death and inflammatory signalling.  We also seek to establish whether cell death signalling can be inhibited therapeutically to treat inflammatory disease or triggered to promote antimicrobial responses.

Dr Lawlor and her team investigate the cross-talk between programmed cell death and inflammatory signalling pathways in disease. In particular, the laboratory studies how cell death induces activation of the NLRP3 inflammasome. Inflammasomes activate pro-inflammatory proteins Interleukin-1β (IL-1β) and IL-18 and induce a lytic form of cell death, called pyroptosis. This activity is critical for clearance of microbial organisms by the immune system. However, excess IL-1β activity can exacerbate rare hereditary autoinflammatory syndromes and common diseases, such as rheumatoid arthritis, type 2 diabetes and cancer.

The Lawlor group utilise a range of cellular and molecular biology methods and preclinical disease models.

The gastrointestinal microbiota plays an essential, though poorly understood role in many aspects of human biology. Emerging evidence suggests the bacterial community structure can impact diseases as diverse as autoimmune diseases, cancers and infections. Despite this importance, many of the species of bacteria that inhabit this environment remain to be grown in the laboratory, let alone genome sequenced or their interactions with the human immune system characterised. Research within the Microbiota and Systems Biology laboratory applies genomics, computational and systems biology, microbiology and immunology to develop our understanding of these bacteria, their genomes and reciprocal interactions with the human immune system that lead to disease or maintain health.

Using cutting edge bacterial culturing, genomics and host-transcriptomics, our research builds on a strong, fundamental understanding of basic microbiology, immunology and systems biology to develop therapeutic options for many conditions and diseases. Potential treatment options developed through this work range from methods of biomarker detection to guide therapy or control the spread of antimicrobial resistance within the healthcare system through to identification of optimal bacterial communities and the development of conventional and bacteriotherapy based clinical interventions to improve human health.

The Viral Immunity and Immunopathology group focuses on understanding the mechanisms involved in the induction and regulation of innate immune responses during viral infections.

One focus is influenza A virus (IAV), the virus responsible for the ‘flu’. There is a continual threat that novel influenza A viruses IAV will be transmitted from birds to humans, an occurrence called ‘cross-over’. These severe infections involving highly pathogenic IAV are associated with hyperinflammatory responses, immunopathology and high mortality rates (30-40 per cent).

Innate immune responses play an important role in providing protection during viral infections, such as those involving IAV. However, an overreaction of the innate immune system, such as that seen during severe IAV infection, causes cellular and tissue damage. Patients often present to hospital with severe disease, several days after the onset of symptoms. There are currently no effective or targeted drugs or therapies in use to limit immunopathology and disease at this stage of the infection.

Utilising a range of preclinical models and techniques, Associate Professor Tate and her team aim to gain a greater understanding of the mechanisms involved in inducing and regulating a hyperinflammatory response in order to identify novel therapeutic targets.

The focus of our research is to determine the mechanisms by which bacterial pathogens interact with their host, then use this information to understand the specific immune responses essential for fighting infections and maintaining immune homeostasis in the body.

Our overarching goals are to make discoveries on the fundamental mechanisms of immunity to infections and inform the future development of therapeutics for bacterial infections and dysregulated immune responses in inflammatory diseases.

The model pathogen that we use in our research is Salmonella enterica. These pathogens are able to colonise a wide range of human and animal hosts and in humans, they can cause disease ranging from gastroenteritis to systemic disease, depending on the serovar of the bacteria. S. enterica serovars Typhi and Paratyphi are human restricted and are known as the ‘Typhoidal’ Salmonella. These serovars cause serious illness as the bacteria disseminates systemically, causing severe fever, nausea, diarrhoea, abdominal cramping and headaches, and if left untreated, can cause death. Other non-typohoidal Salmonella serovars (NTS) include S. enterica serovars Typhimurium and Enteritidis, both of which account for the majority of gastrointestinal disease (salmonellosis) in immunocompetent individuals worldwide. In immunocompromised people however, some NTS strains cause invasive disease and thus more serious illness. S. enterica is endemic in many developing countries and is a constant major health concern in immunocompromised patients with HIV. Interestingly, Australia has one of the highest rates of salmonellosis among developed countries, with 74.6 and 67.9 cases per 100,000 people in 2016 and 2017, respectively.

In our lab, we aim to understand the virulence mechanisms of these pathogens and concurrently the host mechanisms that mediate protection against, or increased susceptibility to disease. We are particularly interested in programmed cell death signalling pathways, including apoptosis, necroptosis and pyroptosis during bacterial gut infection.

Given that we aim to characterise host innate immune signalling pathways that protect against bacterial gut infection, we also have a keen interest in whether these pathways play a role in maintaining homeostasis of the gut in general. What does this mean?

At any time, our gut is full of microbes, some that are relatively harmless and some that have pathogenic potential. How is it that we can generally tolerate all these microbes in our everyday lives? And why do some people develop serious inflammation in the bowel? We would like to know whether our work on pathogenic gut bacteria can provide insights into the specific immune signalling pathways that are most important in protecting against inflammation on an everyday basis. We are also interested in how mutations in these immune signalling pathways or serious gut infections may affect the composition of the gut microbiome, and what the long term implications of this may be in certain individuals.

Research Projects

• In vivo role of necroptosis in bacterial gut infection
• Regulation of TNFR signaling in Salmonella infection
• Characterisation of invasive non-typhoidal Salmonella lineages
• Inflammation and cell death in inflammatory bowel disease
• Bacterial and viral co-infection and potentiation of enteric disease