Translational renal research


Student project opportunities


Research overview
One in six Australians has impaired kidney function, with one in three at risk of developing kidney disease.

The Translational Renal Research group in focussed on improving outcomes for patients with renal diseases, by translating advances in basic science from the bench to the bedside.

The main areas of interest for the group are:

  • Host responses to common viruses causing disease after renal transplantation
  • Quantification of immune function through the assessment of recall antigen responses
  • Interactions between bacteria and peritoneal mesothelial cells and the development of peritoneal-dialysis related peritonitis


The effect of cytomegalovirus on the immune repertoire following renal transplantation

Research area: Infection and immunity    
Chief supervisor:  Dr Aron Chakera
Other supervisors: Dr Alec Redwood
Project suitable for: Masters, PhD
Essential qualification: first class or upper second class honours degree , knowledge of flow cytometry

Project outline
Traditionally, infectious diseases have been studied experimentally in the context of a single infection with one genetically identical clone. However, in the clinical setting multi-strain infections are the norm, and this can change pathogen dynamics, disease course, and transmission. Human cytomegalovirus (HCMV) is ubiquitous, with a prevalence ranging from 50-60% in industrialized countries to almost 100% in developing countries. Although HCMV usually causes asymptomatic infection in the immunocompetent host, in immunocompromised transplant recipients, HCMV replication is associated with significant morbidity and mortality.

Multi-strain infections can alter the course of disease through within-host interactions between the strains of pathogens, or because host immunity to secondary strains is impacted by the primary infection (original antigenic sin). Within host interactions may be complementary, neutral or competitive and may assist in selecting for pathogen traits such as transmissibility, drug resistance or virulence. Despite this, multiple-strain infections remain poorly studied in the clinic and in the laboratory.

Given the clinical importance of CMV in transplant recipients and the frequency with which individuals are infected with multiple strains of HCMV, understanding how multistrain infections affect the individual viral strains as well as the pathobiology of the host immune response will be essential in reducing disease and improving outcomes.

This project will assess whether the nature of the initial host responses to CMV shapes the capacity of the immune system to negotiate re-infection
Aim 1: Prospectively track individual CMV strains and changes in host cellular responses to CMV in renal transplant recipients

  • Isolate and sequence viral genomes
  • Monitor the imprint of CMV on host cellular responses (particularly NK cells) post transplantation


Aim 2: Analyze the effects of multi-strain infection in an outbred mice model of CMV to provide a mechanistic explanation for the results from Aim1

  • Determine whether complementation between viral species occurs in non-manipulated outbred mice
  • Determine the role of NK cells on complementation and viral replication

    
Contact
Dr Aron Chakera - aron.chakera@uwa.edu.au

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Analysis of the biological effects of bacterial pathogens on mesothelial cell function

Research area: Infection and immunity
Chief supervisor:  Dr Aron Chakera
Other supervisors:  Dr Christine Carson, Winthrop Professor Y.C. Gary Lee
Project suitable for:   PhD  
Essential qualifications: First class or upper second class honours degree in microbiology

Project outline
Peritoneal dialysis (PD) is the dialysis modality of choice for many patients with end-stage renal disease. One of the major complications of therapy is the development of peritonitis, which is associated with significant morbidity and economic costs and may be a contributing factor in the deaths of up to 16% of patients on PD. Even in patients who recover from peritonitis, infections can result in shortened modality survival or modality failure.

Cultures of peritoneal fluid from patients with PD peritonitis have revealed a wide range of causative microbes, both Gram positive and Gram negative. The commonest bacteria identified in a previous study in Western Australia were coagulase negative staphylococci, streptococci, Staphylococcus aureus, enterococci, Pseudomonas aeruginosa, Escherichia coli, Klebsiella and Proteus species.

The peritoneal cavity is covered by a monolayer of mesothelial cells that forms the first line of defence against bacterial invasion. How different bacterial species damage mesothelial cells and influence the biology of the host response is poorly understood. By using pure cultures of bacteria known to cause PD peritonitis as well as mutant strains missing specific proteins or with altered surface properties we will be able to improve our understanding of the mechanism by which different bacterial species and strains damage the mesothelium and influence the resultant cellular response.

Key objectives of this project are:
1. To investigate the in vitro biological effects of bacteria known to cause PD peritonitis on peritoneal mesothelial cells with respect to:

  • viability of mesothelial cells
  • apoptosis of mesothelial cells
  • release of cytokines
  • bacterial cell adhesion and migration across a mesothelial layer
  • biofilm formation

2. To elucidate the mechanism(s) by which the bacteria induce their effects using mutant bacteria lacking specific virulence factors and heat-killed bacteria.
Data from this project will have direct relevance to improving outcomes for patients with renal failure who are on peritoneal dialysis. 

Contact
Dr Aron Chakera:  aron.chakera@uwa.edu.au

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The systems biology of sepsis

Research area: Infection and immunity
Chief supervisor:  Dr Aron Chakera
Other supervisors:  Professor Tim Inglis
Project suitable for:  PhD  
Essential qualifications: first class or upper second class honours degree, knowledge of flow cytometry

Project outline
Sepsis is a major health issue accounting for more than 5% of all admissions in Australia in 2012, at an estimated cost to the economy of up to $90,000 per patient. In more severe cases the mortality is over 50%, and in patients who survive the recovery time and degree of residual morbidity can be considerable. Worldwide, sepsis kills more people than cancer and heart disease combined and its incidence is predicted to double over the coming 25-30 years. At the same time many current treatments are expected to become ineffective due to rising levels of antimicrobial resistance.

Despite the importance of sepsis in the hospital setting, to date there have been limited advances leading to better clinical outcomes, as tools to enable the early detection of sepsis and the causative organism(s) have been lacking. Unfortunately, the mainstay of clinical laboratory support remains blood culture, which places the current clinical laboratory contribution to sepsis outside the ability to directly influence critical treatment decisions acutely and the four-hour Emergency Department window. Consequently optimal treatment is inevitably delayed. As the patient’s body responds to the infective agent, a series of pathological processes unfold, which if left unchecked can progress to multiple organ failure and death. The opportunity to treat successfully diminishes rapidly with passing time. To improve patient outcomes in sepsis, the single biggest issue therefore is early appropriate clinical intervention.

We aim to employ a systems biology approach that integrates recent advances in analytical techniques including cell free DNA detection, rapid microbial gene sequencing and protein analysis and detection of volatile microbial metabolic products to dramatically reduce the time required to diagnose sepsis and for pathogen identification and characterization. These tools will:

  • improve patient care, through earlier detection of sepsis and identification of causative pathogens
  • facilitate health-system workflow, through timely prioritization of patients with sepsis
  • accelerate our ability to track hospital-acquired infections and resistance patterns.

The hypothesis for this project is that the targeted application of a suite of novel diagnostic tools will transform the management of sepsis and improve patient outcomes. Collectively these assays will enable us to answer whether the course, cause and best interventions for sepsis can be determined during its early stages; whether there are laboratory indicators of sepsis that can be used across distinct patient groups; and whether the introduction of these indicators results in demonstrable benefits for patients.
To achieve these objectives we propose the following complementary aims based around distinct analytical technologies:

  1. Systematic analysis of serial samples from patients with sepsis to establish temporal changes in novel biomarkers, including cell free DNA, and normal ranges in different patient populations
  2. Application of Matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry for the rapid identification of pathogens in sterile fluids
  3. Development of flow cytometric assays for the rapid identification of bacteria and antimicrobial resistance profiles
  4. Assessment of non-invasive detection methods to identify metabolic markers of bacterial multiplication.

These studies will extend preliminary work that is already being performed on the QEII campus and collectively these aims will be channelled through four key clinical project areas:

  1. Rapid diagnosis of sepsis
  2. Assessment and validation of new biomarkers
  3. Prediction of antibiotic resistance
  4. Tracking and surveillance of hospital infections


Contact
Dr Aron Chakera - aron.chakera@uwa.edu.au

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