Seth Masters-Projects

Seth Masters-Projects

Projects

Biochemical analysis of the inflammasome and inflammatory cell death

The inflammasome is an intracellular protein complex that is a critical part of the innate immune response, however the direct upstream mechanism that leads to its activation remains elusive. When activated, this protein complex can also trigger a new form of inflammatory cell death, known as pyroptosis. Apart from the key inflammatory cytokines IL-1b and IL-18, other factors that are cleaved and secreted during pyroptosis remain undefined.

We have recently generated unique reagents that facilitate analysis of post-translational modification during activation of the inflammasome and inflammatory cell death. This project will utilise biochemical and proteomic techniques to identify binding partners of the inflammasome, and the inflammasome substrates that are cleaved during this new form of cell death. This could lead to the identification of new biomarkers for infection and chronic inflammatory disease, and potentially new therapeutic targets.

Team member: Dr Dominic de Nardo

ResourceNew treatments to prevent the onset of type 2 diabetes

Physiologic roles of the inflammasome during disease

Innate immune receptors can recognize foreign pathogens and alert the host to infection. More recently it has emerged that these same receptors can also recognise host molecules that are exposed as a result of cell stress or injury, as a surrogate marker of infection. However these same danger associated molecular patterns (DAMPs) can be present as a trigger for diseases such as allergy, autoimmunity and chronic inflammatory disease.

This project will uncover the roles of key innate immune receptors in laboratory models of these diseases, such as asthma, lupus and inflammatory bowel disease.

Team member: Dr Hazel Tye

ResourceAustralian researchers find immune 'kill switch', ABC Radio AM

Innate immune activation in patients with inflammatory diseases and sepsis

Genes of the innate immune system are activated by mutations in a number of hereditary periodic fever syndromes (autoinflammatory diseases). However in many cases a mutation cannot be found in the known fever genes. We are working with The Royal Children’s Hospital and The Royal Melbourne Hospital to employ next generation DNA sequencing technology and uncover new genetic causes of periodic fever syndromes.

The innate immune system also triggers a newly identified form of cell death, known as pyroptosis. This cell death could be important to stop the spread of infection, but in the case of sepsis, may go out of control and actually contribute to disease. We are working with the Intensive Care Unit at The Royal Melbourne Hospital to look at the mechanistic basis for this.

 

 

Team member: Mr Paul Baker

ResourceVESKI Innovation Fellow 2012, video

 

 

Australian Autoinflammatory Disease Registry

Rapid advances in genetics are providing unprecedented insight into functions of the innate immune system, with identification of the mutations that cause monogenic autoinflammatory diseases. However, many patients do not have a mutation in one of the known disease causing genes, or have a novel mutation of unknown pathogenicity. 

Therefore we have established an Australian Autoinflammatory Disease Registry (AADRY) with three main goals:

  1. Establish a knowledge base and data set that can be used by registry contributors to facilitate patient care and disseminate relevant information
  2. Identification of patients who tested negative for a known mutation, and offer them the option of participating in a whole exome sequencing project
  3. Validate the pathogenicity of novel variants, or variants in genes not previously associated with autoinflammatory disease

The organising committee for this registry includes clinicians from each of the major centres in Australia that treat patients with autoinflammatory disease. These organisations can enter details of their patients with autoinflammatory disease into an online database managed by the Masters laboratory at the Walter and Eliza Hall Institute.

Clinicians will be able to search de-identified data to find resources, and network with others who have experience in the treatment of these rare conditions. Based on this registry, individuals and several families who tested negative for a mutation in known autoinflammatory disease genes have now been consented for exome sequencing, blood collected, DNA prepared and exomes sequenced.

Most of these families represent two unaffected parents and an affected sibling where the genetic mode of inheritance being tested is homozygous recessive, or a de novo dominant mutation. We are now awaiting the bioinformatics analysis of this first set of data.

In the next five years we hope to capture all Australian autoinflammatory disease patients, which probably numbers between 100-200 people.

Team member: Dr Fiona Moghaddas

Resource: Cause of rare immune disease identified