The role of key driver genes in the pathogenesis of acute renal allograft rejection

Summary

This is a PhD project. The successful applicant will be top up scholarship. This study will lead to publish high quality of papers and apply a new NHMRC project grant.

Supervisor(s)

Professor Philip O'Connell, Dr Min Hu

Research Location

Westmead - Westmead Clinical School

Program Type

PHD

Synopsis

The project aims to identify new treatments for acute kidney transplant rejection. We have identified new gene pathways involved in acute kidney transplant rejection. Drugs approved for use in the clinic of other indications will be tested for their ability to suppress these gene pathways and to see if they may be repurposed for treating acute kidney transplant rejection.

Acute rejection is one the major causes of graft loss and chronic dysfunction in renal. Although there are treatments available to manage the acute manifestations, it leads to graft fibrosis and reduced graft survival. We have identified novel gene pathways that are implicated in the development of acute rejection in kidney transplant patients who were taking standard of care immunosuppression. This project aims to further explore the role of the Caspase 1 signaling pathway in the development of acute rejection by using kidney transplant models, to evaluate new agents for the prevention and treatment of rejection and develop new tools to identify patients at risk of acute rejection. Having highlighted the importance of the Caspase 1/IL-1/IFN-gamma axis in acute rejection we propose to determine which of these molecules and key driver genes are central to its development, as these may be potential targets for new therapeutic approaches for treatment or prevention of AR. Mice with conditional or complete deletions of these key driver or related genes will be studies to determine their impact on rejection. In addition we will use a drug repurposing strategy to evaluate drugs already in use for other indications that can block several of these key genes and to identify new therapeutic agents for their ability to prevent or reverse acute rejection.

Additional Information

We have access to mice with conditional or complete deletions of many of the key driver genes that initiate acute transplant rejection. The mice will be used in a model of kidney transplant rejection to ascertain what effect deletion of these pathways have on the rejection response. Finally we will use novel drug repurposing strategies to identify new therapeutic agents for their ability to prevent or reverse AR.

Keywords

transplantation, Acute rejection, Kidney, Caspase 1, Drug repurposing, genomics

Opportunity ID

The opportunity ID for this research opportunity is: 2259

Other opportunities with Professor Philip O'Connell

• Identifying the causes of fibrosis after kidney transplantation