ProfessorPhilip O'Connell

Project Opportunities

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

Summary of opportunity:

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.

Opportunity 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.

Project Opportunities

Title: Identifying the causes of fibrosis after kidney transplantation

Summary of opportunity:

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.

Opportunity synopsis:

We have identified a 13 gene set that predicts renal transplant fibrosis and graft loss in patients. Interestingly some of these genes are donor as well as recipient related. In this project we aim to investigate these gene pathways in cell lines and animal models to better understand how the cause of renal fibrosis after transplantation.

The aim of this project is to identify gene pathways that are responsible for progressive fibrosis following renal transplantation. We have identified a predictive gene set in renal transplant patients that is capable of classifying renal allografts at risk for progressive injury due to fibrosis and the development of fibrosis at 1 year. The high predictive capacity of the gene set (AUC=0·967) was superior to clinical indicators. The 13-genes also accurately predicted early allograft loss (AUC-0·842 and 0·844 at 2- and 3-yrs respectively). Investigation of the genes indicate that collectively they represent both donor and recipient biological pathways. Donor pathways of potential importance include the Notch/Wnt and HIF pathways. These 13 genes will be selectively and independently deleted using CRISPR/Cas9 in cell lines of proximal tubular cell, endothelial cell and mesangial cell lines to determine if the produce a proinflammatory phenotype. From this assay genes of interest will be screened in Zebra fish wilh a readout for renal impairment and in conditional knock-out mice where available. The role of HIF-1a pathway and its impact on the 13 gene set will be evaluated in with conditional HIF-1a KO targeted at the proximal tubular cell. Recipient gene pathways including the TNF pathway will be evaluated by similar screening methods. Mouse models used to evaluate fibrosis include well established models of renal ischemia reperfusion injury, ureteric obstruction and mouse allogeneic and syngeneic transplantation.

----------Current Research Projects----------

2016-2019 JDRF Australian type 1 diabetes clinical research network: Concept Proposal Title: Expanding the criteria for human islet transplantation by the development of a drug free immunosuppressive protocol. Award: $3.3 million over 4 years. Investigators: PJ O’Connell (PI), S Grey, J Holmes-Walker, S Alexander, K Donaghue, T Kay, P Coates, W Hawthorne. J Gunton.

2018-2021 NH&MRC Project Grant APP1146493. Title: Identifying donor and recipient gene pathways in renal transplant fibrosis.

Award: $1,067,130.00 over 4 years. Investigators: PJ O’Connell, D Harris, S Grey, G Zheng, S Yi.

2019-2023 NH&MRC Program Grant APP1150425. Title: Intervening in the natural history of type 1 diabetes; an integrated approach.

Award: $9.46 million over 5 years. Investigators: T Kay, L Harrison, A Lew, PJ O’Connell.