• Targeting β-catenin/Foxo to maximize anti-inflammatory and wound healing effects while preventing profibrotic effects of TGF-β as a novel treatment of chronic kidney diseases.

Summary

21,000 Australians receive kidney replacement therapy and many more die of kidney failure as a result of kidney fibrosis. TGF-β, a growth factor causing kidney fibrosis, is also anti-inflammatory and promotes healing. We aim to prove that targeting downstream messengers (Foxo/β-catenin) of TGF-β will prevent fibrosis while promoting TGF-β's anti-inflammatory and healing actions. A successful outcome will lead to a novel cure for preventing kidney failure and failure of other organs.

Supervisor(s)

Dr Guoping Zheng, Professor David Harris

Research Location

Westmead - Westmead Institute for Medical Research

Program Type

PHD

Synopsis

Kidney fibrosis is a key process driving progression of chronic kidney disease (CKD) toward end stage kidney disease (ESKD), yet to date there is no established treatment specifically targeting kidney fibrosis. In Australia currently almost 21,000 patients with ESKD require expensive life-long dialysis or a kidney transplant to stay alive. TGF-β has long been identified as the most important cytokine causing fibrosis in all inflammatory diseases. However, inhibition of TGF-β will also suppress its anti-inflammatory and wound healing actions. Our lab was the first to show that β-catenin can be targeted specifically to separate TGF-β's profibrotic and anti-inflammatory effects (published in J Cell Sci) and our preliminary data provide strong evidence that Foxo/β-catenin is the pivotal target to dissect "wanted" from "unwanted" effects of TGF-β in fibrotic inflammatory diseases such as CKD. The hypotheses will be examined in our established in vitro and in vivo models of inflammation and fibrosis and and human kidney biopsy specimens, using robust techniques including T cell fate mapping, CRISPRcase9 gene editing and Cre-lox mediated conditional knockout.

Additional Information

Dr. Guoping Zheng's research has been focused on matrix metalloproteinases (MMPs), epithelial-mesenchymal transition (EMT) and differentiation of TGF-β profibrotic vs anti-inflammatory effect in kidney fibrosis. His PhD degree was supported by a Dora Lush scholarship (NHMRC). By extending his research expertise in cancer research to the field of kidney disease, he has developed several novel proposals which resulted in 3 successful NHMRC project grant applications (APP402435, 632688 as CIB &1046647 as CIA). He was awarded an NHMRC Peter Doherty Fellowship in 2007 for a project using conditional knockout to investigate molecular mechanisms involved in kidney fibrosis. He was awarded Westmead Institute Science Prize in 2006, 2010 & 2013, Westmead Fellowship in 2016, and was the Finalist of Basic Science Award in 2016 APCN/ANZSN.

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Keywords

Chronic kidney diseases, diabetes, kidney transplantation, transforming growth factor beta, E-cadherin, Beta-catenin, FoxOs, Fibrosis, kidney failure

Opportunity ID

The opportunity ID for this research opportunity is: 2215

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