Background
Exposure to toxic insults (carcinogens, poison, drug overdose) is an everyday event. At the cellular level, it triggers acute injury pathways of cell death and inflammation across multiple solid organs (liver, kidney). Rapid recovery is common and is seen in most people. However, the recovery pathway in a significant proportion of people is maladaptive, characterized in the liver and kidney by scarring (fibrogenesis). This project tests the proposition that maladaptive repair in two solid organs is indistinguishable at the cellular and molecular level. The findings will provide important evidence of efficacy for anti-fibrotic agents beyond a single organ system.
External supervisors:
Associate Professor Helen Healy | Helen.Healy@health.qld.gov.au
Approach
To identify the common pro-fibrotic molecular signals in the cellular pathways that trigger toxin-induced scarring in liver and kidneys.
Project potential
The study will use an unbiased multi-omics ‘biomarker discovery’ platform to identify the key signalling mechanisms (exosomes, genes, small RNA, proteins, metabolites) that trigger toxin-induced scarring in liver and kidneys. Data will be generated in established clinical/experimental models, including:
- human kidney tissue (biopsies from patients with toxin-induced acute kidney injury),
- in vitro models of liver (primary murine hepatic stellate cells) and kidney (primary human kidney tubular cells) fibrosis, and
- a murine model of multi-organ liver-kidney fibrosis (thioacetamide-induced toxicity).
The discovery of novel biomarkers will guide next-phase check-point therapeutic targeting in these toxin-induced fibrosis models.
Technologies:
- Spatial multi-omics (RNA-seq, miRNA scope, proteomics, metabolomics)
- Extracellular vesicle and multi-omic profiling
- Multi-parameter immuno-fluorescent microscopy
- In vitro and in vivo check-point targeting
Outcome
The study will generate a functionally validated set of biomarkers activated in toxin-induced liver and kidney fibrosis, guiding future clinical therapeutic translation to patients at presentation that will prevent long-term outcomes of multi-organ scarring.