Human cellular platforms for studying the regulation and therapeutic application of autophagy

Autophagy is an intracellular degradation pathway essential for cell survival. Stimulating this process is beneficial in diverse diseases, including certain neurodegenerative and liver disorders. However, therapeutic exploitation of autophagy in patients has not been achieved. Our studies indicate that not all autophagy inducers identified in non-human or immortalised human cells are effective when applied to people with disease, indicating cell-type specificity of drug action. This discrepancy cannot be resolved until the precise regulation of autophagy in the human system is elucidated.

In this proposal, we aim to establish the first physiological and disease-relevant human cellular platforms to study the autophagy landscape using human embryonic stem cells (hESCs) and hESC-derived disease-relevant cell-types. We have generated stable reporter and autophagy-deficient hESC lines using genome editing. We will investigate the autophagy-regulating kinome in hESCs, and establish hESC-derived neuronal and hepatic cultures with quantifiable autophagy readout to measure the kinetics.

We will extend this study to understand the regulation of autophagy in these human cellular platforms, and to identify human tissue-specific autophagy modulators for therapeutic applications.