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Mar 29, 2019

RPG Seminar Series (Speaker: Miss CHAN Ka Ching / Miss DENG Linyan)

Date: Friday, 29 March 2019

Venue: Seminar Room 4, G/F
Laboratory Block, Faculty of Medicine Building
21 Sassoon Road, Hong Kong

Time: 5:00 p.m.


Title: Discovering Druggable Gene Combinations for Parkinson’s Disease by CombiGEM-CRISPR
Speaker: Miss CHAN Ka Ching (MPhil candidate)

Summary:
Multigenic perturbations lead to many human diseases including Parkinson’s disease (PD), which is the second most common neurodegenerative disease. Discovering synergistic drug combinations that target the perturbed genes could improve motor symptoms and suppress neurodegeneration in PD. However, conventional methods in identifying promising drug combinations are labor intensive and cost-ineffective. Our newly developed screening platform, combinatorial genetics en masse (CombiGEM)-CRISPR enables rapid assembly of barcoded combinatorial genetic libraries for high-throughput functional characterization of genetic perturbations. To facilitate the discovery of effective drug combinations, here we applied CombiGEM-CRISPR to explore the interactions between druggable genes in two widely used PD cell models. A pairwise guide RNA library comprising 7,569 combinations, targeting 28 druggable genes that are shown to modulate PD-related toxicity, was assembled. Specific druggable gene knockouts that rescue cells from toxicities in the two PD models were identified. The identification of effective druggable gene combinations paves the way for exploring the therapeutic efficacy of the corresponding drugs for future therapeutic development.


Title: The role of HSP90β in regulating AChR clustering at developing neuromuscular junction
Speaker: Miss DENG Linyan (PhD candidate)

Summary:
Aggregation of acetylcholine receptors (AChRs) at the postsynaptic membrane represents one of the prominent steps in neuromuscular synaptogenesis. Previous study has shown that heat shock protein 90β (HSP90β) is crucial for AChR clustering at neuromuscular junctions (NMJs). However, the exact role of HSP90β in AChR re-distribution and clustering remains unclear. In this study, we aim to test a hypothesis that HSP90β regulates the assembly of podosome-like-structure (PLS), which in turn control the formation and stability of AChR clusters. When muscle cells were cultured at low temperature, we detected an elevated level of HSP90β expression and an inhibition of AChR cluster formation. A similar observation was seen when HSP90β activity was pharmacologically inhibited by 17-AAG, a potent HSP90 inhibitor derived from the antibiotic geldanamycin. Our preliminary immunostaining data further suggested that HSP90β regulates the formation of aneural AChR clusters by stabilizing focal adhesion kinase (FAK), which may subsequently affect the localization of talin, a PLS cortex marker, at aneural AChR clusters. Future studies will investigate the functional roles of HSP90β-FAK signaling in regulating the redistribution of AChRs from the aneural to the postsynaptic specializations during neuromuscular synaptogenesis through PLS dynamics.

 

ALL ARE WELCOME