Analysis of EZH2 mediated neurogenic-to-gliogenic switch in development of enteric neurons and gastrointestinal motility disorders

Professor Ngan, Elly Sau Wai   (Principal Investigator (PI))

Dr Lau Cynthia Sin Ting   (Co-Investigator)

42

2021-08-01

1500000

Analysis of EZH2 mediated neurogenic-to-gliogenic switch in development of enteric neurons and gastrointestinal motility disorders

enteric nervous system, Hirschsprung disease, human pluripotent stem cell, mouse model, neural crest

Others - Medicine, Dentistry and Health

08192786

Health and Medical Research Fund - Full Grant

2020

On-going

Many of enteric motility disorders are due to the abnormalities in enteric nervous system (ENS), including Hirschsprung (HSCR) disease, chronic intestinal pseudo-obstruction (CIPO) and enteric dysmotility (ED). Our preliminary data suggest that EZH2 is a master regulator for the neurogenic-to-gliogenic differentiation of ENS progenitors and dysregulations of EZH2 direct targets represent one of the major mechanisms underlying various gut motility disorders as seen in human. Objectives: We aim to define the implications of EZH2 in ENS development and the associated diseases. Hypothesis: We hypothesize that the timely expression of EZH2 is critical for regulating neurogenic-to-gliogenic lineage differentiation of ENS progenitors, and EZH2 represents a therapeutic target for various gastrointestinal motility disorders. Design and subjects: We will use our mouse and human models of gut dysmotility to delineate the roles of EZH2 in ENS development and define the therapeutic value of EZH2 inhibitors. Study instruments and interventions: Various in vivo functional characterizations and in vitro differentiation assays will be performed with our mouse mutants and HSCR-induced pluripotent stem cell lines to define the biological roles of EZH2. The corresponding molecular changes will be determined through epigenomic and transcriptomic profiling. Main outcome measures: Functional impacts of EZH2 will be determined based on how they may interfere the formation of various enteric neurons. Data analysis and expected results: The cellular phenotypes and the regulomes of the control and diseased enteric neurons with functional or defective EZH2 will be compared to delineate the therapeutic value of targeting EZH2 for various gastrointestinal motility disorders.