Programme(s) to which this project applies:
|☑ MPhil/PhD||☒ MRes[Med]||☒ URIS|
Hirschsprung (HSCR) disease is the most common congenital enteric neuropathy, caused by the defects of enteric neural crest cells (ENCCs), leading to intestinal obstruction. It is characterized by the absence of nerve cells in the colon along a variable length of the intestine. Surgical resection of the aganglionic bowel is the standard treatment for HSCR patients, but functional outcome is variable, some of HSCR patients still suffer from life-long complications such as intractable constipation or incontinence.
Stem cell therapy is a promising avenue for treating HSCR for functional recovery in the future. Nevertheless, how to guide the transplanted stem cells to make the functional neuronal network is still a formidable challenge. Answering these questions requires a detailed understanding of the key molecular mechanisms underlying the development of the enteric nervous system. We have established various mouse, human pluripotent stem cell (hPSC)-based cell- and organoid-models for disease modelling. Through comparing the transcriptomes of mouse and hPSC-derived ENCCs (hENCCs) at single cell level and building the differentiation trajectories along the neuronal lineage, the key molecular events directing the formation of enteric neurons have been defined and the data emphasize that the in vivo neuronal differentiation process can be nicely recapitulated in vitro using hPSC. The hPSC model allows us to map the genome-wide chromatin accessibility and identify the active enhancers that regulate hENCC gene networks. In addition, through performing a high-resolution single-cell (scRNA-seq) analysis of hENCCs derived from HSCR patients, the core gene set associated with the HSCR and disease severity was defined. The important next step is to make use of these information for the development of a cell-based therapy to restore the ENS function of HSCR patients.
In this project, the team will develop a robust method for (1) the generation of functional enteric neurons from the control and HSCR-hPSC via targeting the key pathways implicated in neurogenesis. In parallel, using mouse model, we will (2) define the signaling molecules regulating the formation of enteric ganglion. In addition, we will (3) evaluate how extrinsic factors influence ENS development using the second generation of colonic organoid model. From these studies, we will obtain the critical information for establishing the regimen to make cells for cell-based replacement therapy of HSCR.
Multiple MPhil and PhD student positions currently available.
Professor ESW Ngan, Department of Surgery
Professor Elly Sau-wai Ngan is a professor in the department of Surgery, LKS Faculty of Medicine. Her main research interest is to translate the genetic data obtained from patients into biology to understand the molecular mechanisms underlying pathogenesis of neural crest associated diseases, with a particular focus on neuroblastoma and Hirschsprung disease (HSCR). Her laboratory has established various disease models using human pluripotent stem cell (hPSC)-derived cell- and organoid models and transgenic/knock-out mice to decode the functional impacts of HSCR associated mutations in enteric nervous system development. The recent focus of her group is to develop methods for generation of functional neurons for cell-based therapy.
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