Stem cell therapy for the treatment of achalasia and gastroparesis
This joint PhD project will be based at The University of Melbourne with a minimum 12 month stay at KU Leuven
Project title: Stem cell therapy for the treatment of gastrointestinal motility disorders: targeting defects in neuronal wiring
Gastroparesis and achalasia are debilitating gastrointestinal disorders caused by the selective loss of nitrergic neurons (which contain neuronal nitric oxide synthase, nNOS) from the enteric nervous system in the stomach and oesophagus, respectively. Patients suffer from severe abdominal pain, nausea, and have chronic long-term problems, including increased risk of oesophageal cancer. These are also some of the most challenging clinical conditions to manage, as there are currently no effective pharmacological treatments. Thus, there is a lot of interest in potential of a stem cell therapy to replace missing enteric neurons, restore ENS circuitry and normal gut motility.
In this PhD project, we will apply the knowledge and techniques that we have developed to investigate the generation and transplantation of nNOS specific precursors for the treatment of achalasia and gastroparesis in an nNOS-/- mouse model. We hypothesise that transplanted nNOS precursors will integrate into the existing circuitry, communicate with muscle cells at the lower oesophageal sphincter (junction of oesophagus and stomach) and pylorus (junction of stomach and small intestinal) to restore normal motility. Further, using knowledge gained from RNAseq analysis of differentiation of nNOS neurons during embryonic development, we will program patient-derived induced pluripotent stem cells (iPSCs) into nNOS specific precursors for transplantation. This will be the first study to investigate stem cell therapy as a potential treatment for achalasia, and the first study to generate patient-derived nNOS precursors.
We will use the knowledge and techniques that we developed to investigate the transplantation of nNOS specific precursors for the treatment of a mouse model of gastroparesis and achalasia. This is the first project to investigate stem cell therapy as a potential treatment for achalasia, and the first study to generate patient-derived nNOS precursors. This will be achieved through the following objectives:
Objective 1: To generate nNOS specific precursors from mice and patient-derived induced pluripotent stem cells (iPSCs).
Hypothesis: iPSCs can be programmed into nNOS precursors by the manipulation of expression of specific transcription factors important in nNOS neuronal differentiation.
Objective 2: To transplant nNOS precursors into the stomach and oesophagus of nNOS-/- mice
Hypothesis: nNOS precursors transplanted into the stomach and at the level of the lower oesophageal sphincter will survive and project to innervate smooth muscle cells.
Objective 3: To investigate integration of transplanted nNOS precursors with the recipient’s neuro-muscular network.
Hypothesis: Transplanted nNOS precursors will integrate into the existing ENS network and communicate with recipient smooth muscle cells.
The project will be complemented by the project on Defects in long-distance neuronal wiring in the large intestine and in Hirschsprung’s Disease and the collaboration will ensure a successful completion of the project.
Principal Investigators (PIs)
Co-Principal Investigators (co-PIs)