Understanding the functional development and plasticity of Interstitial cells of Cajal

Project title: Understanding the functional development and plasticity of Interstitial cells of Cajal: Potential targets for gut motility disorders

Supervisors names
Conor McCann
Simon Eaton

Background
Gastrointestinal (GI) motility disorders exist as a wide range of diseases that can affect nearly all regions of the GI tract. Such conditions arise from disruption of the neuromuscular syncytium, via loss of specific cell populations or disturbances in neuromuscular signalling. GI motility disorders are notoriously difficult to treat, with current treatments limited to chronic pharmacological management of symptoms or surgical intervention which are associated with significant morbidity and poor outcomes. Hence, there is a critical need to develop alternative approaches to treat these diseases.

The case for interstitial cells of Cajal (ICC): ICC, which express the receptor tyrosine kinase c-Kit and exist within extensive networks throughout the intestinal tract, have been shown to play a pivotal role in GI motility through the generation of pacemaker activity, by exhibiting slow-wave potentials, and transducing neural signals to smooth muscle. Crucially, murine studies have demonstrated that loss or disruption of ICC leads to disruption of pacemaker activity and GI dysmotility. Moreover, a reduction in ICC has been noted in various diseased tissues in humans including achalasia, gastroparesis, chronic intestinal pseudo-obstruction, slow transit constipation, Crohn’s disease and Hirschspung disease, demonstrating the critical role that ICC play in gut disease. The long-term vision of this research postulates that pharmacological manipulation of ICC may provide a possible therapeutic application for the treatment of GI motility disorders. 

Aims/Objectives:
1)    Assess the functional development of ICC in the developing human gut.
2)    Develop a conditional mouse model to allow plasticity studies of ICC.
3)    Determine the druggability of ICC as a potential treatment for GI motility disorders.

Contact
Conor McCann (conor.mccann@ucl.ac.uk)