Understanding the functional development and plasticity of Interstitial cells of Cajal: Potential ta

Supervisors: Dr Simon Eaton

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

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.

Methods:
The student will initially characterise the functional development of human ICC, using human fetal material provided via the MRC-Wellcome Trust Human Developmental Biology Resource (HDBR), by a combination of intracellular microelectrode electrophysiology, standard immunohistochemical assays and state-of-the-art imaging techniques. The student will also design and generate a novel mouse model, in collaboration with UCL Transgenic Services. Once generated, the student will examine ICC plasticity using a combination of small animal surgical techniques, intracellular microelectrode electrophysiology and scRNA transcriptomics. Finally, the student will attempt to modulate ICC plasticity, within this novel mouse model, through application of targeted compounds. These studies will generate fundamental insights into the ability to pharmacologically modulate ICC, along with refining our understanding of the functional development of the GI neuromuscular syncytium.

References:

  1. Ward SM, Burns AJ, Torihashi S, Sanders KM. Mutation of the proto-oncogene c-kit blocks development of interstitial cells and electrical rhythmicity in murine intestine. J Physiol. 1994;480 ( Pt 1):91-7.
  2. Sanders KM, Kito Y, Hwang SJ, Ward SM. Regulation of Gastrointestinal Smooth Muscle Function by Interstitial Cells. Physiology (Bethesda). 2016;31(5):316-26.
  3. Chang IY, Glasgow NJ, Takayama I, Horiguchi K, Sanders KM, Ward SM. Loss of interstitial cells of Cajal and development of electrical dysfunction in murine small bowel obstruction. J Physiol. 2001;536(Pt 2):555-68.
  4. McCann CJ, Hwang SJ, Bayguinov Y, Colletti EJ, Sanders KM, Ward SM. Establishment of pacemaker activity in tissues allotransplanted with interstitial cells of Cajal. Neurogastroenterol Motil. 2013;25(6):e418-28. 
  5. McCann CJ, Alves MM, Brosens E, Natarajan D, Perin S, Chapman C, Hofstra RM, Burns AJ, Thapar N. Neuronal Development and Onset of Electrical Activity in the Human Enteric Nervous System. Gastroenterology. 2019;156(5):1483-1495