Understanding how nNOS signaling in the gut influences the development, maintenance and function of interstitial cells of Cajal. (360G-Wellcome-212388_Z_18_Z)

Loss of neuronal nitric oxide synthase (NOS1, a.k.a nNOS) neurons has been implicated in a range of gastrointestinal motility disorders including Achalasia, Gastroparesis and Diabetes. Recent studies have demonstrated that global knockout of Nos1 results in reduced populations of interstitial cells of Cajal (ICC). This key population is crucial for pacemaker function and neurotransmission within the gut wall. Interestingly, rescue of NOS1+ neurons in the Nos1-/- colon after transplantation of enteric neural stem cells leads to restoration of ICC numbers, suggesting NO signaling may be critical for the development of ICC. However, it is unclear whether such changes in ICC are a direct result of NO (nitric oxide) signaling or are a secondary consequence of other phenomena. The goal of this project is to: assess the effects of temporal perturbation of NO signaling on the functional development of ICC. The key aims of this project are to: i) develop an inducible Nos1 conditional knockout mouse model to allow temporal control of NO signaling. ii) assess neuronal composition and iii) the development/function of ICC after inducible knockout of Nos1. This study will provide key evidence as to NO-regulated ICC development, which might play a key role in normal motility and disease.