Gastrointestinal (GI) motility is controlled by intestinal pacemaker cells, smooth muscle cells and the enteric nervous system (ENS) acting independently as the ?second brain? in the gut. ENS abnormalities cause many GI motility disorders. In 1899, Bayliss and Starling proposed the classic ?The law of the intestine? stating that ?excitation at any point of the gut excites contraction above, inhibition below?, suggesting that distinct intrinsic excitatory and inhibitory intestinal motor behaviors can be elicited by mechanical forces. Recent studies have also demonstrated that mechanosensitivity is required to drive intestinal motor behaviors such as the colonic migrating motor complex (CMMC) resulting from either direct activation of ENS or by serotonin release from enterochromaffin cells (ECs) in the gut epithelium by mechanical forces. However, the molecules, cells, and neural circuits governing the process of mechanosensitivity in the gut still remain poorly understood. Membrane-bound ion channels play an essential role in mechanotransduction. Recent exciting studies have identified the mechanosensitive Piezo channels as molecular sensors for mechanical forces in the skin and have significantly advanced our knowledge about the role of the Piezo channels in our senses of light touch and mechanical pain. However, The role of Piezo channels involved in the mechanosensitivity in the gut and other visceral organs is poorly understood. Preliminary studies showed that chemical activation of Piezo1 promotes colon contraction and increases CMMC frequency, suggesting that Piezo1 is functionally expressed by both cholinergic excitatory and nitrergic enteric neural circuits. More importantly, Piezo1 is required for normal colonic motility in vivo. We thus hypothesize that Piezo1 is a molecular sensor for mechanical forces in the GI tract and potentially could serve as a therapeutic drug target for treating GI motility disorders such as slow transit constipation. To test this hypothesis, we will take a multidisciplinary approach using live-cell Ca2+ imaging, patch-clamp recordings and pharmacological approaches in combination to mouse genetics and intestinal motor behavioral methods to elucidate the cellular and molecular mechanisms underlying the Piezo1-mediated mechanosensitivity in both ENS and intestinal epithelium. Successful completion of these studies will advance our understanding of the previously unrecognized roles of Piezo1 and Piezo1-expressing enteric neurons and ECs in controlling GI motility. More importantly, these studies will offer new opportunities for developing effective and safer medicines for GI motility disorders.
Gastrointestinal motility disorders are a major clinic problem and significantly impacts quality of life and productivity. Although ?The law of the intestine? suggests that distinct intrinsic excitatory and inhibitor motor behaviors can be elicited in the intestines by mechanical forces since their introduction by Bayliss and Starling nearly 120 years ago, the mechanisms underlying the conversion of mechanical forces into gastrointestinal motility in the gut are still poorly understood. The current proposal aims to understand the cellular and molecular mechanisms underlying our senses of mechanical forces in the gut and facilitate identification of novel therapeutic approaches for treating gastrointestinal motility disorders.
Showing the most recent 10 out of 16 publications
