Thursday, November 21, 2024
11/21/2024
Summary Colonic motility is the product of myogenic and neurogenic factors that regulate the excitability of smooth muscle cells (SMCs). Part of the myogenic component of regulation is due to interstitial cells of Cajal (ICC) that have critical functions in gastrointestinal (GI) motility. ICC form gap junctions with SMCs and convey regulatory inputs to a syncytium of SMCs and PDGFRa+ cells (SIP syncytium). Some ICC generate pacemaker activity that is responsible for phasic contractions in some regions of the GI tract. ICC are closely associated with motor neurons, express receptors for major neurotransmitters and transduce inputs from enteric motor neuro- transmission. The physiology of ICC is important because multiple studies have suggested that defects in ICC develop in patients and may be responsible for a range of motility disorders. While much has been learned about ICC in other organs of the GI tract, far less is known about ICC in the colon. During the past funding period we characterized the basic behaviors of 3 of the 4 types of colonic ICC. Little is known about ICC in the myenteric region (ICC-MY) that do not act as conventional pacemakers, yet we hypothesize they drive major propulsive contractions in the colon. This hypothesis will be addressed by pursuing three specific aims: 1. Determine mechanisms responsible for propagated Ca2+ waves in ICC-MY. 2. Determine the role of ICC in generating patterned and propulsive contractions in the colon. 3. Characterize mechanisms of action of major neurotransmitters on activation of ICC-MY. To pursue these aims we will use imaging, optogenetic, transgenic, electrophysiological and contractile techniques that allow in depth testing of cellular mechanisms in ICC without disruption of their anatomical and functional interactions with other cells in colonic muscles. Integration of ICC behaviors with SMCs and PDGFRa+ cells will also be investigated to learn how subcellular Ca2+ signaling in ICC can generate whole organ motility patterns. The impact of enteric motor neural inputs on Ca2+ handling mechanisms in ICC-MY will also be investigated to understand previously overlooked mechanisms of neural regulation of colonic motility. Parallel studies will be conducted on human colonic muscles to test the role of signature ICC conductances and Ca2+ handling mechanisms in colonic motor activity. These comparative studies will help develop a generalized concept of ICC functions in colonic motility and determine the validity of using mice to help clarify the functions of ICC in human motility. This project will determine the role of ICC-MY in patterned and propulsive contractions in the colon, and studies of animals with defects in ICC will demonstrate how/why motility is negatively impacted by defects in or loss of ICC.
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