Director, Swallowing and Motility Program, VA Boston Health Care System, West Roxbury Campus
Associate Chief of Research and Development, VA Boston Health Care System, West Roxbury Campus
Dr. Goyal’s research in physiology and pathophysiology of motility disorders includes studies in intact animals, in isolated muscle strips, and in isolated smooth muscle cells. Dr. Goyal’s group uses genetically engineered mice lacking specific enzymes that are involved in the regulation of gastrointestinal motility. Brain stem circuits in swallowing reflex and transient lower esophageal sphincter: In these studies, superior laryngeal nerve and the subdiaphragmatic gastric branches of the vagus are electrically stimulated in the anesthetized mice to elicit swallow-associated esophageal peristalsis and lower esophageal sphincter relaxation. Esophageal motility is recorded by intraluminal manometry and c-fos expression in the brain stem neurons elicited by the above nerve stimulation is examined. The study of c-fos activated neurons provides information on the brain stem circuits that are involved in swallowing and transient lower esophageal sphincter which has been shown to be a major factor in the pathogenesis of gastro-esophageal reflux disease. These studies are focused on identifying the chemical mediators in these circuits and may provide targets for therapeutic agents for the transient lower esophageal sphincter relaxation. Role of neuronal nitric oxide syntheser in esophageal and gastric motility disorders: Mice genetically incapable of expressing either neuronal or endothelial forms of constitutive nitric oxide syntheses (nNOS and eNOS) have been generated by gene targeted disruption. Mice lacking nNOS develop enlarged stomachs. Using transluminal manometry and transit studies, the Goyal laboratory is investigating whether these animals develop esophageal achalasia. Moreover, these animals have been shown to develop gastric stasis and gastric bezoars. Parallel studies in animal models of experimental diabetes with gastroparesis and other models of gastroparesis, such as mice lacking c-kit, are providing new insights in the pathophysiology of gastroparesis associated with diabetes mellitus and other causes. Role of nitric oxide in inhibitory neuro-transmission: Hiroshi Mashimo, M.D., Ph.D., and Hemant Thatte, Ph.D., who are members of the motility group, are investigating the cellular mechanics involved in the nitreregic neurotransmission in different parts of the gut. Their research is focused on identifying the enzymatic source of nitric oxide involved in its neurotransmitter functions. They are also investigating how nitric oxide is produced during neurotransmission. They are testing the hypothesis that peptide VIP, which is localized with nNOS in the nerve terminals, serves as an intermediary in an autoctrine fashion. These studies utilize a variety of techniques including imaging studies using a two-photon confocal microscopy. Biochemical basis of sphincter and non-sphincteric smooth muscles: The myogenic properties of the gastrointestinal sphincters and the non-sphincteric regions are quite distinct. The sphincters develop and maintain spontaneous tone whereas the non-sphincteric muscles do not exhibit spontaneous tone and contract physically upon stimulation. Studies are being performed to identify biochemical differences, if any, in the composition and isoforms of contractile proteins in the two muscle types. Studies so far have shown that there are many important differences between the lower esophageal sphincter (tonic muscle) and the esophageal circular muscle (phasic muscle). The esophageal non-sphincter muscle has a relatively higher ratio of gamma to alpha action, a different myosin isoform, ratio of and caldesmon to calponin as compared to the lower esophageal sphincter. Studies are in progress to identify other potential differences in the two muscle phenotypes and relate the observed differences to their functional phenotype. Ionic basis of smooth muscle contractility and their dysfunction during inflammation: Ion channels govern membrane excitability and therefore regulate the excitation-contraction coupling of gastrointestinal smooth muscle. Hamid Akbarali, Ph.D., is studying the functional role of several types of ion channels in the esophagus. He is using patch clamp techniques, intracellular Ca2+ measurements and biochemical approaches to identify the regulation of ion channels by protein kinases and the physiological role that these channels play in the overall function of the gastrointestinal smooth muscle. His research program is aimed at defining the cellular basis of functional disorders of the esophagus and gastrointestinal smooth muscle. These studies have identified that inflammatory mediators can directly affect ion channel function and in models of colitis, for instance, there is marked downregulation of Ca2+ channels. He has also recently identified a novel K+ channel, the HERG-like channel, that appears to be a potential target for the action of the prokinetic agent, cisapride in the esophagus. The biophysical studies of the HERG-like K+ channel suggest that it plays an important role in maintaining the resting potential of smooth muscle. Since mutations in the HERG channel are known to produce cardiac abnormalities, e.g. long QT syndrome, characterization of the properties of this channel in gastrointestinal smooth muscle are important for the development of novel prokinetic agents. In a second area of research, this laboratory is studying ionic changes in smooth muscle when inflamed. The contractions of the colon, mediated by smooth muscle cells, require increases in intracellular calcium. In colitis, colonic motor activity is markedly depressed. The laboratory has been studying Ca2+ and K+ channels in a chemically-induced model of colitis in mice. A significant decrease in the Ca2+ channel function, with no alteration in the biophysical properties of the K+ channel, has been found. This suggests that changes in ion channel function in colitis are specifically limited to a Ca2+ entry leading to a less excitable smooth muscle. Similar findings in genetic models of colitis are currently being pursued.
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