The overall objective of this proposal is to examine in detail the intramural mechanisms responsible for peristaltic behavior in the smooth muscle portion of the esophagus. Specifically, this will involve the use of electrophysiological intracellular recording techniques to examine synaptic transmission between intramural nerves of the myenteric plexus in the esophagus as well as at the neuromuscular site. The results of these studies should provide an increased understanding of the intramural neuromuscular mechanisms involved in esophageal peristalsis and lead to a better understanding of the pathophysiology and management of such esophageal disorders as achalasia and diffuse esophageal spasm. Dr. Crist is presently an Instructor in Medicine in the Gastroenterology Division of the Beth Israel Hospital and Harvard Medical School. Under the sponsorship of Dr. Raj K. Goyal, he has been the recipient of an Individual National Research Service Award (1983-1985) and a Clinical Investigator Award (1985-1988) to study the mechanisms responsible for esophageal peristalsis. Studies by the candidate during this time period have resulted in six original publications (see Appendix). Through funding provided by the Clinical Investigator Award Dr. Crist has most recently worked in the laboratory of Drs. R.A. North and A. Surprenant at Massachusetts Institute of Technology. This experience has allowed Dr. Crist to become knowledgeable in the electrophysiological techniques to be used in the present proposal. The sponsor, Dr. Raj K. Goyal, is Professor of Medicine at Harvard Medical School and Chief of Gastroenterology at Beth Israel Hospital and is an acknowledged leader in the area of gastrointestinal motility. Dr. Goyal's sponsorship, as well as the surrounding investigators at Beth Israel Hospital and Harvard Medical School, should provide an excellent environment for the candidate's studies and overall development toward becoming an independent investigator.
|Gerthoffer, William T (2005) Signal-transduction pathways that regulate visceral smooth muscle function. III. Coupling of muscarinic receptors to signaling kinases and effector proteins in gastrointestinal smooth muscles. Am J Physiol Gastrointest Liver Physiol 288:G849-53|
|Roth, Ulrike; Curth, Katja; Unterman, Terry G et al. (2004) The transcription factors HIF-1 and HNF-4 and the coactivator p300 are involved in insulin-regulated glucokinase gene expression via the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem 279:2623-31|
|Crist, J R; He, X D; Goyal, R K (1992) Both ATP and the peptide VIP are inhibitory neurotransmitters in guinea-pig ileum circular muscle. J Physiol 447:119-31|
|Crist, J R; He, X D (1991) Noncholinergic membrane potential responses to transmural nerve stimulation in the guinea pig ileum. Am J Physiol 260:G240-9|
|Crist, J R; He, X D; Goyal, R K (1991) The nature of noncholinergic membrane potential responses to transmural stimulation in guinea pig ileum. Gastroenterology 100:1006-15|
|Kauvar, D; Crist, J; Goyal, R K (1989) Effect of cold temperature on membrane potential responses in opossum esophageal circular muscle. Am J Physiol 257:G637-43|