The objectives of the present research proposal are to investigate: 1) details of the nonadrenergic-noncholinergic inhibitory neurotransmission in the IAS; 2) the neural pathways and role of regulatory neurohumoral substances such as opiates in basal IAS tone and rectoanal inhibitory reflex-induced IAS relaxation; and 3) the cellular basis of the intrinsic myogenic tone in the IAS, particularly the so-called latch state. Studies are planned in vivo and in vitro in which the activity of the IAS will be isolated from that of the external anal sphincter (EAS) by simultaneous electrical and mechanical recordings. Studies will be performed to examine the structure-activity relationship, receptor binding, second messengers, immunocytochemical localization of physiologically relevant neuropeptides, radioimmunoassay (RIA) of neuropeptides, the direct release of mediators, membrane potential changes using intracellular electrical recordings, changes in the free intracellular Ca2+, PI turnover, protein kinase C and myosin light chain phosphorylation. While these studies will yield a diverse spectrum of information, they will be specifically aimed at elucidating specific objectives. These studies will be performed in opossums, but other animal species will also be used to determine species differences in the control of the sphincter. The proposed studies should provide important information leading to a better understanding of the pathophysiology and the treatment of anorectal disorders.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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Hamilton, Frank A
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Thomas Jefferson University
Internal Medicine/Medicine
Schools of Medicine
United States
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Singh, Jagmohan; Mohanty, Ipsita; Rattan, Satish (2018) In vivo magnetofection: a novel approach for targeted topical delivery of nucleic acids for rectoanal motility disorders. Am J Physiol Gastrointest Liver Physiol 314:G109-G118
Mohanty, Ipsita; Parija, Subas Chandra; Suklabaidya, Sujit et al. (2018) Acidosis potentiates endothelium-dependent vasorelaxation and gap junction communication in the superior mesenteric artery. Eur J Pharmacol 827:22-31
Kumar, S; Singh, J; Rattan, S et al. (2017) Review article: pathogenesis and clinical manifestations of gastrointestinal involvement in systemic sclerosis. Aliment Pharmacol Ther 45:883-898
Rattan, Satish (2017) Ca2+/calmodulin/MLCK pathway initiates, and RhoA/ROCK maintains, the internal anal sphincter smooth muscle tone. Am J Physiol Gastrointest Liver Physiol 312:G63-G66
Singh, Jagmohan; Mohanty, Ipsita; Addya, Sankar et al. (2017) Role of differentially expressed microRNA-139-5p in the regulation of phenotypic internal anal sphincter smooth muscle tone. Sci Rep 7:1477
Krishna, Chadalavada Vijay; Singh, Jagmohan; Thangavel, Chellappagounder et al. (2016) Role of microRNAs in gastrointestinal smooth muscle fibrosis and dysfunction: novel molecular perspectives on the pathophysiology and therapeutic targeting. Am J Physiol Gastrointest Liver Physiol 310:G449-59
Singh, Jagmohan; Boopathi, Ettickan; Addya, Sankar et al. (2016) Aging-associated changes in microRNA expression profile of internal anal sphincter smooth muscle: Role of microRNA-133a. Am J Physiol Gastrointest Liver Physiol 311:G964-G973
Mandaliya, Rohan; Burkart, Ashlie L; DiMarino, Anthony J et al. (2016) Association between common variable immunodeficiency and collagenous infiltrative disorders of the gastrointestinal tract: A series of four patients. Indian J Gastroenterol 35:133-8
Kumar, Sumit; Singh, Jagmohan; Kedika, Ramalinga et al. (2016) Role of muscarinic-3 receptor antibody in systemic sclerosis: correlation with disease duration and effects of IVIG. Am J Physiol Gastrointest Liver Physiol 310:G1052-60
Mandaliya, Rohan; DiMarino, Anthony J; Moleski, Stephanie et al. (2015) Survey of anal sphincter dysfunction using anal manometry in patients with fecal incontinence: a possible guide to therapy. Ann Gastroenterol 28:469-74

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