Regulation of the Phenotype and Regeneration of ICC

Project 5

Project Leader: Sean M. Ward, Ph.D.

Abstract

Over 20 million people in the US have diabetes mellitus (DM). Of patients with DM, type II accounts for 190-95% of all diagnosed cases. Many diabetic patients develop significant gastrointestinal symptoms, with up to 60% of longstanding diabetics suffering from delayed gastrointestinal transit, diarrhea or constipation. Chronic constipation associated with type II DM, in addition to diarrhea and incontinence, is increasingly regarded as having serious effects on patient quality of life. Current treatments of GI complications have considerable side-effects and therefore a greater understanding of the disease would provide novel targets for treatment and possible cure. The current dogma is that GI disorders associated with type II DM is an ICC pacemaker activity and the 'in-series' relationship that exists between enteric motor nerves and intramuscular ICC. The loss of Kit-labeling of ICC associated with DM in humans and animal models has been attributed to cell death though the apoptotic signaling pathway or transdifferentiation. We investigated whether ICC homeodynamics are affected by increased apoptosis or decreased cell division. The mechanism(s) of cell growth and expansion of ICC populations will be investigated in type II DM tissues allotransplanted with ICC. In summary, this proposal will provide important information about the defects in ICC networks (which are involved in pacemaker activity and in enteric neuromuscular transmission within the GI tract) that occur in the GI tracts of patients with type II DM. New information will be obtained about the processes underlying the disruption of neuromuscular function in the GI tracts of animal models with DM, that may be causative in delayed intestinal transit, constipation or diarrhea in human patients.