Burton Wice, Ph.D.
Instructor in Medicine
| Office Location: | ||
| Mailing Address: | 660 S. Euclid Ave. Campus Box 8127 St. Louis, MO 63110 |
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| Office: | (314) 747-0423 | |
| Laboratory: | (314) 747-3194 | |
| Fax: | (314) 747-2692 | |
| E-mail Address: |
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Education
University of Missouri-Columbia, Columbia, MO (1971-1974)
University of Missouri-St. Louis, St. Louis, MO, B.A. in Biology (1975)
Washington University, St. Louis, MO, Ph.D. (1992)
Active Research (8/21/2000)
A. Insulin is produced only by β -cells in the pancreatic islets of Langerhans and is essential for maintaining normoglycemia and energy balance in post-natal vertebrates. Insulin production and secretion is under tight nutritional, hormonal, and metabolic control. Type 2 diabetes mellitus is characterized by insulin deficiency- both impaired insulin action and a lack of insulin production and secretion. One of the objectives of my laboratory is to understand the molecular mechanisms that regulate insulin production and secretion by islet β -cells. Basic helix loop helix (bHLH) proteins, in cooperation with homeobox proteins, are transcription factors essential for insulin gene expression. Therefore, molecules that regulate bHLH function are predicted to affect insulin transcription. Ids 1-4 are naturally occurring dominant/negative proteins thought to inhibit bHLH activity. We have shown that Ids are expressed at high levels in β -cells and their expression is induced by insulin secretagogs. Ironically, these observations suggest that physiological levels of Id proteins may promote, rather than inhibit, insulin gene transcription by titrating the activity of inhibitory molecules. To test this hypothesis, we are engineering insulinoma cell lines and transgenic mice with β -cell-specific, doxycycline-regulated Id-1 expression- levels of Id-1 will increase with increasing doses of doxycycline. These novel models will be used to discern the physiologic and pathophysiologic roles of Id proteins in β -cell physiology, insulin production/secretion, and glycemic control. We are also trying to understand how nutrients regulate Id-1 gene expression in β -cells. We have shown that the glucose-response element is located in the 5’-region of the Id-1 gene. Unexpectedly, we have demonstrated the presence of a β -cell-specific silencer located downstream of the Id-1 structural gene. Deletion studies are underway to identify the specific cis-acting elements and trans-acting factors responsible for regulated Id-1 gene expression.
B. Type 1 diabetes mellitus (T1DM) is characterized by the absence of pancreatic islet β -cells and thus, insulin production. Patients with this disease require exogenous insulin to control their blood glucose levels. One strategy for treating T1DM is to genetically engineer non-β -cells to transcribe, translate, process, and secrete insulin. However, all studies to date have engineered insulin production/secretion in cell populations that do not recapitulate the correct regulation and timing of insulin production and secretion. For example, "glucose-induced" insulin transcription has been engineered in liver cells but a) this transcriptional response is delayed many hours relative to that of β -cells and b) the insulin is released at all times rather than in response to elevated blood glucose levels. In other words, insulin would be produced and released by hepatocytes even when blood glucose levels are normal. This would subject the patient to the dire consequences of severe hypoglycemia. Endocrine cells of the intestine (entero-endocrine or "EE" cells) represent the largest endocrine organ in the body. Intriguingly, they also express many of the same regulatory genes and exhibit many properties of pancreatic islet β -cells. Incretin-producing EE cells synthesize, process and secrete peptide hormones with regulatory and temporal patterns resembling those of insulin production/secretion by β -cells. For example, incretin hormones are released within minutes of ingesting a meal. EE cells (like other intestinal epithelial cells) are also amenable to permanent transduction using retrovirus-mediated gene transfer techniques. These observations suggest that properly engineered, incretin-producing EE cells should be able to confer nutrient-regulated insulin production/secretion for the lifetime of a patient. We are currently engineering chimeric genes to confer nutrient-regulated insulin production/secretion by EE cells in transgenic mice. Animals will be analyzed to determine whether insulin produced/secreted by the EE cells can restore glucose homeostasis in diabetic mice. Future studies will focus on techniques to introduce transgenes into EE cells of adult animals.
