Professor of Pathology
| Office Location: | West Building 3709 | |
| Mailing Address: | 660 S. Euclid Ave. Campus Box 8118 St. Louis, MO 63110 |
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| Phone: | (314) 362-7435 | |
| Fax: | (314) 362-4096 | |
| E-mail Address: |
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Research Interests
Cytokins (IL-1, TNFë4, IFN() released by both T-lymphocytes and activated macrophages have been implicated as immunological effetor molecules that both inhibit insulin secretion from the pancreatic β-cell and produce β-cell destruction. Our studies have demonstrated that production of the free radical nitric oxide (NO), resulting from the expression of the inductible isoform of NO synthase (iNOS), mediates these dellterious effects. The cellular mechanism responsible for inhibition of β-cell function and destruction by NO involves, in part, inactivation of enzymes specifically localized to the β-cell mitochondria that contain iron-sulfur centers or clusters. Recent studies indicate that IL-1 co-expresses both iNOS and the cytokine-inducible isoform of cyclooxygenase, COX-2. The expression of COX-2 results in the overproduction of the proinflammatory prostaglandins (PGE2) and thromboxanes. Studies to identify the signaling mechanisms that mediate IL-1-induced co-expression of iNOS and COX-2 include characterization of the IL-1 receptor, tyrosine kinases(s), the proteasome complex, and the transcription factor NF6B.
Although growth factors and nutrients stimulate β-cell growth, the specific mitogenic signals responsible for this effect are not clearly defined. Insulin and other growth factors induce increases in protein syntheses, in part, by stimulating mRNA translation. PHAS-I, a recently identified binding protein of the initiation factor, eIF-4E, exerts a key role in this process. Recent studies have implicated a signaling pathway involving the mammalian target of rapamycin (mTOR) as an upstream regulator of PHAS-I phosphorylation. Our findings indicate that the nutrient, glucose, mediates the phosphorylation of PHAS-I by stimulating insulin secretion which then interacts in an autocrine manner with its own insulin receptor on the β-cell. Furthermore, rapamycin inhibits both glucose-stimulated protein synthesis by isolated islets and serum-induced cell proliferation by β-cell target downstream signaling proteins, mTOR and PHAS-I, in β-cells and this may represent an important cellular mechanism for the regulation of β-cell function and growth.
