John Turk, MD, PhD
Professor of Medicine and Director, Mass Spectrometry Resource
Academic Positions
1982-1986 Assistant Professor of Medicine, of Pharmacology, and of Pathology, Washington University, St. Louis, MO
1986-1987 Associate Director of Exploratory Clinical Pharmacology, Ciba-Geigy Corporation, Pharmaceuticals Division, Summit, NJ
1988-1994 Associate Professor of Medicine and of Pathology, Washington University, St. Louis, MO
1994-present Professor of Medicine and of Pathology, Washington University, St. Louis, MO
Research Interests
The hypothesis that a pancreatic islet Ca2+-independent phospholipase A2 (iPLA2β) is activated by secretagogues and that its products participate in b-cell signaling is being pursued with recently developed tools, including insulinoma cells with stably altered iPLA2β expression that exhibit secretory and proliferative properties and sensitivities to Endoplasmic Reticulum (ER) stress that correlate with iPLA2βb expression level. New ESI/MS/MS methods for lipid analyses reveal that iPLA2β overexpression enhances stress-induced ceramide accumulation and increases lysophosphatidylcholine (LPC) levels. New proteomics tools reveal that β-cells proteolytically remove an iPLA2β inhibitory domain and that iPLA2β hydrolyzes its inhibitor BEL to an intermediate that alkylates cysteine. New iPLA2β fluorescent constructs reveal that iPLA2β translocates to perinuclear membranes in stimulated β-cells, and it interacts with Ca2+/calmodulin-dependent protein kinase IIb. Recently generated iPLA2β-null mice have reduced male fertility and impaired macrophage NO synthase induction and become more glucose intolerant than wild-type mice on a high-fat diet. The emphasis is now shifting to in vivo studies, but work continues on Aims to: 1.) Characterize insulinoma cells with altered iPLA2β or g expression with respect to secretion, proliferation, ER stress, and ion channel function; 2.) Characterize diet-induced changes in b-cell and tissue desaturases and lipids; 3.) Characterize iPLA2β protein modifications; 4.) Conduct cell biologic studies of iPLA2β isoform-specific organelle association and protein interactions; and 5.) Characterize genetically modified mice with altered iPLA2 expression. With iPLA2β-null and transgenic mice, insulin sensitivity and secretion are being examined in vivo, as are dietary effects on glucose-tolerance, body composition, and mortality; macrophage sensitivity to cholesterol-induced apoptosis; and atherogenesis in apoE-/-/iPLA2β-/- double knockout mice. Goals also include preparing mice with tissue-specific alterations of iPLA2β expression or altered iPLA2γ expression. The public health relevance is that manipulating iPLA2 expression might be useful in genetic engineering of β-cell lines for Type I diabetes mellitus (DM) cellular replacement therapy, and mechanisms to expand β-cell mass and improve insulin secretion in Type II DM could also be identified. Studies with iPLA2β-null mice could also provide evidence that iPLA2β pharmacologic inhibitors might have beneficial therapeutic effects, and our iPLA2β inactivation studies might provide insight into inhibitor design.
Awards and Honors
- National Merit Scholarship, 1966-1970
- National Merit Scholarship, 1966-1970
- Wallace Award in History, Washington University, 1968
- Elected to Phi Beta Kappa honor society, Washington University, 1969
- National Science Foundation Undergraduate Research Fellowship, 1969
- A.B. summa cum laude, Washington University, 1970
- Medical Scientist Training Program Award, Washington University, 1970-1976
- Cori Award in Biological Chemistry, Washington University School of Medicine, 1972
- Elected to Alpha Omega Alpha honor society, Washington University, 1975
- Career Development Award, Pharmaceutical Manufacturer’s Association, 1983-1985
- Research Career Development Award, National Institutes of Health, 1987-1992
- Elected to American Society for Clinical Investigation honor society, 1991
- Study Section Membership, National Institutes of Health, 1992-1996
- MERIT Award, National Institutes of Health, 1993-2001
- Elected to Association of American Physicians honor society, 2001
- MERIT Award, National Institutes of Health, 2001-2011
- Appointed to the Editorial Board, Journal of Biological Chemistry, 2007-2012