Sally Twining, Ph.D.

Professor

Dr. Twining received her Doctorate degree in Physiological Chemistry from Ohio State University. She did postdoctoral work at the Mayo Clinic in immunochemistry and at the Medical College of Wisconsin in proteinase activation. 

Contact Information

stwining@mcw.edu
Phone: (414) 456-8431
Fax: (414) 456-6510 

Research Interests

The two major projects in the laboratory are elucidation of the role of proteinases and proteinase inhibitors in corneal wound healing and corneal ulceration and exploration of the effects of maspin in corneal wound healing and in carcinogenesis.

The cornea has two functions; refraction of light and protection of the eye. Retention of the avascularity and transparency of the cornea is crucial for vision. Understanding the mechanism of normal and abnormal corneal wound healing is important because of the number of refractive surgeries of performed each year. Upon wounding, the external barrier is reassembled through the movement of the epithelial cells from the non-injured regions of the cornea followed by cell division and stratification of the epithelial layer. In the stroma, the cells near the injury undergo apoptosis. Cells more distant from the wound divide and undergo a phenotypic change to form mobile fibroblasts and with time the formation of contractile myofibroblasts. The fibroblasts and myofibroblasts remodel the area of apoptosis. With time this area is repopulated with the quiescent normal keratocytes. In humans, this process can continue for 7-10 years.

Maspin is a non-inhibitory member of the Serpin (SERpin Protease INhibitor) family. It stimulates adhesion of cells to extracellular matrix molecules and inhibits migration and invasion of cells including corneal stromal fibroblasts and carcinoma cells. Our previous work showed that the reactive site loop peptide is sufficient for activity. Our model of maspin function in the cornea includes regulation of migration of corneal cells by downregulation of maspin synthesis in the stromal fibroblast and myofibroblast phenotypes which allows migration of these cells into the wounded area. Maspin released by the intact epithelial layer above the wounded cornea inhibits migration of the cells as they repopulate the wounded area. Maspin also regulates wound healing by modifying the levels of proteins involved in this process. Other functions of maspin on corneal and on carcinoma cells are now being pursued.

During wound healing, cornea synthesized thrombin, the last enzyme of the coagulation pathway, is activated by coagulation factors synthesized by the corneal cells. The roles of thrombin, in addition to cleavage of fibrinogen to fibrin, in cornealwound healing are being explored. Whether the mechanism of thrombin function in the cornea involves the activation of the thrombin sensitive protease activated receptors is being studied.

One of the major causes of corneal ulceration is bacterial keratitis. Bacteria invasion of host tissues requires proteinases that degrade host tissues. Corneal isolates of Pseudomonas aeruginosa synthesize two forms of elastase. The difference in these forms is currently being studied.

Selected Publications

"Regulation of the Urokinase Pathway by Corneal Fibroblasts and Myofibroblasts." A.M. Bernstein, S.S. Twining, D.J. Warejcka, E. Tall, and S.K. Masur. Mol. Biol. Cell, 18, 2716-2727 (2007)

"Corneal activiation of prothrombin to thrombin independent of vascular injury." A. Ayala, D.J. Warejcka, M. Olague-Marchan and S.S. Twining. Invest. Ophthalmol. Vis. Sci., 48, 134-143 (2007)

"Differential conversion of plasminogen to angiostatin by human corneal cell populations." D.J. Warejcka, K.A. Vaughan, A.M. Bernstein and S.S. Twining.  Mol. Vis. 47, 859-868 (2005)

"The Fibrinolysis Inhibitor alpha2-Antiplasmin in the human Cornea." A. Ayala, D.J. Warjecka, K. Vaughan, BYJT Yue and S.S. Twining. Curr. Eye Res. 1097-1103 (2005)

"Specific conformational changes of plasminogen induced by chloride ions, 6-aminohexanoic acid and benzamidine but not the overall openness of plasminogen regulate production of biologically active angiostatins." D.J. Warejcka and S.S. Twining. Biochem. J., 392, 703-712 (2005)

"Identification of a Novel Secreted Protease from Pseudomonas aeruginosa that Causes Corneal Erosions." M.E. Marquart, A.R. Caballero, M. Chomnawang, B.A. Thibodeaux, S.S. Twining, R.J. O'Callaghan. Invest. Ophthalmol. Vis. Sci., 46(10):3761-3768 (2005)

"The effects of sub-solar levels of UV-A and UV-B on rabbit corneal and lens epithelial cells." C.S. Rogers, L.M. Chan, Y.S. Sims, K.D. Byrd, D.L. Hinton and S.S. Twining. Exp. Eye Res., 78(5):1007-1014 (2004)

"Mutation of lasA and lasB reduces Pseudomonas aeruginosa invasion of epithelial cells."B.A. Cowell, S.S. Twining, J.A. Hobden, M.S. Kwong and S.M. Fleiszig. Microbiology, 149(Pt 8):2291-2299 (2003)

"Sufficiency of the reactive site loop of maspin for induction of cell-matrix adhesion and inhibition of cell invasion. Conversion of ovalbumin to a maspin-like molecule." C. Ngamkitidechakul, D.J. Warejcka, J.M. Burke, W.J. O'Brien and S.S. Twining. J. Biol. Chem., 278(34): 31796-31806 (2003)

"Buffered non-fermenter system for lab-scale production of secreted recombinant His-tagged proteins in Saccharomyces cerevisiae." C. Ngamkitidechakul and S.S. Twining. Biotechniques., 33(6): 1296-1300 (2002)

"Functional characterization of arginine 30, lysine 40, and arginine 62 in Tn5 transposase." S.S. Twining, I.Y. Goryshin, A. Bhasin, W.S. Reznikoff. J. Biol. Chem., 276(25): 23135-23143 (2001)

"Maspin: synthesis by human cornea and regulation of in vitro stromal cell adhesion to extracellular matrix." C. Ngamkitidechakul, J.M. Burke, W.J. O'Brien, S.S. Twining. Invest. Ophthalmol. Vis. Sci., 42(13): 3135-41(2001)

"A critical role for neutrophil elastase in experimental bullous pemphigoid." Z. Liu, S.D. Shapiro, X. Zhou, S.S. Twining, R.M. Senior, G.J. Giudice, J.A. Fairley, L.A. Diaz. J. Clin. Invest., 105(1): 113-123 (2000)

"Blood glucose laboratory for first-year medical students: an interdisciplinary model for nutrition-focused diabetes management." S.A. Reiter, C.R. McGill, S.L. Lawrence, S.S. Twining. J. Am. Diet Assoc., 100(5): 570-572 (2000)

"A disease-associated glycine substitution in BP180 (type XVII collagen) leads to a local destabilization of the major collagen triple helix." M. Olague-Marchan, S.S. Twining, M.K. Hacker, J.A. McGrath, L.A. Diaz, G.J. Giudice. Matrix Biol., 19(3): 223-233 (2000)

"The serpin alpha1-proteinase inhibitor is a critical substrate for gelatinase B/MMP-9 in vivo." Z. Liu, X. Zhou, S.D. Shapiro, J.M. Shipley, S.S. Twining, L.A. Diaz, R.M. Senior, Z. Werb. Cell, 102(5): 647-655 (2000)

"Extrahepatic Synthesis of Plasminogen in the Human Cornea is Up-Regulated by Interleukins-1 S.S. Twining, P.M. Wilson, and C. Ngamkitdaichakul. Biochem. J., 339: 705-712 (1999)

"Tn5: A molecular window on transposition." W.S. Reznikoff, A. Bhasin, D.R. Davies, I.Y. Goryshin, L.A. Mahnke, T. Naumann, I. Rayment, M. Steiniger-White, S.S. Twining. Biochem. Biophys. Res. Commun., 266(3): 729-734 (1999)

"Involvement of Sp1 Elements in the Promoter Activity of the Y. Li, L. Zhou, S.S. Twining, J. Sugar, and B.Y.T. Yue. J. Biol. Chem., 273: 9959-9965 (1998)

"Local control of alpha1-proteinase inhibitor levels: regulation of alpha1-prote inase inhibitor in the human cornea by growth factors and cytokines." G. Boskovic, S.S. Twining. Biochim. Biophys. Acta., 1403(1): 37-46 (1998)

"Changes in Rat Corneal Matrix Metalloproteinases and Serine Proteinases under Vitamin A Deficiency." S.S. Twining, D.P. Schulte, P.M. Wilson, B. Fish and J. Moulder. Curr. Eye Res., 16: 156-165 (1997)

"Retinol and Retinaldehyde Specifically increase G. Boskovic and S.S. Twining. Biochem. J., 322: 751-756 (1997)