Office of Research and Development

Home

 

Departments

 

Search

 

Department · Name/Training · Academic Degrees · Contact Information · Grant Support · Publications · Previous Graduate Students · Current Research Projects · Specialized Lab/Clinical Research Resources · Back to Department List  

Eppley Institute

Oksana Lockridge, Ph.D.

Back to Top

ACADEMIC DEGREES:
Medical/Graduate School: Northwestern University, Evanston, IL
Residency/Fellowship Training
Post-doctoral Training: University of Michigan Medical School, Ann Arbor, MI

Back to Top

Contact Name:  Oksana Lockridge, Ph.D.
Phone Numbers: 402 559-6032
e-mail address:  olockrid@unmc.edu

Back to Top

Principal investigator on W911SR-04-C-0019 from Department of the Army.  Project period 01 March 2004 to 28 February 2007.  Total cost (direct and indirect) $950,000.  Title:  Molecular toxicology and proteomics to identify biomarkers of chemical agent toxicity.

Co-Investigator on W81XWH-06-1-0102 Department of Defense.  Steven H. Hinrichs PI.  Total cost (direct and indirect) $864,763.  Amount for O. Lockridge project $300,000.  21 October 2005 to 20 October 2006. Title:  Neurotoxin mitigation.

Back to Top

Masson P, Nachon F, Bartels CF, Froment MT, Ribes F, Matthews C, Lockridge O (2003) High activity of human butyrylcholinesterase at low pH in the presence of excess butyrylthiocholine. Eur J Biochem 270:315-324. 

Li B, Duysen EG, Volpicelli LA, Levey AI, Lockridge O (2003)  Regulation of muscarinic acetylcholine receptor function in acetylcholinesterase knockout mice.  Pharmacology, Biochemistry, and Behavior 74: 977-986 

Volpicelli-Daley LA, Duysen EG, Lockridge O, Levey AI (2003) Altered hippocampal muscarinic receptors in acetylcholinesterase-deficient mice. Ann Neurol 53:788-96. 

Bernard V, Brana C, Liste I, Lockridge O, Bloch B (2003) Dramatic depletion of cell surface m2 muscarinic receptor due to limited delivery from intracytoplasmic stores in neurons of acetylcholinesterase-deficient mice. Mol Cell Neurosci 23:121-33. 

Saxena A, Fedorko JM, Vinayaka CR, Medhekar R, Radic Z, Taylor P, Lockridge O, Doctor BP (2003) Aromatic amino-acid residues at the active and peripheral anionic sites control the binding of E2020 (Aricept) to cholinesterases. Eur J Biochem 270: 4447-4458. 

Nicolet Y, Lockridge O, Masson P, Fontecilla-Camps JC, Nachon F (2003) Crystal structure of human butyrylcholinesterase and of its complexes with substrate and products.  J Biol Chem 278: 41141-41147. 

Volpicelli-Daley LA, Hrabovska A, Duysen EG, Ferguson SM, Blakely RD, Lockridge O, Levey AI (2003) Altered Striatal Function And Muscarinic Cholinergic Receptors In Acetylcholinesterase Knockout Mice. Mol Pharmac 64: 1309-1316. 

Masson P, Goldstein BN, Debouzy JC, Froment MT, Lockridge O, Schopfer LM (2004) Damped oscillatory hysteretic behaviour of butyrylcholinesterase with benzoylcholine as substrate.  Eur J Biochem 271: 220-234. 

Masson P, Bec N, Froment MT, Nachon F, Balny C, Lockridge O, Schopfer LM (2004) Rate-determining step of butyrylcholinesterase-catalyzed hydrolysis of benzoylcholine and benzoylthiocholine.  Volumetric study of wild-type and D70G mutant behaviour.  Eur J Biochem 271: 1980-1990. 

Wang Y, Boeck AT, Duysen EG, Van Keuren M, Saunders T, Lockridge O (2004) Resistance to organophosphorus agent toxicity in transgenic mice expressing the G117H mutant of human butyrylcholinesterase.  Toxicol Appl Pharmacol 196: 356-366. 

Wang Y, Schopfer LM, Duysen EG, Nachon F, Masson P, Lockridge O (2004) Screening assays for cholinesterases resistant to inhibition by Organophosphorus toxicants.  Anal Biochem 329: 131-138. 

Schopfer LM, Boeck AT, Broomfield CA, Lockridge O.  (2004) Mutants of human butyrylcholinesterase with organophosphate hydrolase activity;  evidence that His117 serves as a general base catalyst in the hydrolysis of echothiophate.  J Med Chem Defense 2: 1-21 (online publication) 

Adler M, Manley HA, Purcell AL, Deshpande SS, Hamilton TA, Kan KR, Oyler G, Lockridge O, Duysen EG, Sheridan RE (2004) Reduced acetylcholine receptor density, morphological remodeling, and butyrylcholinesterase activity can sustain muscle function in acetylcholinesterase knockout  mice.  Muscle Nerve 30: 317-327. 

Bytyqi AH, Lockridge O, Duysen E, Wang Y, Wolfrum U, Layer PG (2004) Impaired formaton of the inner retina in an AChE knockout mouse results in degeneration of all photoreceptors.  Eur J Neurosci 20: 2953-2962. 

Nachon F, Asojo OA, Borgstahl G, Masson P, Lockridge O (2004) Role of water in aging of human butyrylcholinesterase inhibited by echothiophate.  The crystal structure suggests two alternative mechanisms of aging.  Biochemistry.  In press. 

Peeples ES, Schopfer LM, Duysen EG, Spaulding R, Voelker T, Thompson CM, Lockridge O (2005) Albumin, a new biomarker of organophosphorus toxicant exposure, identified by mass spectroscopy.  Tox Sci 83: 303-312 

Lockridge O, Duysen EG, Voelker T, Thompson CM, Schopfer LM (2005) Life without acetylcholinesterase:  the implications of cholinesterase inhibitor toxicity in AChE-knockout mice.  Environmental Toxicology and Pharmacology 19: 463-469. 

Schopfer LM, Voelker T, Bartels CF, Thompson CM, Lockridge O (2005) Reaction kinetics of biotinylated organophosphorus toxicant,  FP-biotin, with human acetylcholinesterase and human butyrylcholinesterase.  Chem Res Toxicol 18: 747-754. 

Saez-Valero J, Perez de Gracia JA, Lockridge O (2005) Intraperitoneal administration of 340 kDa human plasma butyrylcholinesterase increases the level of the enzyme in the cerebrospinal fluid (2005) Neuroscience Letters 383: 93-98. 

Lockridge O, Schopfer LM, Winger G, Woods JH (2005)  Large scale purification of butyrylcholinesterase from human plasma suitable for injection into monkeys;  a potential new therapeutic for protection against cocaine and nerve agent toxicity.   J Medical Chemical  Biological & Radiological Defense Volume 3, published online 1 Jul 2005. 

Schopfer LM, Champion MM, Tamblyn N, Thompson CM, Lockridge O (2005) Characteristic Mass Spectral Fragments of the Organophosphorus Agent FP-biotin and FP‑biotinylated Peptides from Trypsin and Bovine Albumin (Tyr410). Anal Biochem 345: 122-132. 

Li B, Sedlacek M, Manoharan I, Boopathy R, Duysen EG, Masson P, Lockridge O (2005)  Butyrylcholinesterase, paraoxonase, and albumin esterase, but not carboxylesterase,  are present in human plasma.  Biochem Pharmacol 70: 1673-1684. 

Hrabovska A, Duysen EG, Sanders JD, Murrin LC, Lockridge O (2005)  Delivery of human acetylcholinesterase by adeno-associated virus to the acetylcholinesterase knockout mouse.  Chem Biol Interact  157-158: 71-78. 

Masson P, Schopfer LM, Froment MT, Debouzy JC, Nachon F, Gillon E, Lockridge O, Hrabovska A, Goldstein BN (2005) Hysteresis of butyrylcholinesterase in the approach to steady-state kinetics.  Chem Biol Interact 157-158: 143-152. 

Nachon F, Asojo OA, Borgstahl G, Masson P, Lockridge O (2005) Structural data on the aging of diethylphosphoryl-butyrylcholinesterase.  Chem Biol Interact 157-158: 408-409. 

Li H, Schopfer L, Spaulding R, Thompson CM, Lockridge O (2005) Identification of organophosphate-reactive proteins by tandem mass spectrometry.  Chem Biol Interact 157-158: 383-384. 

Li B, Duysen EG, Poluektova LY, Murrin LC, Lockridge O (2006) Protection from the toxicity of diisopropylfluorophosphate by adeno-associated virus expressing acetylcholinesterase.  Toxicol Appl Pharmacol . Epub ahead of print. 

De Jaco A, Comoletti D, Kovarik Z, Gaietta G, Radic Z, Lockridge O, Ellisman MH, Taylor P (2006) A mutation linked with autism reveals a common mechanism of endoplasmic reticulum retention for the alpha, beta hydrolase-fold protein family.  J Biol Chem.  Epub ahead of print.

Back to Top   

  • PREVIOUS GRADUATE STUDENTS/POST-DOCTORAL FELLOWS (present location):

Dr. Arnaud Chatonnet, research scientist at INRA-ENSA, Montpellier, France
Dr. Martine Arpagaus, research scientist at INRA-ENSA, Montpellier, France
Dr. Gus Vatsis, research scientist at University of Michigan Medical School, Ann Arbor, MI
Dr. Morena Kris, Florida
Dr. Denis Josse, research scientist in France
Dr. Florian Nachon, research scientist in France
Dr. Anna Hrabovska, research scientist in Slovakia
Dr. Yuxia Wang, research scientist in China

Graduate students:
Dr. Renee Blong, Professor in Sioux City, Iowa
Dr. Cibby Varkey-Altamirano, Post-doctoral fellow in Los Angeles, CA
Weihua Xie, M.S. research manager at Duke University, NC
Dr. Bin Li, Post-doctoral fellow at UNMC

Back to Top

Organophosphorus compounds are used as pesticides, plasticizers, pharmaceuticals, in hydraulic fluid, in jet engine fuel, and as chemical warfare agents.  Acute toxicity from exposure to organophosphorus agents is due to inhibition of acetylcholinesterase.  Our laboratory made the acetylcholinesterase knockout mouse using the technique of gene targeting.  One of the interesting features of this mouse is that it is supersensitive to the toxic effects of organophosphorus pesticides.  For over 50 years the dogma has been that organophosphorus toxicity is due to inhibition of acetylcholinesterase.  Why then in the absence of acetylcholinesterase is the mouse sensitive to organophosphorus agents? We think there are other targets of toxicity and we have made it our goal to identify these other targets.  Identification of novel targets for organophosphorus toxicity may lead to an understanding of Gulf War Illness, chemical sensitivity, and airline cabin crew illness.  We are using mass spectrometry to identify proteins that react with organophosphorus compounds.

To evaluate the pharmacological significance of a protein suspected to be involved in organophosphorus toxicity, we are making other knockout mice.  For example, we are making the butyrylcholinesterase knockout mouse. 

Back to Top

Techniques used in our laboratory include mass spectrometry to identify proteins, PCR, enzyme activity assays, gel electrophoresis, cloning, expression of recombinant enzymes in cultured cells, purification of enzymes by column chromatography and HPLC, maintaining our knockout mouse colony, genotyping, and toxicity studies in mice.  In the current year our focus is heaviest on mass spectrometry.

Back to Top