Vanderbilt University School of Medicine

Davies, Sean S. , Ph.D.
Assistant Professor of Pharmacology

Lab Url: http://www.mc.vanderbilt.edu/root/vumc.php?site=seandavieslab

Phone Number: 322-5049

Email Address:Sean.Davies@vanderbilt.edu

Davies, Sean's picture

Office Address   Mailing Address

506A RRB

506A RRB Clinical Pharmacology 6602


Research Keywords
Oxidative Stress, Lipid Aldehydes, Protein Modification, Microbiota, Peptide Therapeutics, Drug Delivery, Chronic Diseases

Research Specialty
Treatment of chronic disease by modulating oxidative stress

Research Description
Oxidative stress, defined as abnormally high levels of reactive oxygen species, has been implicated in a variety of chronic diseases including atherosclerosis, diabetes, and Alzheimer?s disease. The overarching theme of my research is to utilize pharmacological interventions to determine the role of oxidative stress in human physiology and pathophysiology. The three major research foci of my lab are 1) the role of specific products of oxidative stress, the isoketals, in the pathogenesis of chronic disease such as atherosclerosis, diabetes, and Alzheimer?s disease, 2) the mechanisms whereby risk factors such as obesity and aging increase oxidative stress in these diseases, and 3) development of better long-term treatment strategies for chronic diseases using enteric bacteria engineered to produce therapeutic compounds.

ISOKETALS

Oxidative stress generates many lipid peroxidation products that may be important in chronic diseases. My interest focuses on reactive gamma-ketoaldehydes isoketals (IsoKs), that are some of the most highly toxic products of lipid peroxidation. Therefore, abrogating their effects may be crucial to treating chronic conditions linked to oxidative stress. The IsoKs rapidly adduct to lysyl residues of proteins and exogenously added IsoK disrupts the function of a number of critical cellular enzymes. We measure adducts by LC/MS/MS and anti-isoketal antibody immunostaining. Ongoing studies to identify sites of IsoK adduction will yield important mechanistic insights into how IsoKs induce cellular and organ dysfunction.

MECHANISMS OF OXIDATIVE INJURY

Understanding how known risk factors for chronic diseases induce oxidative injury should provide additional targets for therapeutic interventions. I have chosen to focus on obesity and aging. Obesity significantly increases oxidative stress in both rodents and humans. Studies in obese rodents indicate that systemic lipid peroxidation levels (measured as F2-isoprostanes (IsoP) levels) correlate with visceral fat mass. Caloric restriction rapidly and markedly reduces system lipid peroxidation levels in certain models, without markedly reducing absolute visceral fat mass. We therefore are examining the mechanisms linking obesity, caloric restriction, and systemic lipid peroxidation.

Aging, like obesity, is a common risk factor for many chronic diseases. Interestingly, systemic levels of IsoPs are no higher in healthy older adults than young adults. We hypothesize that older adults can maintain control over reactive oxygen species formation under resting conditions, but lose the ability to maintain control under significant stress (e.g. infectious disease or physical trauma) leading to dramatically increased oxidative injury during these acute events. We test this hypothesis using moderate forearm ischemia/reperfusion (I/R). In collaboration with the Kronos Longevity Research Institute, we study the response of young and older adults after various interventions to this I/R challenge.

BACTERIALLY PRODUCED PEPTIDES FOR TREATMENT OF CHRONIC DISEASE

Drug therapy for hypercholesterolemia, hypertension, obesity, and hyperglycemia (all linked to oxidative stress) lowers the incidence of cardiovascular disease. Unfortunately, the cost of long-term therapy is a tremendous economic burden and limits the feasibility of novel therapies that might provide benefit only if given prophylactically for many years. We are investigating a novel approach to long-term drug production and delivery utilizing stable colonization of enteric bacteria to express drugs such as omega-3 desaturase, ApoAI mimetic peptides, ACE inhibitor-like peptides, GLP-1, insulin, or lovastatin. Efficacy will be examined in atherosclerotic mice. This approach essentially takes the notion of gene therapy and rather than altering the genomic DNA, instead alters the DNA of commensal bacteria, a far more tractable system.


Publications
Chopra, N, Laver, D, Davies, SS, Knollmann, BC. Amitriptyline activates cardiac ryanodine channels and causes spontaneous sarcoplasmic reticulum calcium release. Mol Pharmacol, 75(1), 183-95, 2009. PMCID:2685059

Bernardo, A, Harrison, FE, McCord, M, Zhao, J, Bruchey, A, Davies, SS, Jackson Roberts, L, Mathews, PM, Matsuoka, Y, Ariga, T, Yu, RK, Thompson, R, McDonald, MP. Elimination of GD3 synthase improves memory and reduces amyloid-beta plaque load in transgenic mice. Neurobiol Aging, , , 2008.

Davies, SS. Modulation of protein function by isoketals and levuglandins. Subcell Biochem, 49, 49-70, 2008.

Davies, SS, Amarnath, V, Brame, CJ, Boutaud, O, Roberts, LJ. Measurement of chronic oxidative and inflammatory stress by quantification of isoketal/levuglandin gamma-ketoaldehyde protein adducts using liquid chromatography tandem mass spectrometry. Nat Protoc, 2(9), 2079-91, 2007.

Davies, SS, Brantley, EJ, Voziyan, PA, Amarnath, V, Zagol-Ikapitte, I, Boutaud, O, Hudson, BG, Oates, JA, Roberts, LJ. Pyridoxamine analogues scavenge lipid-derived gamma-ketoaldehydes and protect against H2O2-mediated cytotoxicity. Biochemistry, 45(51), 15756-67, 2006. PMCID:2597444

Davies, SS, Zackert, W, Luo, Y, Cunningham, CC, Frisard, M, Roberts, LJ. Quantification of dinor,dihydro metabolites of F(2)-isoprostanes in urine by liquid chromatography/tandem mass spectrometry. Anal Biochem, 348(2), 185-91, 2006.

Talati, M, Meyrick, B, Peebles, RS, Davies, SS, Dworski, R, Mernaugh, R, Mitchell, D, Boothby, M, Roberts, LJ, Sheller, JR. Oxidant stress modulates murine allergic airway responses. Free Radic Biol Med, 40(7), 1210-9, 2006.

Fukuda, K, Davies, SS, Nakajima, T, Ong, BH, Kupershmidt, S, Fessel, J, Amarnath, V, Anderson, ME, Boyden, PA, Viswanathan, PC, Roberts, LJ, Balser, JR. Oxidative mediated lipid peroxidation recapitulates proarrhythmic effects on cardiac sodium channels. Circ Res, 97(12), 1262-9, 2005.

Roberts, LJ, Fessel, JP, Davies, SS. The biochemistry of the isoprostane, neuroprostane, and isofuran Pathways of lipid peroxidation. Brain Pathol, 15(2), 143-8, 2005.

Brame, Cynthia J., Boutaud, Olivier, Davies, Sean S., Yang, Tao, Oates, John A., Roden, Dan, Roberts, L. Jackson. Modifcation of proteins by isoketal-containing oxidized phospholipids. J Biol Chem, , , 2004.

Davies, SS, Amarnath, V, Roberts, LJ. Isoketals: highly reactive gamma-ketoaldehydes formed from the H2-isoprostane pathway. Chem Phys Lipids, 128(1-2), 85-99, 2004.

Davies, SS, Talati, M, Wang, X, Mernaugh, RL, Amarnath, V, Fessel, J, Meyrick, BO, Sheller, J, Roberts, LJ. Localization of isoketal adducts in vivo using a single-chain antibody. Free Radic Biol Med, 36(9), 1163-74, 2004.

Boutaud, Olivier, Li, Junyu, Zagol, Irene, Shipp, Elizabeth A, Davies, Sean S, Roberts, L Jackson, Oates, John A. Levuglandinyl adducts of proteins are formed via a prostaglandin H2 synthase-dependent pathway after platelet activation. J Biol Chem, 278(19), 16926-8, 2003.

Davies, Sean S, Ju, Won-Kyu, Neufeld, Arthur H, Abran, Daniel, Chemtob, Sylvain, Roberts, L Jackson. Hydrolysis of bimatoprost (Lumigan) to its free acid by ocular tissue in vitro. J Ocul Pharmacol Ther, 19(1), 45-54, 2003.

Davies, Sean S, Amarnath, Ventkataraman, Montine, Kathleen S, Bernoud-Hubac, Nathalie, Boutaud, Olivier, Montine, Thomas J, Roberts, L Jackson. Effects of reactive gamma-ketoaldehydes formed by the isoprostane pathway (isoketals) and cyclooxygenase pathway (levuglandins) on proteasome function. FASEB J, 16(7), 715-7, 2002.

Bernoud-Hubac, N, Davies, S S, Boutaud, O, Montine, T J, Roberts, L J. Formation of highly reactive gamma-ketoaldehydes (neuroketals) as products of the neuroprostane pathway. J Biol Chem, 276(33), 30964-70, 2001.

Davies, S S, Pontsler, A V, Marathe, G K, Harrison, K A, Murphy, R C, Hinshaw, J C, Prestwich, G D, Hilaire, A S, Prescott, S M, Zimmerman, G A, McIntyre, T M. Oxidized alkyl phospholipids are specific, high affinity peroxisome proliferator-activated receptor gamma ligands and agonists. J Biol Chem, 276(19), 16015-23, 2001.

Harrison, K A, Davies, S S, Marathe, G K, McIntyre, T, Prescott, S, Reddy, K M, Falck, J R, Murphy, R C. Analysis of oxidized glycerophosphocholine lipids using electrospray ionization mass spectrometry and microderivatization techniques. J Mass Spectrom, 35(2), 224-36, 2000.

Marathe, G K, Davies, S S, Harrison, K A, Silva, A R, Murphy, R C, Castro-Faria-Neto, H, Prescott, S M, Zimmerman, G A, McIntyre, T M. Inflammatory platelet-activating factor-like phospholipids in oxidized low density lipoproteins are fragmented alkyl phosphatidylcholines. J Biol Chem, 274(40), 28395-404, 1999.


Postdoctoral Position Available
No

Postdoctoral Position Details
N/A

Updated Date
06/04/2010



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