Biology8
McDowell_Susan

Susan McDowell

Professor

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CL 171c  Phone: 765-285-8846  

Postdoctoral Fellowship, 2001-2003
Lilly Research Laboratories, Indianapolis, IN
College of Medicine, University of Cincinnati Ph.D. 2001
Thomas More College B.A. 1987

Research Interests

My general interests are in the development of alternatives to antibiotics.

Specific Goal: 

Named “Researcher of the Year-2015”, Susan McDowell’s research with her colleagues and students is explored in “A Possible Treatment When Antibiotics Don’t Work”.

Susan McDowell

In the aging US population, the rate of hip and knee replacements doubled between 2000 and 2010. Although an individual’s risk for infection remains low, the high frequency of replacements is increasing the number of infections and the burden of infectious disease. Infections routinely are recalcitrant to antibiotic therapies regardless of whether the infecting bacteria are susceptible or resistant to current standard of care, including antibiotics. Following an initial acute phase, infection commonly evolves into a chronic inflammatory osteomyelitis as episodes of relapsing infection develop within surrounding bone and joint tissue. The source of relapsing infection remains incompletely understood. Clinical and experimental evidence suggests that bacteria invade host cells surrounding the implanted prosthetic device and evade antibiotic therapies to reemerge as a source of relapsing infection. The personal and economic burden of chronic, relapsing infections underscores the need for alternative and adjunctive therapeutic approaches.

Our research groups are focused on developing therapies that limit host cell invasion to break the cycle of relapsing infection. We have discovered a host protein used for invasion by Staphylococcus aureus, the infecting agent commonly identified in prosthetic joint infections. We have characterized pharmacology of ML141, a small molecule inhibitor with specificity for the host protein. We are examining the hypothesis that by targeting this host protein, ML141 would be efficacious in limiting relapsing S. aureus infection.

Susan McDowell's figure

Schematic models of Staphylococcus aureus host cell invasion and inhibition by ML141 

Panel A.  1 In the absence of ML141, S. aureus bound to host fibronectin interacts with the host cell integrin 51, stimulating GTP-loading and activation of CDC42. 2 GTP-loading of CDC42 increases affinity for the p85 regulatory subunit of phosphoinositide 3-kinase (PI3K).  CDC42, coupled to PI3K through the p85 subunit, positions the catalytic domain p110 in proximity with phosphoinositide4,5-bisphosphate (PI4,5).  3 The product of the phosphorylation of PI4,5 by p110 is PI 3,4,5-trisphosphate (PIP3), capable of promoting endocytosis of the bacterium/fibronectin/integrin complex4. Panel B.  In response to the inhibition of GTP-loading of CDC42 by ML 141, 1CDC42 remains uncoupled from p85. Consequently, p110 remains within the cytosol. By sequestering p110 within the cytosol, membrane-bound PI4,5 is not accessible, diminishing PIP3 production. Diminished generation of PIP32  limitsendocytic uptake of the bacterium/fibronectin/integrin complex, protecting the host cell from bacterial invasion.

Publications listing

McDowell, S.A., Bruns, H.A. Short term, low dose simvastatin pretreatment alters memory immune function following secondary Staphylococcus aureus infection
Current Pharmaceutical Biotechnology: March 1, 2016.

Cordero, D., Fullenkamp,C.R., Pelly, R.R., Reed, K.M., Caffo, L.M., Zahrt, A.N., Newman, M., Komanapalli, S., Niemeier, E.M., Bishop, D.L., Bruns, H.A., Haynes, M.K., Sklar, L.A., Sammelson, R.E., and McDowell, S.A.
Small Molecule Inhibitors Limit Endothelial Cell Invasion by Staphylococcus aureus.Current Pharmaceutical Biotechnology.Current Pharmaceutical Biotechnology: 15, 727-737, 2014

DeWalt, R.I., Petkovich, D.A., Zahrt, A.N., Bruns, H.A., and McDowell, S. A. Host cell invasion by Staphylococcus aureus stimulates the shedding of microvesiclesBiochemical and Biophysical Research Communications. 432: 695-700, 2013.

Smith, A.R., Ellison, A.L., Robinson, A.L., Drake, M.A., McDowell, S.A., Mitchell, J.K., Gerard, P.D., Heckler, R.A., and McKillip, J.L. Enumeration of Sublethally Injured Escherichia coli O157:H7 ATCC 43895 and Escherichia coli Strain B-41560 Using Selective Agar Overlays versus Commercial Methods. J. Food Protection. 76: 674-679, 2013.

Burns, E.M, Smelser, L.K., Glassburn, J.E., Stankiewicz, T.E., Kushdilian, M., McDowell, S.A., and Bruns, H.A. Short term statin treatment improves survival and differentially regulates macrophage-mediated responses to Staphylococcus aureus.  Current Pharmaceutical Biotechnology.14: 233-41, 2013.

McDowell S.A., Yan M., Ryosuke K. and AkinbiH.T. Simvastatin is protective during Staphylococcus aureus pneumonia. Current Pharmaceutical Biotechnology.12: 1455-1462, 2011.

Stankiewicz, T.E., Haaning, K.L., Owens, J.M., Jordan, A.S., Gammon, K., Bruns, H.A., and McDowell, S. A. GTPase activating protein function of p85 facilitates uptake and recycling of the 1 integrin. Biochemical and Biophysical Research Communications. 391: 443-448, 2010.

Horn, M.P., Knecht, S.M., Rushing, F.L. Birdsong, J., Siddall, C.P., Johnson, C.M., Abraham, T.N., Brown, A., Volk, C.B., Gammon, K., Bishop, D.L., McKillip, J.L. and McDowell, S.A. Simvastatin inhibits Staphylococcus aureus host cell invasion through modulation of isoprenoid intermediates. The Journal of Pharmacology and Experimental Therapeutics. 326: 135-143, 2008.

Mallakin, A., Kutcher, L.W., McDowell, S.A.Kong, S., Schuster, R., Lentsch, A.B., Aronow, B.J., Leikauf, G.D., Waltz, S.E. Gene Expression profiles of Mst1r deficient mice during nickel-induced acute lung injury. American Journal of Respiratory Cell and Molecular Biology. 34:15-27, 2006.

Wesselkamper, S.C., McDowell, S.A.Medvedovic, M., Dalton, T.P., Deshmukh, H.S., Sartor, M.A., Case, L.M., Henning, L.N., Borchers, M.T., Tomlinson, C.R., Prows, D.R.,Leikauf, G.D.The role of metallothionein in the pathogenesis of acute lung injury.American Journal of Respiratory Cell and Molecular Biology. 34: 73-82, 2006.

McDowell, S.A., McCall, E., Matter, W.F., Estridge, T.B., Vlahos, C.J. Phosphoinositide 3-kinase (PI3K) regulates excitation-contraction coupling in neonatal cardiomyocytes. American Journal of Physiology; 286: H796-805, 2004.

Jeffrey A. Whitsett, Cindy J. Bachurski, Kathleen C. Barnes, Paul A. Bunn, Jr., Lisa M. Case, Donald N. Cook, Denise Crooks, Mark W. Duncan, Lori Dwyer-Nield, Robert C. Elston, Michael B. Fessler, Wilbur A. Franklin, Nir Friedman, Joe G. N. Garcia, Mark W. Geraci, Connie Glasgow, Stephan W. Glasser, William D. Hardie, Lisa M. Henning, Gary L. Johnson, KamonKawkitinarong, Robert L. Keith, Thomas R. Korfhagen, George D. Leikauf, Stephen B. Liggett, Kenneth C. Malcolm, Alvin M. Malkinson, Thomas J. MarianiSusan A. McDowell, Dennis W. McGraw, Mario Medvedovic, Joel Moss, Lawrence M. Nogee, Stephanie Nonas, Gustavo Pacheco-Rodriguez, Lyle J. Palmer, David G. Peters, Daniel R. Prows, Susan Redline, Aviv Regev, Maureen A. Sartor, David A. Schwartz, Edwin K. Silverman, Wendy K. Steagall, Robert S. Stearman, Angelo Taveira-DaSilva, Jay W. Tichelaar, Craig R. Tomlinson, KatsuyaTsukada, Timothy E. Weaver, Susan E. Wert, Scott C. Wesselkamper, G. S. Worthen, Yan Xu, Laura Zerbe, Yi Zhang, Yingze Zhang, Augustine M. K. Choi and Naftali Kaminski. Functional Genomics of Lung Disease.American Journal of Respiratory Cell and Molecular Biology. 31: S1-S81, 2004.

Vlahos, C.J., McDowell, S.A., and Clerk, A.  Kinases as therapeutic targets for heart disease.Nature-Reviews Drug Discovery. 2:  99-113, 2003.

Prows, D.R., McDowell, S.A.Aronow, B.J., and Leikauf, G.D. Genetic susceptibility to nickel-induced acute lung injury.Chemosphere. 51: 1139-1148, 2003.

McDowell, S.A., Gammon, K, Zingarelli, B., Bachurski, C.J., Aronow, B.J., Prows, D.R., and Leikauf, G.D.  Inhibition of NO restores surfactant gene expression following nickel-induced acute lung injury.  American Journal of Respiratory Cell and Molecular Biology.  28:  188-198, 2003.

McDowell, S.A.Mallakin, A., Toney-Early, K., Bruno, T., Melin-Aldana, H., Prows, D.R., Bachurski, C.J., Degen, S.J. FrieznerLeikauf, G.D., and Waltz, S.E.  The role of the receptor tyrosine kinase Ron in nickel-induced acute lung injury.  American Journal of Respiratory Cell and Molecular Biology.  26:  99-104, 2002.

Leikauf, G. D., McDowell, S. A., Wesselkamper, S. C., Hardie, W. D., Leikauf, J. E. Korfhagen, T. R., and Prows, D. R.  Acute lung injury: functional genomics and genetic susceptibility.  Chest. 121, 3 Suppl:  70S-75S.  2002.

Stark, J. M., McDowell, S. A.Koenigsknecht, V., Prows, D. R., Leikauf, J. E., Le Vine, A. M., and Leikauf, G. D.  Genetic susceptibility to respiratory syncytial virus infection in inbred mice.Journal of Medical Virology.  67:  92-100.  2002.

Leikauf, G. D., McDowell, S. A.Wesselkamper, S. C., Miller, C.R., Hardie, W. D., Gammon, K, Biswas, P.P., Korfhagen, T. R., Bachurski, C. J., Wiest, J.S., Willeke, K., Bingham, E, Leikauf, J. E., Aronow, B.J., and Prows, D. R.  Pathogenomic mechanisms for particulate matter induction of acute lung injury and inflammation in mice.  Health Effects Institute Research Report Number 105.  2001.

Leikauf, G. D., McDowell, S. A.Bachurski, C. J., Aronow, B. J., Gammon, K., Wesselkamper, S. C., Hardie, W., Wiest, J. S., Leikauf, J. E., Korfhagen, T. R., and Prows, D. R.  Functional genomics of oxidant-induced lung injury.  Advances in Experimental Medical Biology.  500:  479-87, 2001. 

Leikauf, G.D., McDowell, S.A., Gammon, K., Wesselkamper, S.C., Bachurski, C.J., Puga, A., Wiest, J.S., Leikauf, J.E., and Prows, D.R.  Functional genomics of particle-induced lung injury.Inhalation Toxicology.  12: 59-73, 2000.

McDowell, S.A., Gammon, K., Bachurski, C.J., Wiest, J.S., Leikauf, J.E., Prows, D.R., and Leikauf, G.D. Differential gene expression in the initiation and progression of nickel-induced acute lung injury. American Journal of Respiratory Cell and Molecular Biology.  23:  466-474, 2000. 

Rihn, B.H., Mohr, S., McDowell, S.A., Binet, S, Loubinoux, J., Galateau, F., Keith, G., and Leikauf, G.D. Differential gene expression in mesothelioma.  FEBS Letters.  24028: 1-6, 2000.

Degen, S.J. FrieznerMcDowell, S.A., Waltz, S.E., Gould, F., Stuart, L.A., and Carritt, B.  Structure of the human D1F15S1A locus: a chromosome 1 locus with 97% identity to the chromosome 3 gene coding for hepatocyte growth factor-like protein.  DNA Sequence-The Journal of Sequencing and Mapping.  8:  409-413, 1998.

Waltz, S.E., Toms, C.L.V., McDowell, S.A., Clay, L.A., Muraoka, R.S., Air, E.L, Sun, W.Y., Thomas, M.B., and Degen, S.J. Friezner.  Characterization of the mouse Ron/Stk receptor tyrosine kinase gene.  Oncogene.  16:  27-42, 1998.

Waltz, S.E., McDowell, S.A., Muraoka, R.S., Air E.L., Flick, L.M., Chen, Y-Q, Wang, M-H, and Degen, S.J. Friezner.  Functional characterization of domains contained in hepatocyte growth factor-like protein.  Journal of Biological Chemistry.  272: 30526-30537, 1997.

Waltz, S.E., Gould, F.K., Air, E.L., McDowell, S.A., and Degen, S.J. Friezner.  Hepatocyte nuclear factor-4 is responsible for the liver-specific expression of the gene coding for hepatocyte growth factor-like protein. Journal of Biological Chemistry.  271:  9024-9032, 1996.

Jamison, C.S., McDowell, S.A.Marlar, R.A. and Degen, S.J. Friezner.  Developmental expression of protein C and protein S in the rat.  Thrombosis Research.  78:  407-419, 1995.

Degen, S.J. FrieznerMcDowell, S.A., Sparks, L.M. and Scharrer, I.  Prothrombin Frankfort: a dysfunctional prothrombin characterized by substitution of Glu-466 by Ala.  Thrombosis and Haemostasis.  73:  203-209, 1995.

Bancroft, J.D., McDowell, S.A. and Degen, S.J. Friezner.  The human prothrombin gene: transcriptional regulation in HepG2 cells.  Biochemistry.  31:  12469-12476, 1992.

Patents:

United States Patent.S. A. McDowell, R. E. Sammelson, L. A. Sklar and M. K. Haynes.Efficacy in treating bacterial infections. (US 20130217744) Submitted August 2013.Issued February 16, 2016.Patent Number 9,259,415.

Funding:

PI: SundeepRayatCo-PI: Emil Khisamutdinov, MahamudSubir, Eric Rubenstein, Susan McDowell, TykonZubkov, Philip Albiniak, James Poole
Title: MRI: Acquisition of a Liquid Chromatography-Mass Spectrometry System for Research and Research TrainingFunding Source: National Science Foundation
Duration: September, 2015-August, 2018
Amount Awarded: $196,968

PI: Derron Bishop Co-PI: Muhammad Magbool, Susan McDowell, Bartholomew Pederson, TykhonZubkov, Randi Bernot
Title: MRI: Acquisition of a Transmission Electron Microscope for Interdisciplinary Research and Teaching
Funding Source: National Science Foundation
Duration: 2011-2013
Amount Awarded: $497,500

PISusan A. McDowell
TitleStatins as Inhibitors of Bacterial Host Cell Invasion 
Funding SourceNational Institutes of Health – AREA 
Duration2008-2011; no cost extension: 2012
Amount Awarded$216,750.00

PISusan A. McDowell
TitleImmersive Experience with DOW AgroSciences
Funding SourceDOW AgroScience
DurationMay-December 2008
Amount Awarded$50,000

PISusan A. McDowell
TitleInvestigating the Inhibition by Simvastatin of Staphylococcus aureus Host Cell Invasion
Funding SourceIndiana Academy of Science
Duration2007-2008
Amount Awarded$3000.00

PISusan A. McDowell
TitleNon Lipid-lowering Statin Effects Mediated by PI3K 
Funding SourceNational Institutes of Health - AREA 
Duration2005-2008
Amount Awarded$203,750.00 ($15,000 matching funds)

PICarolyn Vann CO-PI: Donald Ruch, Susan A. McDowell
TitleLI-COR Genomics Education
Funding SourceLI-COR (Match of 50% from Lilly V) 
Duration2005-2006
Amount Awarded$98,798

PISusan A. McDowell
TitleCharacterization of the PI3K Signaling Pathway in Exercise-induced Cardiac Hypertrophy
Funding SourceIndiana Academy of Science
Duration2004-2005
Amount Requested$3000.00 Amount Awarded$3000.00

PISusan A. McDowell
TitlePI3K as a Target for Cancer Chemotherapy: What is the Cardiovascular Impact?
Funding SourceCancer Services of Delaware County.
Duration2003-2005.
Amount Awarded$4000.00

PISusan A. McDowell
Funding SourceEnvironmental Protection Agency's STAR (Science to Achieve Results) Graduate Fellowship
DurationJuly, 2000–July, 2003
Amount Awarded$91,873.00