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Ulla Knaus

Professor of Immunobiology

School Of Medicine & Medical Science
Conway Institute
Belfield
Dublin 4

Tel: +353 1 7166719
Email: ulla.knaus@ucd.ie

Biography

2008-present SFI Stokes Professor, School of Medicine & Medical Science, Conway Institute
2009-present Adjunct Associate Professor, Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA, USA
2000-2008 Associate Professor, Department of Immunology & Microbial Science, The Scripps Research Institute
1994-2000 Assistant Professor, Department of Immunology, The Scripps Research Institute
1992-1993 Senior Research Associate, Department of Immunology, The Scripps Research Institute
1990-1992 Postdoctoral Research Fellow (DFG), Department of Immunology, The Scripps Research Institute, La Jolla, CA, USA
1985-1989 Ph.D., Institute of Pharmaceutical Biology, University of Munich, Germany
1984 Approbation as Pharmacist, Germany

1977-1983 School of Pharmacy, ETH Zürich, Switzerland

Research Interests

Innate and Mucosal Immune Response in Inflammation and Infection

NADPH Oxidases in Health and Disease

Signal Transduction by Rho GTPases and their Effectors

Professional

Honours and Awards

Year: 1990.
Title: Postdoctoral Fellowship
Year: 1992.
Title: Postdoctoral Fellowship
Year: 1992.
Title: Louis N. Katz Basic Science Award
Year: 1992.
Title: Finalist, Young Investigator Award

Associations

Association: American Association of Immunologists, Function/Role: Member
Association: Society for Leukocyte Biology, Function/Role: Member
Association: American Society for Biochemistry and Molecular Biology, Function/Role: Member
     

Conference Contributions

Knaus UG (2012) International meeting. [Invited Oral Presentation], From molecular mechanisms to integrated life processes, Grenoble, France , 21-NOV-12 - 23-NOV-12.
Knaus UG (2012) International meeting. [Invited Oral Presentation], New concepts on the mechanisms of inflammation, autoimmunity and tumorigenesis, Kazan, Russia , 17-MAY-12 - 19-MAY-12.
Knaus, UG; (2010) Gordon Research Conference. [Invited Oral Presentation], NOX family NADPH oxidases, Les Diablerets , 06-JUN-10 - 11-JUN-10.
Knaus, UG; (2010) Symposium. [Invited Oral Presentation], Oxidases and Cell Signaling, Pittsburgh , 04-MAY-10 - 05-MAY-10.
Knaus, UG; (2009) Symposium. [Plenary Lecture], 40 years Pharmacy, Saarbruecken, Germany , 25-JUN-09 - 27-JUN-09.
Knaus, UG; (2008) Gordon Research Conference. [Chaired Session], NOX family NADPH oxidases, New London , 01-JUN-08 - 06-JUN-08.
Knaus, UG; (2008) European Society of Clinical Investigation. [Invited Oral Presentation], Phagocyte Workshop, Geneva, Switzerland , 26-MAR-08 - 29-MAR-08.
Knaus, UG; (2007) NIH/NIAID. [Invited Oral Presentation], Viral Immunity Workshop, Bethesda, Maryland , 27-NOV-07 - 28-NOV-07.
Knaus, UG; (2007) Gordon Research Conference. [Invited Oral Presentation], Phagocytes, Smithfield, RI , 10-JUN-07 - 15-JUN-07.
Knaus, UG; (2007) San Diego Signaling. [Conference Organising Committee Chairperson], Microbial Pathogenesis and Lung Host Defense, La Jolla, CA , 25-MAY-07 - 26-MAY-07.
Knaus, UG; (2006) The Banbury Center. [Invited Oral Presentation], Redox Regulation of Signal Transduction, Cold Spring Harbor , 03-DEC-06 - 06-DEC-06.
Knaus, UG; (2006) FASEB Summer Research Conference. [Oral Presentation], Regulation and Function of Small GTPases, Saxtons River, USA , 15-JUL-06 - 20-JUL-06.
Knaus, UG; (2006) Gordon Research Conference. [Invited Oral Presentation], NOX family NADPH oxidases, Les Diableret, Switzerland , 15-OCT-06 - 20-OCT-06.
Knaus, UG; (2006) German Heart Center. [Invited Oral Presentation], Microcirculation and Vascular Biology, Munich, Germany , 12-OCT-06 - 14-OCT-06.
Knaus, UG; (2006) Regional Center of Excellence. [Invited Oral Presentation], Pacific Southwest RCE meeting, University of Nevada, Reno , 24-JUL-06 - 25-JUL-06.
Knaus, UG; (2005) Society for Leukocyte Biology. [Invited Oral Presentation], Symposium Signaling in Innate Immunity, San Diego , 16-FEB-05 - 18-FEB-05.
Knaus, UG; (2004) Callaway Gardens. [Invited Oral Presentation], 2nd. Int. Conference on NADPH oxidases, Pine Mountain, Georgia , 11-APR-04 - 16-APR-04.

Committees

Committee : COST action EU-ROS
Committee : Irish Transgenic Network
Committee : UCD BMF committee
         

Journals Edited

Journal Of Biological Chemistry: Editor.

Other Activities

Review for funding agencies (NIH, NSF, AHA, European funding agencies) and journals

Publications

Books

Strengert M, Knaus UG (2011) Analysis of epithelial barrier integrity in polarized lung epithelial cells. USA: Springer. [Details]
Ruse M, Knaus, UG; (2008) The role of small Rho GTPases in TLR signaling. Methods in Signal Transduction Series: CRC. [Details]
Knaus UG, Bamberg A, Bokoch GM; (2007) Rac and Rap GTPases activation assays. Methods Mol Biol: Springer. [Details]
King CC, Reilly AM, Knaus UG; (2000) Purification and in vitro activities of p21-activated kinases. Methods Enzymol: Elsevier Inc. [Details]
Knaus UG, Bokoch GM; (1995) Purification of Rac2 from human neutrophils. Methods Enzymol: Elsevier Inc. [Details]

Book Chapters

Jennings RT, Knaus UG (2014) 'Rho family and Rap GTPase activation assays' In: Quinn MT, DeLeo, FR (eds). Methods Mol Biol. New Yory: Humana Press. , pp.79-88 [Details]
Jennings RT, Knaus UG (2014) 'Neutrophil migration through extracellular matrix' In: Quinn MT, DeLeo, FR (eds). Methods Mol Biol. New York: Humana Press. , pp.209-218 [Details]
 

Peer Reviewed Journals

Koenigs V, Jennings R, Vogl T, Horsthemke M, Bachg AC, Xu Y, Grobe K, Brakebusch C, Schwab A, Baehler M, Knaus UG, Hanley PJ (2014) 'Mouse macrophages completely lacking Rho (RhoA, RhoB and RhoC) have severe lamellipodial retraction defects, but robust chemotactic navigation and increased motility'. J BIOL CHEM, . [Details]
Jennings RT, Strengert M, Hayes P, El-Benna J, Brakebusch C, Kubica M, Knaus UG (2014) 'RhoA determines disease progression by controlling neutrophil motility and restricting hyperresponsiveness'. Blood, 123 (23):3635-3645. [Details]
Strengert M, Jennings R, Davanture S, Hayes P, Gabriel G, Knaus UG (2014) 'Mucosal reactive oxygen species are required for antiviral response: Role of Duox in Influenza A virus infection'. Antioxidants & Redox Signaling, 20 (17):2695-2709. [Details]
Alvarez LA, Bourke B, Pircalabioru G, Georgiev AY, Knaus UG, Daff S, Corcionivoschi N. (2013) 'Cj 1411c encodes for a cytochrome P450 involved in Campylobacter jejuni 81-176 pathogenicity'. PLoS ONE, 8 (9). [Details]
Hayes, P; Knaus, UK (2013) 'Balancing ROS in the epigenome: NADPH oxidases as target and perpetrator'. Antioxidants & Redox Signaling, 18 (15):1937-1945. [Details]
Corcionivoschi N, Alvarez LA, Sharp TH, Strengert M, Alemka A, Mantell J, Verkade P, Knaus UG, Bourke B (2012) 'Mucosal reactive oxygen species decrease virulence by disrupting Campylobacter jejuni phosphotyrosine signaling'. Cell Host and Microbe, 12 (1):47-59. [Details]
Ghosh CC, Mukherjee A, David S, Knaus UG, Stearns-Kurosawa DJ, Kurosawa S, Parikh SM. (2012) 'Impaired function of the Tie-2 receptor contributes to vascular leakage and lethality in anthrax'. Proceedings of the National Academy of Sciences USA, 109 (25):10024-10029. [Details]
Munson, JM, Fried, L, Rowson, SA, Bonner, MY, Karumbaiah, L, Diaz, B, Courtneidge, SA, Knaus, UG, Brat, DJ, Arbiser, JL, Bellamkonda, RV (2012) 'Anti-invasive adjuvant therapy with imipramine blue enhances chemotherapeutic efficacy against glioma'. science translational medicine, 4 (127). [Details]
Von Loehneysen, K, Noack, D, Hayes, P, Friedman, JS, Knaus, UG (2012) 'Constitutive NADPH oxidase 4 activity resides in the composition of the B-loop and the penultimate C terminus'. Journal of Biological Chemistry, 287 (12):8737-8745. [Details]
Al Ghouleh, I, Khoo, NK, Knaus, UG, Griendling, KK, Touyz, RM, Thannickal, VJ, Barchowsky, A, Nauseef, WM, Kelley, EE, Bauer, PM, Darley-Usmar, V, Shiva, S., Cifuentes-Pagano, E, Freeman, BA, Gladwin, MT, Pagano, PJ (2011) 'Oxidases and peroxidases in cardiovascular and lung disease:new concepts in reactive oxygen species signaling'. Free Radical Biology and Medicine, . [Details]
von Lohneysen, K,Noack, D,Wood, MR,Friedman, JS,Knaus, UG; (2010) 'Structural Insights into Nox4 and Nox2: Motifs Involved in Function and Cellular Localization'. Molecular and Cellular Biology, 30 :961-975. [DOI] [Details]
Bhandarkar SS, Jaconi M, Fried LE, Bonner MY et al.; (2009) 'Fulvene-5 potently inhibits NADPH oxidase 4 and blocks the growth of endothelial tumors in mice'. J Clin Invest, 119 (8):2359-2365. [Details]
Mandy Lehmann, Deborah Noack, Malcolm Wood, Marta Perego, Ulla G Knaus; (2009) 'Lung Epithelial Injury by B. Anthracis Lethal Toxin Is Caused by MKK-Dependent Loss of Cytoskeletal Integrity'. Plos One, 4 (3). [Details]
Sylvia Luxen, Deborah Noack, Monika Frausto, Suzel Davanture, Bruce E. Torbett and Ulla G. Knaus; (2009) 'Heterodimerization controls localization of Duox-DuoxA NADPH oxidases in airway cells'. J Cell Sci, 122 :1238-1247. [Details]
Manukyan M, Nalbant P, Luxen S, Hahn K, Knaus UG; (2009) 'RhoA GTPase activation by TLR2 and TLR3 ligands: connecting via Src to NF-kB'. J IMMUNOL, 182 (6):3522-3529. [Details]
von Lohneysen K, Noack D, Jesaitis AJ, Dinauer MC, Knaus UG; (2008) 'Mutational analysis reveals distinct features of the Nox4-p22phox complex'. J BIOL CHEM, . [Details]
Pacquelet S, Lehmann M, Luxen S, Regazzoni K, Frausto M, Noack D, Knaus UG; (2008) 'Inhibitory action of NoxA1 on dual oxidase activity in airway cells'. J BIOL CHEM, 283 (36):24649-24658. [Details]
Luxen S, Belinsky SA, Knaus UG; (2008) 'Silencing of DUOX NADPH oxidases by promoter hypermethylation in lung cancer'. Cancer Research, 68 (4):1037-1045. [Details]
Lozano E, Frasa MA, Smolarczyk K, Knaus UG, Braga VM; (2008) 'PAK is required for the disruption of E-cadherin adhesion by the small GTPase Rac'. J Cell Sci, 121 (Pt7):933-938. [Details]
Maroto B, Ye MB, von Lohneysen K, Schnelzer A, Knaus UG; (2008) 'p21-activated kinase is required for mitotic progression and regulates Plk1'. Oncogene, 27 (36):4900-4908. [Details]
Kim JS, Diebold BA, Babior BM, Knaus UG, Bokoch GM; (2007) 'Regulation of Nox1 activity via protein kinase A-mediated phosphorylation of NoxA1 and 14-3-3 binding'. J BIOL CHEM, 282 (48):34787-34800. [Details]
Lombardo E, Alvarez-Barrientos A, Maroto B, Bosca L, Knaus UG; (2007) 'TLR4-mediated survival of macrophages is MyD88-dependent and requires TNF-alpha autocrine signaling'. J IMMUNOL, 178 (6):3731-3739. [Details]
Zhu Y, Marchal CC, Casbon AJ, Stull N, von Lohneysen K, Knaus UG, Jesaitis AJ, McCormick S, Nauseef WM, Dinauer MC; (2006) 'Deletion mutagenesis of p22phox subunit of flavocytochrome b558: identification of regions critical for gp91phox maturation and NADPH oxidase activity'. J BIOL CHEM, 281 (41):30336-30346. [Details]
Kravchenko VV, Kaufmann GF, Mathison JC, Scott DA, Katz AZ, Wood MR, Brogan AP, Lehmann M, Mee JM, Iwata K, Pan Q, Fearns C, Knaus UG, Meijler MM, Janda KD, Ulevitch RJ; (2006) 'N-(3-oxo-acyl) homoserine lactones signal cell activation through a mechanisms distinct from the canonical pathogen-associated molecular pattern recognition receptor pathways'. J BIOL CHEM, 281 (39):28822-28830. [Details]
Perry BN, Govindarajan B, Bhandarkar SS, Knaus UG, Valo M, Sturk C, Carillo CO, Sohn A, Cerimele F, Dumont D, Losken A, Willimas J, Brown LF, Tan X, Ioffe E, Yancopoulos GD, Arbiser JL; (2006) 'Pharmacologic blockade of angiopoietin-2 is efficacious against model hemangiomas in mice'. J Invest Dermatol, 126 (10):2316-2322. [Details]
Ruse M, Knaus, UG; (2006) 'New players in TLR-mediated innate immunity: PI3K and small Rho GTPases'. Immunol Res, 34 (1):33-48. [Details]
Martyn KD, Frederick LM, von Lohneysen K, Dinauer MC, Knaus UG; (2006) 'Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases'. Cell Signal, 18 (1):69-82. [Details]
Martyn KD, Kim MJ, Quinn MT, Dinauer MC, Knaus UG; (2005) 'p21-activated kinase (Pak) regulates NADPH oxidase activation in human neutrophils'. Blood, 106 (12):3962-3969. [Details]
Yamauchi A, Marchal CC, Molitoris J, Pech N, Knaus U, Towe J, Atkinson SJ, Dinauer MC; (2005) 'Rac GTPase isoform-specific regulation of NADPH oxidase and chemotaxis in murine neutrophils in vivo'. J BIOL CHEM, 280 (2):953-964. [Details]
Chan AY, Coniglio SJ, Chuang YY, Michaelson D, Knaus UG, Philips MR, Symons M; (2005) 'Roles of the Rac1 and Rac3 GTPases in human tumor cell invasion'. Oncogene, 24 (53):7821-7829. [Details]
Teusch N, Lombardo E, Eddleston J, Knaus UG; (2004) 'The low molecular weight GTPase RhoA and atypical protein kinase Czeta are required for TLR2-mediated gene transcription'. J IMMUNOL, 173 (1):507-514. [Details]
Shalom-Barak T, Knaus UG; (2002) 'A p21-activated kinase-controlled metabolic switch up-regulates phagocytic NADPH oxidase'. J BIOL CHEM, 277 (43):40659-40665. [Details]
Price MO, McPhail LC, Lambeth JD, Han CH, Knaus UG, Dinauer MC; (2002) 'Creation of a genetic system for analysis of the phagocyte respiratory burst: high-level reconstitution of the NADPH oxidase in a nonhematopoietic system'. Blood, 99 (8):2653-2661. [Details]
Price MO, Atkinson SJ, Knaus UG, Dinauer MC; (2002) 'Rac activation induces NADPH oxidase activity in transgenic COSphox cells, and the level of superoxide production is exchange factor-dependent'. J BIOL CHEM, 277 (21):19220-19228. [Details]
Arbibe L, Mira JP, Teusch N, Kline L, Guha M, Mackman N, Godowski PJ, Ulevitch RJ, Knaus UG; (2000) 'Toll-like receptor2-mediated NF-kappaB activation requires a Rac1-dependent pathway'. Nat Immunol, 1 (6):533-540. [Details]
Schnelzer A, Prechtel D, Knaus U, Dehne K, Gerhard M, Graeff H, Harbeck N, Schmitt M, Lengyel E; (2000) 'Rac1 in human breast cancer: overexpression, mutation analysis, and characterization of a new isoform, Rac1b'. Oncogene, 19 (26):3013-3020. [Details]
Knaus UG; (2000) 'Rho GTPase signaling in inflammation and transformation'. Immunol Res, 21 (2-3):103-109. [Details]
Mira JP, Benard V, Groffen J, Sanders LC, Knaus UG; (2000) 'Endogenous, hyperactive Rac3 controls proliferation of breast cancer cells by a p21-activated kinase-dependent pathway'. PNAS, 97 (1):185-189. [Details]
Wen Y, Gu J, Knaus UG, Thomas L, Gonzales N, Nadler JL; (2000) 'Evidence that 12-lipoxygenase product 12-hydroxyeicosatetranoic acid activates p21-activated kinase'. Biochem J, 349 (Pt2):481-487. [Details]
Fazal N, Knaus UG, Sabeh F, Gamelli RL, McNulty JA, Sayeed MM; (1999) 'Enhanced expression of neutrophil NADPH oxidase components in intestine of rats after burn injury'. Shock, 12 (6):438-442. [Details]
Lopes LR, Hoyal CR, Knaus UG, Babior BM; (1999) 'Activation of the leukocyte NADPH oxidase by protein kinase C in a partially recombinant cell-free system'. J BIOL CHEM, 274 (22):15533-15537. [Details]
Brzeska H, Young R, Knaus UG, Korn ED; (1999) 'Myosin I heavy chain kinase: cloning of the full-length gene and acidic lipid-dependent activation by Rac and Cdc42'. PNAS, 96 (2):394-399. [Details]
Knaus Ug, Wang Y, Reilly AM, Warnock D, Jackson JH; (1998) 'Structural requirements for PAK activation by Rac GTPases'. J BIOL CHEM, 273 (34):21512-21518. [Details]
Jones SL, Knaus UG, Bokoch GM, Brown EJ; (1998) 'Two signaling mechanisms for activation of alphaM beta2 avidity in polymorphonuclear neutrophils'. J BIOL CHEM, 273 (17):10556-10566. [Details]
Bokoch GM, Reilly AM, Daniels RH, King CC, Olivera A, Spiegel S, Knaus UG; (1998) 'A GTPase-independent mechanism of p21-activated kinase activation. Regulation by sphingosine and other biologically active lipids'. J BIOL CHEM, 273 (14):8137-8144. [Details]
Sells MA, Knaus UG, Bagrodia S, Ambrose DM, Bokoch GM, Chernoff J; (1997) 'Human p21-activated kinase (Pak1) regulates actin organization in mammalian cells'. Current Biology, 7 (3):202-210. [Details]
Brzeska H, Knaus UG, Wang ZY, Bokoch GM, Korn ED; (1997) 'p21-activated kinase has substrate specificity similar to Acanthamoeba myosin I heavy chain kinase and activates Acanthamoeba myosin I'. PNAS, 94 (4):1092-1095. [Details]
Ding J, Knaus UG, Lian JP, Bokoch GM, Badwey JA; (1996) 'The renaturable 69 and 63-kDa protein kinases that undergo rapid activation in chemoattractant-stimulated guinea pig neutrophils are p21-activated kinases'. J BIOL CHEM, 271 (40):24869-24873. [Details]
Bokoch GM, Vlahos CJ, Wang Y, Knaus UG, Traynor-Kaplan AE; (1996) 'Rac GTPase interacts specifically with phosphatidylinositol 3-kinase'. Biochem J, 315 (Pt3):775-779. [Details]
Knaus UG, Wagner H; (1996) 'Effects of boswellic acid of Boswellia serrata and other triterpenic acids on the complement system'. Phytomedicine, 3 :77-81. [Details]
Bokoch GM, Wang Y, Bohl BP, Sells MA, Quilliam LA, Knaus UG; (1996) 'Interaction of the Nck adapter protein with p21-activated kinase (PAK1)'. J BIOL CHEM, 271 (42):25746-25749. [Details]
Zhang S, Han J, Sells MA, Chernoff J, Knaus UG, Ulevitch RJ, Bokoch GM; (1995) 'Rho family GTPases regulate p38 mitogen-activated protein kinase through the downstream mediator Pak1'. J BIOL CHEM, 270 (41):23934-23936. [Details]
Knaus UG, Morris S, Dong HJ, Chernoff J, Bokoch GM; (1995) 'Regulation of human leukocyte p21-activated kinases through G protein-coupled receptors'. Science, 269 (5221):221-223. [Details]
Heyworth PG, Knaus UG, Settleman J, Curnutte JT, Bokoch GM; (1993) 'Regulation of NADPH oxidase activity by Rac GTPase activating protein(s)'. Mol Biol Cell, 4 (11):1217-1223. [Details]
Heyworth PG, Knaus UG, Xu X, Uhlinger DJ, Conroy L, Bokoch GM, Curnutte JT; (1993) 'Requirement for posttranslational processing of Rac GTP-binding proteins for activation of human neutrophil  NADPH oxidase'. Mol Biol Cell, 4 (3):261-269. [Details]
Chuang TH, Xu X, Knaus UG, Hart MJ, Bokoch GM; (1993) 'GDP dissociation inhibitor prevents intrinsic and GTPase activating protein-stimulated GTP hydrolysis by the Rac GTP-binding protein'. J BIOL CHEM, 268 (2):775-778. [Details]
Puhlmann J, Knaus U, Tubaro A, Schaefer W, Wagner H; (1992) 'Immunologically active metallic ion-containing polysaccharides of Achyrocline Satureioides'. Phytochemistry, 31 :2617-2621. [Details]
Knaus, UG, Heyworth, PG, Kinsella, BT, Curnutte, JT, Bokoch, GM, ; (1992) 'Purification and characterization of Rac2 - a cytosolic GTP-binding protein that regulates human neutrophil NADPH oxidase'. J BIOL CHEM, 267 (33):23575-23582. [Details]
Knaus UG, Heyworth PG, Kinsella BT, Curnutte JT, Bokoch GM; (1992) 'Purification and characterization of Rac2. A cytosolic GTP-binding protein that regulates the human neutrophil NADPH oxidase'. J BIOL CHEM, 267 (33):23575-23582. [Details]
Knaus UG, Heyworth PG, Evans T, Curnutte JT, Bokoch GM; (1991) 'Regulation of phagocyte oxygen radical production by the GTP-binding protein Rac2'. Science, 254 (5037):1512-1515. [Details]
Knaus UG, Wagner H; (1988) 'Effects of various polysaccharides on the complement system'. Planta Medica, 54 :565-566. [Details]
Wagner H, Fessler B, Knaus UG, Wierer N; (1987) 'Zum Wirknachweis antiphlogistischer wirksamer Arzneidrogen'. Zeitschrift fuer Phytotherapie, 8 :135-140. [Details]

Other Journals

Ruse M, Knaus UG; (2006) 'Where do viruses meet their match and who is coming to the reception? Insights into dsRNA-dependent signaling pathways mediated by Toll-like receptor3' Cell Science Reviews 3 (2) :15-20. [Details]
Bokoch GM, Knaus UG; (2003) 'NADPH oxidases:not just for leukocytes anymore!' Trends Biochem Sci 28 (9) :502-508. [Details]
Knaus UG, Bokoch GM; (1998) 'The p21Rac/Cdc42-activated kinases (PAKs)' Int J Biochem Cell Biol 30 (8) :857-862. [Details]
Bokoch GM, Knaus UG; (1994) 'The role of small GTP-binding proteins in leukocyte function' Curr Opin Immunol 6 (1) :98-105. [Details]
Bokoch GM, Knaus UG; (1994) 'Ras-related GTP-binding proteins and leukocyte signal transduction' Curr Opin Hematol 1 (1) :53-60. [Details]
                                                                                           

Research

Research Interests


Innate immune cells and mucosal barrier tissues are the first line of defense in the fight against invading pathogens. Our group focuses on understanding molecular mechanisms that innate and mucosal immune host defense use to protect the host from microbial insult, and how some responses wind up damaging the host. For example, second messengers such as reactive oxygen species (ROS) or nitric oxide that are produced during infection can have beneficial as well as detrimental effects. The overall outcome depends on precise spatial and temporal regulation of these second messengers by the affected cell populations. The intracellular signaling pathways that regulate the production of these molecules constitute an ideal target for intervention in disease. Our laboratory employs structure-function studies, modeling and inhibitor design/validation to gain knowledge for targeting NADPH oxidases with drugs in disease.

Almost all of the processes connected to pathogen up-take, pathogen elimination, or sustained inflammation are governed by small GTPases of the Rho family. Research in our laboratory centers on Rac, Cdc42, and RhoA, which control various leukocyte functions ranging from ROS production to chemotaxis and phagocytosis. Superoxide generation is accomplished by the Rac-dependent NADPH oxidase Nox2 upon stimulation with chemotactic factors or phagocytic stimuli. GTPases of the Rho family are also involved in signaling cascades, which originate from Toll-like receptors (TLR) and lead to gene transcription. Our laboratory studies different aspects of host-pathogen communication in immune cells and genetically altered mouse models. 

A related area of research is the interaction between mucosal epithelia, immune cells, commensals and pathogens.  Several ex vivo and in vivo models are used to study the influence of pathogens, bacterial-derived ligands and toxins on barrier function and how the host responds. Of particular interest are ROS-generating NADPH oxidases, which are a crucial part of the first line of host defense.  Nox/Duox proteins serve as compartmentalized signaling modules, thereby activating or inhibiting signaling cascades, as host defense mechanism, or as pro-inflammatory triggers. Elucidating physiological stimuli and control mechanisms for these Nox/Duox enzymes combined with structure-function studies will help defining the biological functions of oxidases in health and disease, and constitutes a prerequisite for drug development and therapeutic intervention in oxidant-induced stress and tissue injury.
 
A new concept of pathogen control are host cell-mediated changes in pathogens. Long range signaling by ROS released into the lumen attenuates virulence by disabling the bacterial phosphotyrosine network in Campylobacter jejuni. Current studies address the molecular mechanisms involved and how generalizable the phenomenon will be for other intestinal pathogens. Understanding how bacterial tyrosine kinases, a promising drug target, regulate bacterial virulence, is being pursued. 


Research Projects

Sponsor : National Children's Research Centre, Our Lady's Children's Hospital, Crumlin (CRC)
Title : Reactive oxygen species targeting the bacterial phosphotyrosine network as defence strategy against mucosal pathogens
Start Date / End Date : 01-JAN-13 / 31-DEC-16
Sponsor : Higher Education Authority (HEA)
Title : PRTLI 5: ITN
Start Date / End Date : 01-JAN-11 / 31-DEC-15
Sponsor : Health Research Board (HRB)
Title : Trafficking to the Lung: Neutrophil Migration in Inflammatory Disease
Start Date / End Date : 01-OCT-11 / 01-JUL-15
Sponsor : Science Foundation Ireland (SFI)
Title : ROS Signalling in the Lung - Control Mechanisms and Functional Consequences
Start Date / End Date : 01-MAR-11 / 01-MAR-16
Sponsor : Science Foundation Ireland (SFI)
Title : Stokes Professorship 2007
Start Date / End Date : 01-OCT-08 / 30-SEP-13

Recent Postgraduates

Mandy Lehmann PhD

Sylvia Luxen PhD

Monika Strengert PhD

Richard Jennings PhD

Current Postgraduate Students

Gratiela Pircalabioru, Doctor of Philosophy (PhD)   -   Thesis Supervisor
Heini Ruhanen, Doctor of Philosophy (PhD)   -   Thesis Supervisor

Collaborators

Internal Collaborators

Postdoctoral Fellows

Luis Alvarez, PhD 

Gabriella Aviello, PhD
 
Patti Hayes, PhD 

Malgorzata Kubica, PhD

Suisheng Zhang, PhD

Richard Jennings, PhD

Lidija Kovacic, PhD

Collaborators

Dr. Billy Burke, Dr. Nicolae Corcionivoschi

Dr. Jeremy Simpson

 

External Collaborators

Dr. Jonathan Chernoff

Fox Chase Cancer Center
Philadelphia, USA

Dr. Mary Dinauer


Washington University School of Medicine
St Louis, USA