Smyth Lab

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Lab Members
Susan Smyth, M.D., Ph.D.
J. Anthony Brandon, Ph.D.
Shaojing Ye
Gabriela Hernandez
Liping Yang
Travis Sexton, PhD
Therese Stearns
Julia Vandra
Mardo Ubele

The lab Goes Red for Women Febuary 2017


To read more about the research, click here

inflam

Inflammation and Thrombosis Program 

 Drawing on a long-standing interest in platelet biology, our groups has established animal models for studying the role of platelet membrane proteins in thrombosis and the response to arterial injury, and has delineated specific signaling systems responsible for mediating platelet-leukocyte interactions and for inflammation in the context of arterial injury and cardiac hypertrophy.  

  • Smyth S. S., Reis E.D, Väänänen H., Zhang W., Scudder L.E., and Coller B.S. Mice Lacking GPIIb/IIIa and αVβ3 are variably protected from thrombosis, depending on the mechanism of thrombus initiation. (2001) Blood 98:1055-62. 
  • Smyth,S.S., Reis E.D, Zhang W., Fallon J.T., Gordon R.E., and Coller B.S. β3-Integrin-deficient mice, but not P-selectin-deficient mice, develop intimal hyperplasia after vascular injury: correlation with leukocyte recruitment to adherent platelets one hour post injury. (2001) Circulation, 103:2501-7. 
  • Evangelista V, Pamuklar Z, Totani L., Rojas MR, Federico L, and Smyth SS. Src kinase activity is required to sustain neutrophil interactions with adherent platelets (2006) Blood 109:2461-9. 
  • Yang F, Dong A, Mueller P, Caicedo J, Moore A, Odetunde ZJ, Barrick C, Smyth SS. Coronary artery remodeling in a model of left ventricular pressure overload is influenced by platelets and inflammatory cells. (2012) Plos One;7(8):e40196.
  • Totani L, Piccoli A, Concetta A, Di Santo A, Martelli N, Federico L, Pamuklar Z, Smyth S, Evangelista V. Phosphodiesterases type-4 blockade prevents platelet-mediated neutrophil recruitment at the site of vascular injury (2014) Arterioscler Thromb Vasc Biol.  
  • Yang F, Dong A, Ahamed J, Sunkara M, Smyth SS. Granule cargo release from bone marrow-derived cells sustains cardiac hypertrophy. Am J Physiol Heart Circ Physiol. 2014 Nov 15;307(10):H1529-38
  • Ye S, Huang Y, Joshi S, Zhang J, Yang F, Zhang G, Smyth SS, Li Z, Takai Y, Whiteheart SW. Platelet secretion and hemostasis require syntaxin-binding protein STXBP5J Clin Invest. 2014 Oct;124(10):4517-28.

Smyth’s interest in understanding the functional interplay between thrombosis and inflammation has resulted in observations about beneficial effects of antiplatelet drugs in infectious and inflammatory states of pneumonia and sepsis. This work has also spawned clinical trials of the effects of antithrombotic therapy on inflammation and the identification of biomarkers of ischemic heart disease. Her research group continues to identify novel signaling pathways in platelets, which likely will be the target for future translational studies.  

  • Campbell CL, Smyth SS, Montalescott G, and Steinhubl S.  What is the correct dose of aspirin for cardiovascular disease prevention ? (2007) JAMA, 297: 2018-24. 
  • Li G, Keenan AC, Young J, Hall M, Pamuklar Z, Ohman EM, Steinhubl SR, and Smyth SS,.  Effects of heparin and glycoprotein IIb/IIIa antagonists versus bilavirudin on  myeloperoxidase release from neutrophils.  (2007) Arterioscler Thromb Vasc Biol, 27:1850
  • Selim S, Sunkara M, Salous AK, Berdyshev EV, Bailey A, Campbell CL, Charnigo R, Morris AJ, Smyth SS. Plasma levels of sphingosine 1 phosphate are strongly correlated with hematocrit but variably restored by red blood cell transfusions. Clin Sci (Lond). 2011 121(12):565-72 PMC3174054. 
  • Gross K, Dunn SP, Feola DJ, Martin CA, Charnigo R, Li Z, Abdel-Latif A, and Smyth SS. Clopidogrel treatment on the incidence and severity of community acquired pneumonia in a cohort study and meta-analysis of antiplatelet therapy in pneumonia and critical illness.  (2013) J Thromb Thrombolysis;35:147-5. PMCID: PMC3732820. 
  • Xiang B, Zhang G, Guo L, Li XA, Morris AJ, Daugherty A, Whiteheart SW, Smyth SS, Li Z. Platelets protect from septic shock by inhibiting macrophage-dependent inflammation via the cyclooxygenase 1 signalling pathway.  (2013) Nat Commun. 4:2657. 
  • Storey RF, Kotha J, Smyth S, Moliterno DJ, Rorick TL, Moccetti T, Valgimigli M, Dery JP, Cornel JH, Thomas GS, Huber K, Harrington RA, Hord E, Judge HM, Chen E, Strony J, Mahaffey KW, Tricoci P, Becker RC, Jennings LK. Effects of vorapaxar on platelet reactivity and biomarker expression in non-ST-elevation acute coronary syndromes. The TRACER Pharmacodynamic Substudy. Thromb Haemost. 2014 Jan 9;111 
  • Sexton TR, Wallace EL, Macaulay TE, Charnigo RJ, Evangelista V, Campbell CL, Bailey AL, Smyth SS. The effect of rosuvastatin on platelet-leukocyte interactions in the setting of acute coronary syndrome. J Am Coll Cardiol. 2015 Jan 27;65(3):306-7

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Lysolipid Signaling Program

Our group also has a longstanding research interest in the role of bioactive lysophospholipid, such as lysophosphatidic acid (LPA), as mediators of cardiovascular disease. The lysophospholipase D autotaxin (ATX) catalyzes the hydrolysis of circulating or cell-associated lysophosphatidylcholine (LPC) to generate LPA, which has potent, receptor-mediated effects on blood and vascular cells.  LPA is a proteotypic member of a family of bioactive lipid phosphoric acids that function as receptor-active mediators with roles in cell growth, differentiation, apoptosis and development.  Our contributions to the literature include characterizing pathways for production and metabolism of LPA in the circulation; providing the first evidence of a pathologic role for LPA receptors in the response to arterial injury; identifying key structural and functional elements of ATX and mechanisms for regulation of ATX function by localization along cell surfaces.  Current work is focused on identifying mechanistic links between dietary intake of lipids and cardiovascular disease risk. Current investigations are exploring the possibility that choline-containing lipids and adipose-derived ATX serve as links between diet and cardiovascular disease risk.

  • Panchatcharam M, Miriyala S, Yang F, End C, Vallant C, Dong A, Lynch K, Chin J, Morris AJ, Smyth SS. Lysophosphatidic acid receptors 1 and 2 play roles in regulation of vascular injury responses, but not blood pressure. (2008) Circulation  Research, 103:662-70. 
  • Pamuklar Z, Federico L, Liu S, Goto M, Dong A, Panchatcharam M, Fulkerson Z, Berdyshev E, Natarajan V, Fang F, Mills GB, Morris AJ, and Smyth SS. Autotaxin/lysophospholipase D and lysophosphatidic acid regulate thrombosis and hemostasis in mice.  (2009) J. Biol Chem, 284:7385-7394. 
  • Albers HMHG, Dong A, van Meeteren LA, Egan DA, Sunkara M, van Tilburg EW, Schuurman K, van Tellingen O, Morris AJ, Smyth SS, Moolenaar WH, Ovaa H.  Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation. (2010)  PNAS, 107:7257-62. 
  • Im E, Rhee SH, Federico L, Kim T, Motiejunaite R, Clair C, Stracke M, Smyth S,  Kazlauskas A. PLCγ activation drives increased production of autotaxin in endothelial cells and LPA-dependent regression. (2010)  Mol Cell Biol, 10:2401-10. 
  • Hausmann J, Kamtekar S,  Christodoulou E, Day JE, Wu T, Fulkerson ZF, Albers HMHG, van Meeteren LA, Houben A, van Zeijl L, Jansen S, Andries M, Hall T, Pegg LE, Benson TE, Kasiem M, Harlos K, Van der Kooi C, Smyth SS, Ovaa H, Bollen M, Morris AJ, Moolenaar WH and Perrakis A. Structural basis for substrate discrimination and integrin binding by autotoxin. (2011) Nature Structural Biology,18(2):198-204. 
  • Fulkerson Z,Wu T, Sunkara M, Vander Kooi C, Morris AJ, Smyth S. Binding of autotaxin to integrins localizes lysophosphatidic acid production to platelets and mammalian cells. (2011)  J. Biol Chem, 286(40):34654-63 PMC3186383.Highlighted in Science Signaling, Editors’ Choice October 2011 ”Localizing LPA Production”. 
  • Federico L, Ren H, Mueller PA, Wu T, Liu S, Popovic J,Blalock EM, Moolenaar WH, Ovaa H, Albers HM, Mills GB, Morris AJ and Smyth SS.  Autotaxin and its product lysophosphatidic acid suppress brown adipose differentiation and promote diet induced obesity in mice. (2012) Molec Endocrinology, 26(5):786-97.  Cover article. 
  • Wu T, Vander Kooi C, Shah P, Charnigo R, Huang C, Smyth SS, Morris AJ. Integrin-mediated cell surface recruitment of autotaxin promotes persistent directional cell migration. (2013) FASEB J, 2013 Feb;28(2):861-70. 

LPA can hydrolyzed and inactivated by lipid phosphate phosphatase (LPP) enzymes present on cell membranes.  A genome-wide association studies (GWAS) identified the PPAP2B gene encoding LPP3 as a novel loci associated with coronary artery disease susceptibility.  We have established that LPP3 expression in mice is critical to attenuate inflammation, reduce smooth muscle cell proliferation, and maintain endothelial barrier function following vascular injury in an LPA-dependent manner. Current studies are focused on understanding how heritable human variation in PPAP2B predisposes to the development and/or complications of atherosclerosis, which may ultimately translate into the validation of novel pathways for disease prevention. 

  • Smyth S.S., Sigal Y., Sciorra V., Pamuklar, Z. Yong Xu, Prestwich G.D., and Morris, A.J. Lysophosphatidic acid phosphatase 1 regulates lysophosphatidic acid signaling in human platelets. (2003) J Biol Chem, 278:43214-23. 
  • Miriyala S, Thangaiah S, Panchatcharam M, Ren H, Sunkara M, Drennan T, Smyth S, Spielmann HP, Morris AJ. Functional characterization of the atypical integral membrane lipid phosphatase PDP1/PAPDC2 identifies a pathway for interconversion of isoprenols and isoprenoid phosphates in mammalian cells. (2010)  J Biol Chem, 285:13918-29 
  • Panchatcharam M, Miriyala S, Salous A, Wheeler J, Dong A, Mueller P, Sunkara M, Esclante-Alcalde D, Morris AJ, Smyth S. Lipid phosphate phosphatase 3 negatively regulates smooth muscle cell phenotypic modulation to limit intimal hyperplasia. Arterioscler Thromb Vasc Biol, 2013; 33:52-9. 
  • Salous AK, Panchatcharam M, Sunkara M, Mueller P, Dong A, Wang Y, Graf GA, Smyth SS, Morris AJ. Mechanism of rapid elimination of lysophosphatidic acid and related lipids from the circulation of mice. (2013)  J Lipid Res, 54:2775-84. 
  • Panchatcharam M, Salous AK, Brandon J, Miriyala S, Wheeler J, Patil P, Sunkara M, Morris AJ, Escalante-Alcalde D, Smyth SS. Mice with targeted inactivation of Ppap2b in endothelial and hematopoietic cells display enhanced vascular inflammation and permeability. (2014) Arterioscler Thromb Vasc Biol, 34:837-45. 
  • Smyth SS, Mueller P, Yang F, Brandon JA, Morris AJ. Arguing the case for the autotaxin-lysophosphatidic Acid-lipid phosphate phosphatase 3-signaling nexus in the development and complications of atherosclerosis. (2014)  Arterioscler Thromb Vasc Biol, 34(3):479-86.
  • Reschen ME, Gaulton KJ, Lin D, Soilleux EJ, Morris AJ, Smyth SS, O'Callaghan CA. Lipid-induced epigenomic changes in human macrophages identify a coronary artery disease-associated variant that regulates PPAP2B Expression through Altered C/EBP-beta binding. PLoS Genet. 2015 Apr 2;11(4):e1005061

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