Kevin R. Lynch

Education

  • MS, University of Rhode Island, Kingston, RI
  • BS, Pennsylvania State University, University Park, PA
  • PhD, University of Rhode Island, Kingston, RI
  • Postdoc, Columbia University, New York, NY

Primary Appointment

  • Professor, Pharmacology

Contact

Research Interest(s)

Molecular pharmacology of lysophospholipid mediators

Research Description

The over-arching goal of our research is to understand better the biology of sphingosine 1-phosphate (S1P), particularly in the context of disease. S1P is a pleiotropic extracellular lipid that is implicated in control of lymphocyte trafficking, heart rate and vascular leakage. Recently, a S1P receptor agonist pro-drug, fingolimod, was approved as immune system modulator in the treatment of multiple sclerosis.

Our central strategy remains the development of tools (mostly small molecules) with which to probe S1P biology. We complement our chemical biology approach with mouse genetics. The new chemical entities that we have developed including S1P receptor agonists and antagonists. The synthesis of these molecules was accomplished in the laboratory of our long term collaborator, Professor Timothy L. Macdonald (Univ. VA Chemistry).

The current focus of our work is to develop reagents to explore the mechanisms whereby S1P plasma levels (300 nM) are maintained and consequences of manipulating vascular S1P tone. To this end, we have developed potent inhibitors of the S1P synthetic enzyme, sphingosine kinase (SphK). Administration of our inhibitors to mice and rats revealed that circulating S1P decreased rapidly (minutes) in response to SphK1 inhibition. We have also developed SphK2-selective inhibitors in collaboration with Professor Webster L. Santos (VA Tech Chemistry). Among our current challenges is modifying our SphK inhibitors to make them more persistent in vivo while retaining potency and selectivity. Such molecules will allow testing of the hypothesis that interdicting S1P synthesis at the level of SphK will influence the course of disease in models of inflammation and cancer.

Our work is funded by the National Institutes of Health (NIGMS, NICHD), a private foundation and the pharmaceutical industry.

Selected Publications

  • Bajwa A, Rosin D, Chroscicki P, Lee S, Dondeti K, Ye H, Kinsey G, Stevens B, Jobin K, Kenwood B, Hoehn K, Lynch K, Okusa M. Sphingosine 1-Phosphate Receptor-1 Enhances Mitochondrial Function and Reduces Cisplatin-Induced Tubule Injury. Journal of the American Society of Nephrology : JASN. 2014. PMID: 25145931
  • Kenwood B, Weaver J, Bajwa A, Poon I, Byrne F, Murrow B, Calderone J, Huang L, Divakaruni A, Tomsig J, Okabe K, Lo R, Cameron Coleman G, Columbus L, Yan Z, Saucerman J, Smith J, Holmes J, Lynch K, Ravichandran K, Uchiyama S, Santos W, Rogers G, Okusa M, Bayliss D, Hoehn K. Identification of a novel mitochondrial uncoupler that does not depolarize the plasma membrane. Molecular metabolism. 2014;3(2): 114-23. PMID: 24634817 | PMCID: PMC3953706
  • Building a better sphingosine kinase-1 inhibitor. The Biochemical journal. 2012;444(1): e1-2. PMID: 22533672
  • Bajwa A, Huang L, Ye H, Dondeti K, Song S, Rosin D, Lynch K, Lobo P, Li L, Okusa M. Dendritic cell sphingosine 1-phosphate receptor-3 regulates Th1-Th2 polarity in kidney ischemia-reperfusion injury. Journal of immunology (Baltimore, Md. : 1950). 2012;189(5): 2584-96. PMID: 22855711 | PMCID: PMC3433235
  • Gellett A, Kharel Y, Sunkara M, Morris A, Lynch K. Biosynthesis of alkyl lysophosphatidic acid by diacylglycerol kinases. Biochemical and biophysical research communications. 2012;422(4): 758-63. PMID: 22627129 | PMCID: PMC3377814
  • Kharel Y, Raje M, Gao M, Gellett A, Tomsig J, Lynch K, Santos W. Sphingosine kinase type¬†2 inhibition elevates circulating sphingosine 1-phosphate. The Biochemical journal. 2012;447(1): 149-57. PMID: 22747486 | PMCID: PMC3443596
  • Knott K, Kharel Y, Raje M, Lynch K, Santos W. Effect of alkyl chain length on sphingosine kinase 2 selectivity. Bioorganic & medicinal chemistry letters. 2012;22(22): 6817-20. PMID: 22321213 | PMCID: PMC3394931
  • Awad A, Rouse M, Khutsishvili K, Huang L, Bolton W, Lynch K, Okusa M. Chronic sphingosine 1-phosphate 1 receptor activation attenuates early-stage diabetic nephropathy independent of lymphocytes. Kidney international. 2011;79(10): 1090-8. PMID: 21289599 | PMCID: PMC3155206
  • East J, Carter K, Kennedy P, Schulte N, Toews M, Lynch K, Macdonald T. Development of a phosphatase-resistant, L-tyrosine derived LPA1/LPA3 dual antagonist. MedChemComm. 2011;2(4): 325-330. PMID: 22180836 | PMCID: PMC3237054
  • Kennedy A, Mathews T, Kharel Y, Field S, Moyer M, East J, Houck J, Lynch K, Macdonald T. Development of amidine-based sphingosine kinase 1 nanomolar inhibitors and reduction of sphingosine 1-phosphate in human leukemia cells. Journal of medicinal chemistry. 2011;54(10): 3524-48. PMID: 21495716 | PMCID: PMC3119570
  • Kennedy P, Zhu R, Huang T, Tomsig J, Mathews T, David M, Peyruchaud O, Macdonald T, Lynch K. Characterization of a sphingosine 1-phosphate receptor antagonist prodrug. The Journal of pharmacology and experimental therapeutics. 2011;338(3): 879-89. PMID: 21632869 | PMCID: PMC3164350
  • Kharel Y, Mathews T, Gellett A, Tomsig J, Kennedy P, Moyer M, Macdonald T, Lynch K. Sphingosine kinase type¬†1 inhibition reveals rapid turnover of circulating sphingosine 1-phosphate. The Biochemical journal. 2011;440(3): 345-53. PMID: 21848514 | PMCID: PMC3443603
  • Kharel Y, Mathews T, Kennedy A, Houck J, Macdonald T, Lynch K. A rapid assay for assessment of sphingosine kinase inhibitors and substrates. Analytical biochemistry. 2011;411(2): 230-5. PMID: 21216217 | PMCID: PMC3049835
  • Raje M, Knott K, Kharel Y, Bissel P, Lynch K, Santos W. Design, synthesis and biological activity of sphingosine kinase 2 selective inhibitors. Bioorganic & medicinal chemistry. 2011;20(1): 183-94. PMID: 22137932 | PMCID: NIHMS338841
  • Bajwa A, Jo S, Ye H, Huang L, Dondeti K, Rosin D, Haase V, Macdonald T, Lynch K, Okusa M. Activation of sphingosine-1-phosphate 1 receptor in the proximal tubule protects against ischemia-reperfusion injury. Journal of the American Society of Nephrology : JASN. 2010;21(6): 955-65. PMID: 20338995 | PMCID: PMC2900956
  • East J, Kennedy A, Tomsig J, De Leon A, Lynch K, Macdonald T. Synthesis and structure-activity relationships of tyrosine-based inhibitors of autotaxin (ATX). Bioorganic & medicinal chemistry letters. 2010;20(23): 7132-6. PMID: 20951039 | PMCID: PMC2975792
  • Mathews T, Kennedy A, Kharel Y, Kennedy P, Nicoara O, Sunkara M, Morris A, Wamhoff B, Lynch K, Macdonald T. Discovery, biological evaluation, and structure-activity relationship of amidine based sphingosine kinase inhibitors. Journal of medicinal chemistry. 2010;53(7): 2766-78. PMID: 20205392 | PMCID: PMC2875079
  • Foss F, Mathews T, Kharel Y, Kennedy P, Snyder A, Davis M, Lynch K, Macdonald T. Synthesis and biological evaluation of sphingosine kinase substrates as sphingosine-1-phosphate receptor prodrugs. Bioorganic & medicinal chemistry. 2009;17(16): 6123-36. PMID: 19632123 | PMCID: PMC2793099
  • Okusa M, Lynch K. Targeting sphingosine 1 phosphate receptor type 1 receptors in acute kidney injury. Drug discovery today. Disease mechanisms. 2009;4(1): 55-59. PMID: 19448841 | PMCID: PMC2682423
  • Petrie Aronin C, Sefcik L, Tholpady S, Tholpady A, Sadik K, Macdonald T, Peirce S, Wamhoff B, Lynch K, Ogle R, Botchwey E. FTY720 promotes local microvascular network formation and regeneration of cranial bone defects. Tissue engineering. Part A. 2009;16(6): 1801-9. PMID: 20038198 | PMCID: PMC2949231
  • Tomsig J, Snyder A, Berdyshev E, Skobeleva A, Mataya C, Natarajan V, Brindley D, Lynch K. Lipid phosphate phosphohydrolase type 1 (LPP1) degrades extracellular lysophosphatidic acid in vivo. The Biochemical journal. 2009;419(3): 611-8. PMID: 19215222 | PMCID: PMC2677185
  • Hughes J, Srinivasan S, Lynch K, Proia R, Ferdek P, Hedrick C. Sphingosine-1-phosphate induces an antiinflammatory phenotype in macrophages. Circulation research. 2008;102(8): 950-8. PMID: 18323526 | PMCID: PMC2875063
  • Jo S, Bajwa A, Awad A, Lynch K, Okusa M. Sphingosine-1-phosphate receptors: biology and therapeutic potential in kidney disease. Kidney international. 2008;73(11): 1220-30. PMID: 18322542 | PMCID: PMC2614447
  • Jo S, Bajwa A, Ye H, Vergis A, Awad A, Kharel Y, Lynch K, Okusa M. Divergent roles of sphingosine kinases in kidney ischemia-reperfusion injury. Kidney international. 2008;75(2): 167-75. PMID: 18971925 | PMCID: PMC2646633
  • Lynch K, Macdonald T. Sphingosine 1-phosphate chemical biology. Biochimica et biophysica acta. 2008;1781(9): 508-12. PMID: 18638568 | PMCID: PMC3412363
  • Rivera-Lopez C, Tucker A, Lynch K. Lysophosphatidic acid (LPA) and angiogenesis. Angiogenesis. 2008;11(3): 301-10. PMID: 18504643 | PMCID: PMC2677190
  • Wamhoff B, Lynch K, Macdonald T, Owens G. Sphingosine-1-phosphate receptor subtypes differentially regulate smooth muscle cell phenotype. Arteriosclerosis, thrombosis, and vascular biology. 2008;28(8): 1454-61. PMID: 18535287 | PMCID: PMC2605659
  • Cui P, McCalmont W, Tomsig J, Lynch K, Macdonald T. alpha- and beta-substituted phosphonate analogs of LPA as autotaxin inhibitors. Bioorganic & medicinal chemistry. 2007;16(5): 2212-25. PMID: 18082408 | PMCID: PMC2907913
  • Cui P, Tomsig J, McCalmont W, Lee S, Becker C, Lynch K, Macdonald T. Synthesis and biological evaluation of phosphonate derivatives as autotaxin (ATX) inhibitors. Bioorganic & medicinal chemistry letters. 2007;17(6): 1634-40. PMID: 17257836 | PMCID: NIHMS20052
  • Srinivasan S, Bolick D, Lukashev D, Lappas C, Sitkovsky M, Lynch K, Hedrick C. Sphingosine-1-phosphate reduces CD4+ T-cell activation in type 1 diabetes through regulation of hypoxia-inducible factor short isoform I.1 and CD69. Diabetes. 2007;57(2): 484-93. PMID: 18003758
  • Zhu R, Snyder A, Kharel Y, Schaffter L, Sun Q, Kennedy P, Lynch K, Macdonald T. Asymmetric synthesis of conformationally constrained fingolimod analogues--discovery of an orally active sphingosine 1-phosphate receptor type-1 agonist and receptor type-3 antagonist. Journal of medicinal chemistry. 2007;50(25): 6428-35. PMID: 17994678 | PMCID: PMC2895489
  • Awad A, Ye H, Huang L, Li L, Foss F, Macdonald T, Lynch K, Okusa M. Selective sphingosine 1-phosphate 1 receptor activation reduces ischemia-reperfusion injury in mouse kidney. American journal of physiology. Renal physiology. 2006;290(6): F1516-24. PMID: 16403835
  • Foss F, Snyder A, Davis M, Rouse M, Okusa M, Lynch K, Macdonald T. Synthesis and biological evaluation of gamma-aminophosphonates as potent, subtype-selective sphingosine 1-phosphate receptor agonists and antagonists. Bioorganic & medicinal chemistry. 2006;15(2): 663-77. PMID: 17113298 | PMCID: PMC1963459